Trial Outcomes & Findings for Enzalutamide With Ribociclib in Treating Patients With Metastatic Castrate-Resistant, Chemotherapy Naive Prostate Cancer That Retains Retinoblastoma Expression (NCT NCT02555189)

Last Updated: 2026-04-22

Results Overview

The primary objective for the phase II component of this study is to determine efficacy with respect to the proportion of subjects that achieve a ≥ 50% reduction in PSA at 12 weeks.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

52 participants

Primary outcome timeframe

12 weeks

Results posted on

2026-04-22

Participant Flow

Participant milestones

Participant milestones
Measure	Phase I: 400 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 600 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase II: Enzalutamide Only Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.	Ribociclib at RP2D + Enzalutamide Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.	Phase I: 200 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
Phase I: 200 mg STARTED	0	0	0	0	3
Phase I: 200 mg COMPLETED	0	0	0	0	1
Phase I: 200 mg NOT COMPLETED	0	0	0	0	2
Phase I: 400 mg STARTED	3	0	0	0	0
Phase I: 400 mg COMPLETED	0	0	0	0	0
Phase I: 400 mg NOT COMPLETED	3	0	0	0	0
Phase I: 600 mg STARTED	0	6	0	0	0
Phase I: 600 mg COMPLETED	0	1	0	0	0
Phase I: 600 mg NOT COMPLETED	0	5	0	0	0
Phase II Expansion STARTED	0	0	12	28	0
Phase II Expansion COMPLETED	0	0	2	4	0
Phase II Expansion NOT COMPLETED	0	0	10	24	0
Phase I: Follow-up STARTED	3	6	0	0	3
Phase I: Follow-up COMPLETED	0	1	0	0	1
Phase I: Follow-up NOT COMPLETED	3	5	0	0	2
Phase II: Follow-up STARTED	0	0	11	27	0
Phase II: Follow-up COMPLETED	0	0	2	4	0
Phase II: Follow-up NOT COMPLETED	0	0	9	23	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase I: 400 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 600 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase II: Enzalutamide Only Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.	Ribociclib at RP2D + Enzalutamide Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.	Phase I: 200 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.
Phase I: 200 mg Death	0	0	0	0	1
Phase I: 200 mg Study Termination	0	0	0	0	1
Phase I: 400 mg Death	3	0	0	0	0
Phase I: 600 mg Death	0	3	0	0	0
Phase I: 600 mg Study Termination	0	2	0	0	0
Phase II Expansion Withdrawal by Subject	0	0	0	1	0
Phase II Expansion Physician Decision	0	0	1	1	0
Phase II Expansion Death	0	0	7	8	0
Phase II Expansion Study Termination	0	0	2	14	0
Phase I: Follow-up Death	3	3	0	0	1
Phase I: Follow-up Study Termination	0	2	0	0	1
Phase II: Follow-up Physician Decision	0	0	0	1	0
Phase II: Follow-up Death	0	0	7	8	0
Phase II: Follow-up Study Termination	0	0	2	14	0

Baseline Characteristics

The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I: 200 mg Ribociclib + Enzalutamide n=3 Participants Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 400 mg Ribociclib + Enzalutamide n=3 Participants Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills)once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 600 mg Ribociclib + Enzalutamide n=6 Participants Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase II: Enzalutamide Only n=12 Participants Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.	Ribociclib at RP2D + Enzalutamide n=28 Participants Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.	Total n=52 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=3 Participants	0 Participants n=3 Participants	0 Participants n=6 Participants	0 Participants n=12 Participants	0 Participants n=28 Participants	0 Participants n=52 Participants
Age, Categorical Between 18 and 65 years	1 Participants n=3 Participants	1 Participants n=3 Participants	3 Participants n=6 Participants	6 Participants n=12 Participants	10 Participants n=28 Participants	21 Participants n=52 Participants
Age, Categorical >=65 years	2 Participants n=3 Participants	2 Participants n=3 Participants	3 Participants n=6 Participants	6 Participants n=12 Participants	18 Participants n=28 Participants	31 Participants n=52 Participants
Sex: Female, Male Female	0 Participants n=3 Participants	0 Participants n=3 Participants	0 Participants n=6 Participants	0 Participants n=12 Participants	0 Participants n=28 Participants	0 Participants n=52 Participants
Sex: Female, Male Male	3 Participants n=3 Participants	3 Participants n=3 Participants	6 Participants n=6 Participants	12 Participants n=12 Participants	28 Participants n=28 Participants	52 Participants n=52 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=3 Participants	1 Participants n=3 Participants	0 Participants n=6 Participants	1 Participants n=12 Participants	0 Participants n=28 Participants	2 Participants n=52 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=3 Participants	2 Participants n=3 Participants	6 Participants n=6 Participants	10 Participants n=12 Participants	24 Participants n=28 Participants	45 Participants n=52 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=3 Participants	0 Participants n=3 Participants	0 Participants n=6 Participants	1 Participants n=12 Participants	4 Participants n=28 Participants	5 Participants n=52 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=3 Participants	0 Participants n=3 Participants	0 Participants n=6 Participants	0 Participants n=12 Participants	0 Participants n=28 Participants	0 Participants n=52 Participants
Race (NIH/OMB) Asian	0 Participants n=3 Participants	0 Participants n=3 Participants	0 Participants n=6 Participants	1 Participants n=12 Participants	0 Participants n=28 Participants	1 Participants n=52 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=3 Participants	0 Participants n=3 Participants	0 Participants n=6 Participants	0 Participants n=12 Participants	0 Participants n=28 Participants	0 Participants n=52 Participants
Race (NIH/OMB) Black or African American	1 Participants n=3 Participants	0 Participants n=3 Participants	1 Participants n=6 Participants	0 Participants n=12 Participants	1 Participants n=28 Participants	3 Participants n=52 Participants
Race (NIH/OMB) White	2 Participants n=3 Participants	3 Participants n=3 Participants	5 Participants n=6 Participants	10 Participants n=12 Participants	25 Participants n=28 Participants	45 Participants n=52 Participants
Race (NIH/OMB) More than one race	0 Participants n=3 Participants	0 Participants n=3 Participants	0 Participants n=6 Participants	0 Participants n=12 Participants	0 Participants n=28 Participants	0 Participants n=52 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=3 Participants	0 Participants n=3 Participants	0 Participants n=6 Participants	1 Participants n=12 Participants	2 Participants n=28 Participants	3 Participants n=52 Participants
Region of Enrollment United States	3 participants n=3 Participants	3 participants n=3 Participants	6 participants n=6 Participants	12 participants n=12 Participants	28 participants n=28 Participants	52 participants n=52 Participants
AST (units/L)	23 units/L STANDARD_DEVIATION 4 • n=3 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	27 units/L STANDARD_DEVIATION 10 • n=3 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	26 units/L STANDARD_DEVIATION 10 • n=6 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	26 units/L STANDARD_DEVIATION 7 • n=12 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	26 units/L STANDARD_DEVIATION 14 • n=27 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	26 units/L STANDARD_DEVIATION 11 • n=51 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.
Lactase dehydrogenase (LDH) (uKat/L)	3.84 uKat/L STANDARD_DEVIATION 0.60 • n=3 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	4.68 uKat/L STANDARD_DEVIATION 1.18 • n=3 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	6.43 uKat/L STANDARD_DEVIATION 5.22 • n=6 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	3.60 uKat/L STANDARD_DEVIATION 1.23 • n=11 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	4.95 uKat/L STANDARD_DEVIATION 3.52 • n=28 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	4.75 uKat/L STANDARD_DEVIATION 3.24 • n=51 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.
Creatinine (umol/L)	88 umol/L STANDARD_DEVIATION 15 • n=3 Participants	91 umol/L STANDARD_DEVIATION 36 • n=3 Participants	94 umol/L STANDARD_DEVIATION 23 • n=6 Participants	87 umol/L STANDARD_DEVIATION 20 • n=12 Participants	84 umol/L STANDARD_DEVIATION 18 • n=28 Participants	86 umol/L STANDARD_DEVIATION 19 • n=52 Participants
Calcium (mmol/L)	2.40 mmol/L STANDARD_DEVIATION 0.05 • n=3 Participants	2.37 mmol/L STANDARD_DEVIATION 0.02 • n=3 Participants	2.35 mmol/L STANDARD_DEVIATION 0.07 • n=6 Participants	2.39 mmol/L STANDARD_DEVIATION 0.08 • n=12 Participants	2.38 mmol/L STANDARD_DEVIATION 0.10 • n=28 Participants	2.38 mmol/L STANDARD_DEVIATION 0.08 • n=52 Participants
BUN (mmol/L)	6.42 mmol/L STANDARD_DEVIATION 0.95 • n=3 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	6.07 mmol/L STANDARD_DEVIATION 0.72 • n=3 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	6.72 mmol/L STANDARD_DEVIATION 1.81 • n=6 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	7.23 mmol/L STANDARD_DEVIATION 2.12 • n=12 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	6.69 mmol/L STANDARD_DEVIATION 2.35 • n=27 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	6.77 mmol/L STANDARD_DEVIATION 2.08 • n=51 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.
Total Bilirubin (umol/L)	14.3 umol/L STANDARD_DEVIATION 8.1 • n=3 Participants	6.3 umol/L STANDARD_DEVIATION 1.0 • n=3 Participants	6.0 umol/L STANDARD_DEVIATION 1.8 • n=6 Participants	7.7 umol/L STANDARD_DEVIATION 3.3 • n=12 Participants	8.3 umol/L STANDARD_DEVIATION 3.9 • n=28 Participants	8.1 umol/L STANDARD_DEVIATION 4.1 • n=52 Participants
Albumin (g/L)	43.00 g/L STANDARD_DEVIATION 2.00 • n=3 Participants	43.33 g/L STANDARD_DEVIATION 2.52 • n=3 Participants	42.50 g/L STANDARD_DEVIATION 1.64 • n=6 Participants	42.83 g/L STANDARD_DEVIATION 2.25 • n=12 Participants	41.43 g/L STANDARD_DEVIATION 3.06 • n=28 Participants	42.08 g/L STANDARD_DEVIATION 2.69 • n=52 Participants
Alkaline Phosphatase (uKat/L)	1.71 uKat/L STANDARD_DEVIATION 0.70 • n=3 Participants	3.05 uKat/L STANDARD_DEVIATION 2.08 • n=3 Participants	1.92 uKat/L STANDARD_DEVIATION 1.50 • n=6 Participants	3.73 uKat/L STANDARD_DEVIATION 7.82 • n=12 Participants	1.98 uKat/L STANDARD_DEVIATION 1.68 • n=28 Participants	2.42 uKat/L STANDARD_DEVIATION 3.96 • n=52 Participants
Magnesium (mmol/L)	0.92 mmol/L STANDARD_DEVIATION 0.09 • n=3 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	0.84 mmol/L STANDARD_DEVIATION 0.03 • n=3 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	0.92 mmol/L STANDARD_DEVIATION 0.13 • n=6 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	0.85 mmol/L STANDARD_DEVIATION 0.08 • n=12 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	0.88 mmol/L STANDARD_DEVIATION 0.17 • n=27 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	0.88 mmol/L STANDARD_DEVIATION 0.14 • n=51 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.
Phosphorous (mmol/L)	1.01 mmol/L STANDARD_DEVIATION 0.10 • n=3 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	1.10 mmol/L STANDARD_DEVIATION 0.13 • n=3 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	1.10 mmol/L STANDARD_DEVIATION 0.14 • n=6 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	1.18 mmol/L STANDARD_DEVIATION 0.15 • n=12 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	1.14 mmol/L STANDARD_DEVIATION 0.20 • n=27 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.	1.13 mmol/L STANDARD_DEVIATION 0.17 • n=51 Participants • The number of participants analyzed is lower than the overall because only participants who started study treatment and had available baseline assessments were included. Participants who has missing baseline data are not included in the baselines analysis.
Baseline Metastasis Site Bone	3 Participants n=3 Participants	3 Participants n=3 Participants	4 Participants n=6 Participants	8 Participants n=12 Participants	24 Participants n=28 Participants	42 Participants n=52 Participants
Baseline Metastasis Site Lymph Node	2 Participants n=3 Participants	2 Participants n=3 Participants	5 Participants n=6 Participants	8 Participants n=12 Participants	13 Participants n=28 Participants	30 Participants n=52 Participants
Baseline Metastasis Site Viscera	0 Participants n=3 Participants	1 Participants n=3 Participants	0 Participants n=6 Participants	1 Participants n=12 Participants	4 Participants n=28 Participants	6 Participants n=52 Participants
Baseline Metastasis Site Other	0 Participants n=3 Participants	1 Participants n=3 Participants	0 Participants n=6 Participants	1 Participants n=12 Participants	7 Participants n=28 Participants	9 Participants n=52 Participants
Baseline Metastasis Site No baseline metastases reported	0 Participants n=3 Participants	0 Participants n=3 Participants	0 Participants n=6 Participants	0 Participants n=12 Participants	0 Participants n=28 Participants	0 Participants n=52 Participants
Baseline ECOG 0	3 Participants n=3 Participants	2 Participants n=3 Participants	1 Participants n=6 Participants	10 Participants n=12 Participants	23 Participants n=28 Participants	39 Participants n=52 Participants
Baseline ECOG 1	0 Participants n=3 Participants	1 Participants n=3 Participants	5 Participants n=6 Participants	2 Participants n=12 Participants	5 Participants n=28 Participants	13 Participants n=52 Participants
Baseline PSA	12 ng/mL n=3 Participants	56 ng/mL n=3 Participants	23 ng/mL n=6 Participants	12 ng/mL n=12 Participants	10 ng/mL n=28 Participants	12 ng/mL n=52 Participants
Gleason Score 3+4	0 Participants n=3 Participants	0 Participants n=3 Participants	2 Participants n=6 Participants	0 Participants n=12 Participants	1 Participants n=28 Participants	3 Participants n=52 Participants
Gleason Score 4+3	0 Participants n=3 Participants	0 Participants n=3 Participants	1 Participants n=6 Participants	2 Participants n=12 Participants	3 Participants n=28 Participants	6 Participants n=52 Participants
Gleason Score 8	1 Participants n=3 Participants	1 Participants n=3 Participants	1 Participants n=6 Participants	2 Participants n=12 Participants	5 Participants n=28 Participants	10 Participants n=52 Participants
Gleason Score 9-10	2 Participants n=3 Participants	2 Participants n=3 Participants	2 Participants n=6 Participants	6 Participants n=12 Participants	17 Participants n=28 Participants	29 Participants n=52 Participants
Gleason Score Not reported	0 Participants n=3 Participants	0 Participants n=3 Participants	0 Participants n=6 Participants	2 Participants n=12 Participants	2 Participants n=28 Participants	4 Participants n=52 Participants
Measurable disease	2 Participants n=3 Participants	3 Participants n=3 Participants	2 Participants n=6 Participants	6 Participants n=12 Participants	12 Participants n=28 Participants	25 Participants n=52 Participants

PRIMARY outcome

Timeframe: 28 days

Population: This outcome measure was only assessed in the Phase Ib arm. No data was collection for Phase II.

Will be defined as an adverse event or clinically significant abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications. All analysis will be descriptive.

Outcome measures

Outcome measures
Measure	Ribociclib at RP2D + Enzalutamide Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.	Phase I: 200 mg Ribociclib + Enzalutamide n=3 Participants Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 400 mg Ribociclib + Enzalutamide n=3 Participants Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills)once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 600 mg Ribociclib + Enzalutamide n=6 Participants Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase II: Enzalutamide Only Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
Number of Dose Limiting Toxicity of Ribociclib (Phase IB)	—	0 Participants	0 Participants	0 Participants	—

PRIMARY outcome

Timeframe: 12 weeks

Population: No participants were analyzed for this outcome measure for Phase I because the Phase Ib portion of the study was designed solely to determine the recommended Phase II dose and evaluate safety. Efficacy outcome data were not collected or analyzed for Phase Ib participants.

The primary objective for the phase II component of this study is to determine efficacy with respect to the proportion of subjects that achieve a ≥ 50% reduction in PSA at 12 weeks.

Outcome measures

Outcome measures
Measure	Ribociclib at RP2D + Enzalutamide n=28 Participants Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.	Phase I: 200 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 400 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills)once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 600 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase II: Enzalutamide Only n=12 Participants Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
Number of Patients With a >= 50% Reduction in Prostate Specific Antigen (PSA) (Phase II)	28 Participants	0 Participants	0 Participants	0 Participants	9 Participants

SECONDARY outcome

Timeframe: Time of first dose until progression (25% increase in PSA from nadir) or death, assessed up to 2 years

Summarized by treatment arm using Kaplan-Meier plots. Median PFS will be estimated from the Kaplan-Meier analysis.

Outcome measures

Outcome measures
Measure	Ribociclib at RP2D + Enzalutamide n=28 Participants Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.	Phase I: 200 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 400 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills)once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 600 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase II: Enzalutamide Only n=12 Participants Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
PSA Progression Free Survival (PFS)	14.8 months Interval 6.7 to 35.9	—	—	—	10.1 months Interval 1.8 to 33.1

SECONDARY outcome

Timeframe: From first dose to disease progression in bone or soft-tissue, or death, whichever occurs first, assessed up to 40 months

Summarized using Kaplan-Meier plots. Median rPFS will be estimated from the Kaplan-Meier analysis.

Outcome measures

Outcome measures
Measure	Ribociclib at RP2D + Enzalutamide n=28 Participants Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.	Phase I: 200 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 400 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills)once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 600 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase II: Enzalutamide Only n=12 Participants Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
Radiographic PFS (rPFS)	27 months Interval 11.3 to 37.0	—	—	—	10.9 months Interval 2.5 to 45.9

SECONDARY outcome

Timeframe: From first dose until death from any cause, assessed up to 60 months

To determine the overall safety and survival for patients treated with enzalutamide with and without ribociclib in patients with chemotherapy naïve mCRPC.

Outcome measures

Outcome measures
Measure	Ribociclib at RP2D + Enzalutamide n=28 Participants Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.	Phase I: 200 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 400 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills)once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 600 mg Ribociclib + Enzalutamide Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase II: Enzalutamide Only n=12 Participants Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
Overall Survival	58.1 months Interval 33.4 to The upper bound is undefined. The upper bound cannot be calculated due to the low number of events.	—	—	—	31.2 months Interval 15.0 to The upper bound is undefined. The upper bound cannot be calculated due to the low number of events.

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline

Population: 1 subject was not evaluable for Phase I: 600 mg Ribociclib + Enzalutamide

The proportion of patients with RB positive tumors among the screened patients by IHC and gene signature will be estimated

Outcome measures

Outcome measures
Measure	Ribociclib at RP2D + Enzalutamide n=28 Participants Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.	Phase I: 200 mg Ribociclib + Enzalutamide n=3 Participants Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 400 mg Ribociclib + Enzalutamide n=3 Participants Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills)once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 600 mg Ribociclib + Enzalutamide n=5 Participants Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase II: Enzalutamide Only n=12 Participants Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
Number of Patients With RB Positive Tumors	11 Participants	3 Participants	3 Participants	5 Participants	8 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline

Proportion of samples where RB status can successfully be obtained. Estimated as a measure of feasibility.

Outcome measures

Outcome measures
Measure	Ribociclib at RP2D + Enzalutamide n=28 Participants Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.	Phase I: 200 mg Ribociclib + Enzalutamide n=3 Participants Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 400 mg Ribociclib + Enzalutamide n=3 Participants Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills)once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 600 mg Ribociclib + Enzalutamide n=5 Participants Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase II: Enzalutamide Only n=12 Participants Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
Number of Participants With Samples Where RB Status Can Successfully be Obtained	12 Participants	3 Participants	3 Participants	5 Participants	8 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 2 years

Population: No data was collected or analyzed for this outcome measure. As a result, there were no analyzable results.

Association of androgen profiles with clinical outcomes will use logistic regression or Cox proportional hazards regression, as appropriate.

Outcome measures

Outcome data not reported

Adverse Events

Phase I: 200 mg Ribociclib + Enzalutamide

Serious events: 3 serious events

Other events: 3 other events

Deaths: 1 deaths

Phase I: 400 mg Ribociclib + Enzalutamide

Serious events: 3 serious events

Other events: 3 other events

Deaths: 3 deaths

Phase I: 600 mg Ribociclib + Enzalutamide

Serious events: 3 serious events

Other events: 6 other events

Deaths: 3 deaths

Phase II: Enzalutamide Only

Serious events: 11 serious events

Other events: 11 other events

Deaths: 7 deaths

Ribociclib at RP2D + Enzalutamide

Serious events: 14 serious events

Other events: 28 other events

Deaths: 8 deaths

Serious adverse events

Serious adverse events
Measure	Phase I: 200 mg Ribociclib + Enzalutamide n=3 participants at risk Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 400 mg Ribociclib + Enzalutamide n=3 participants at risk Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 600 mg Ribociclib + Enzalutamide n=6 participants at risk Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase II: Enzalutamide Only n=12 participants at risk Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.	Ribociclib at RP2D + Enzalutamide n=28 participants at risk Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
Cardiac disorders Myocardial infarction	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Colitis	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Pancreatitis	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
General disorders Non-cardiac chest pain	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Infections and infestations Sepsis	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Investigations Creatinine increased	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Metabolism and nutrition disorders Hyperglycemia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Musculoskeletal and connective tissue disorders Back pain	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Nervous system disorders Intracranial hemorrhage	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Nervous system disorders Seizure	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Renal and urinary disorders Acute kidney injury	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Renal and urinary disorders Urinary tract obstruction	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Cardiac disorders Angina pectoris	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Large intestinal haemorrhage	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
General disorders Death	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	100.0% 3/3 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	50.0% 3/6 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	58.3% 7/12 • Number of events 7 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	28.6% 8/28 • Number of events 8 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.

Other adverse events

Other adverse events
Measure	Phase I: 200 mg Ribociclib + Enzalutamide n=3 participants at risk Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 200 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 400 mg Ribociclib + Enzalutamide n=3 participants at risk Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 400 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase I: 600 mg Ribociclib + Enzalutamide n=6 participants at risk Enzalutamide will be administered at a dose of 160 mg (40 mg X 4 pills) once daily. 600 mg Ribociclib will be given daily for 21 out of 28 days. The phase I portion of this study will follow a traditional 3+3 design, escalating to the next higher dose cohort if 3 patients are treated and no DLTs are observed in the first cycle of therapy.	Phase II: Enzalutamide Only n=12 participants at risk Patients receive Enzalutamide 160mg PO QD once daily on Days 1-28 of each 28-day cycle. This is one of two randomized arms in the Phase II portion. Treatment continues until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.	Ribociclib at RP2D + Enzalutamide n=28 participants at risk Patients receive Ribociclib 600mg PO QD once daily on Days 1-21 of each 28-day cycle in combination with Enzalutamide 160mg PO QD once daily. This is one of two randomized arms in the Phase II portion. Patients will continue treatment until disease progression or unacceptable toxicity. Patients also undergo blood sample collection, tumor biopsy, ECHO or MUGA, bone scan, and CT or MRI on study.
Blood and lymphatic system disorders Anemia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	7.1% 2/28 • Number of events 5 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Cardiac disorders Chest pain - cardiac	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Cardiac disorders Cardiac disorders - Other, specify	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Cardiac disorders Myocardial infarction	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Cardiac disorders Palpitations	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Cardiac disorders Sinus tachycardia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Cardiac disorders Ventricular arrhythmia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Cardiac disorders Ventricular tachycardia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Ear and labyrinth disorders Tinnitus	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Ear and labyrinth disorders Vertigo	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Eye disorders Cataract	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Eye disorders Dry eye	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Eye disorders Eye pain	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Eye disorders Glaucoma	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Eye disorders Eye disorders - Other, specify	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Eye disorders Blurred vision	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Abdominal pain	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 2/6 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	21.4% 6/28 • Number of events 7 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Colitis	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Constipation	66.7% 2/3 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 2/6 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	35.7% 10/28 • Number of events 11 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Diarrhea	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	66.7% 2/3 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	50.0% 3/6 • Number of events 4 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	35.7% 10/28 • Number of events 19 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Flatulence	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Gastroesophageal reflux disease	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	7.1% 2/28 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Gingival pain	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Hemorrhoids	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Nausea	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	66.7% 2/3 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	50.0% 3/6 • Number of events 5 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	35.7% 10/28 • Number of events 13 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Pancreatitis	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Rectal hemorrhage	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Toothache	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Vomiting	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
General disorders Chills	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	7.1% 2/28 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
General disorders Fatigue	100.0% 3/3 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	50.0% 3/6 • Number of events 8 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	58.3% 7/12 • Number of events 10 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	75.0% 21/28 • Number of events 35 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
General disorders Flu like symptoms	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	7.1% 2/28 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
General disorders Non-cardiac chest pain	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
General disorders Edema limbs	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	50.0% 3/6 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 2/12 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	21.4% 6/28 • Number of events 6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Dysphasia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Infections and infestations Bronchial infection	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Infections and infestations Infections and infestations - Other, specify	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Infections and infestations Penile infection	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Infections and infestations Upper respiratory infection	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Infections and infestations Nail infection	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Infections and infestations Pharyngitis	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Infections and infestations Sinusitis	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Dental caries	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	7.1% 2/28 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Infections and infestations Sepsis	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Injury, poisoning and procedural complications Injury, poisoning and procedural complications - Other, specify	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Investigations Alanine aminotransferase increased	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	7.1% 2/28 • Number of events 4 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Investigations Aspartate aminotransferase increased	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	7.1% 2/28 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Investigations Alkaline phosphatase increased	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 5 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	7.1% 2/28 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Investigations Blood bilirubin increased	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Investigations Cholesterol high	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Investigations Creatinine increased	33.3% 1/3 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Investigations Electrocardiogram QT corrected interval prolonged	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Investigations INR increased	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Investigations Lymphocyte count decreased	33.3% 1/3 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 2/6 • Number of events 5 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	7.1% 2/28 • Number of events 5 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Investigations Neutrophil count decreased	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	66.7% 4/6 • Number of events 10 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	35.7% 10/28 • Number of events 27 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Investigations Platelet count decreased	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Investigations Weight loss	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	14.3% 4/28 • Number of events 4 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Investigations White blood cell decreased	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	66.7% 4/6 • Number of events 28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	14.3% 4/28 • Number of events 28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Metabolism and nutrition disorders Anorexia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	66.7% 2/3 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 2/6 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	14.3% 4/28 • Number of events 6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Metabolism and nutrition disorders Hypercalcemia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Metabolism and nutrition disorders Hyperglycemia	33.3% 1/3 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	66.7% 2/3 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	25.0% 3/12 • Number of events 5 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	14.3% 4/28 • Number of events 6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Metabolism and nutrition disorders Hyperkalemia	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	66.7% 4/6 • Number of events 10 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	17.9% 5/28 • Number of events 12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Metabolism and nutrition disorders Hypertriglyceridemia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Metabolism and nutrition disorders Hypocalcemia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Metabolism and nutrition disorders Hypoglycemia	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Metabolism and nutrition disorders Hypomagnesemia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Metabolism and nutrition disorders Hyponatremia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Metabolism and nutrition disorders Hypophosphatemia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Musculoskeletal and connective tissue disorders Arthralgia	33.3% 1/3 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	14.3% 4/28 • Number of events 4 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Musculoskeletal and connective tissue disorders Arthritis	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	7.1% 2/28 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Musculoskeletal and connective tissue disorders Back pain	33.3% 1/3 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	25.0% 3/12 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	21.4% 6/28 • Number of events 9 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Musculoskeletal and connective tissue disorders Muscle weakness lower limb	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Dyspepsia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	14.3% 4/28 • Number of events 4 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Musculoskeletal and connective tissue disorders Neck pain	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	10.7% 3/28 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Nervous system disorders Ataxia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Ear and labyrinth disorders Vestibular disorder	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Nervous system disorders Nervous system disorders - Other, specify	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Nervous system disorders Dizziness	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	25.0% 7/28 • Number of events 8 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Nervous system disorders Dysgeusia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	14.3% 4/28 • Number of events 5 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Nervous system disorders Intracranial hemorrhage	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Nervous system disorders Headache	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	10.7% 3/28 • Number of events 5 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Nervous system disorders Memory impairment	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Nervous system disorders Paresthesia	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	7.1% 2/28 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Nervous system disorders Peripheral sensory neuropathy	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	14.3% 4/28 • Number of events 5 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Nervous system disorders Presyncope	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Nervous system disorders Extrapyramidal disorder	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Nervous system disorders Seizure	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Nervous system disorders Tremor	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Psychiatric disorders Anxiety	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	14.3% 4/28 • Number of events 5 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Psychiatric disorders Confusion	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Psychiatric disorders Depression	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	10.7% 3/28 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Psychiatric disorders Hallucinations	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Psychiatric disorders Insomnia	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	25.0% 3/12 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Psychiatric disorders Restlessness	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Renal and urinary disorders Acute kidney injury	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Renal and urinary disorders Chronic kidney disease	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Renal and urinary disorders Hematuria	33.3% 1/3 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Renal and urinary disorders Urinary urgency	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 2/12 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Renal and urinary disorders Renal and urinary disorders - Other, specify	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Renal and urinary disorders Proteinuria	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Renal and urinary disorders Urinary incontinence	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 2/12 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Renal and urinary disorders Urinary retention	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Renal and urinary disorders Urinary tract obstruction	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	14.3% 4/28 • Number of events 5 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Respiratory, thoracic and mediastinal disorders Voice alteration	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Respiratory, thoracic and mediastinal disorders Dyspnea	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 2/12 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	28.6% 8/28 • Number of events 12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Respiratory, thoracic and mediastinal disorders Sore throat	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Respiratory, thoracic and mediastinal disorders Productive cough	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Respiratory, thoracic and mediastinal disorders Allergic rhinitis	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Vascular disorders Hot flashes	66.7% 2/3 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	66.7% 2/3 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 2/12 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	7.1% 2/28 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Nervous system disorders Sinus pain	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Respiratory, thoracic and mediastinal disorders Sleep apnea	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Respiratory, thoracic and mediastinal disorders Postnasal drip	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Skin and subcutaneous tissue disorders Alopecia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	7.1% 2/28 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Skin and subcutaneous tissue disorders Rash acneiform	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Skin and subcutaneous tissue disorders Dry skin	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders - Other, specify	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	10.7% 3/28 • Number of events 3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Skin and subcutaneous tissue disorders Immune system disorders - Other, specify	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Skin and subcutaneous tissue disorders Rash maculo-papular	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Vascular disorders Thromboembolic event	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Vascular disorders Hypertension	33.3% 1/3 • Number of events 8 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	83.3% 5/6 • Number of events 10 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 4/12 • Number of events 14 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	64.3% 18/28 • Number of events 36 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Oral dysesthesia	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Colonic hemorrhage	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Infections and infestations Bladder infection	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Infections and infestations Rhinitis infective	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	7.1% 2/28 • Number of events 2 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Gastrointestinal disorders Stomach pain	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	16.7% 1/6 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/12 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	3.6% 1/28 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.
Musculoskeletal and connective tissue disorders Pain	33.3% 1/3 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/3 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/6 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	8.3% 1/12 • Number of events 1 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.	0.00% 0/28 • All subjects will be followed up for safety up to 30 days following the last dose of study treatment, up to 60 months Patient deaths occurred outside the 30 day reporting window, therefore no deaths were included in the SAE section. These have been recorded in the all cause mortality.

Additional Information

William Kevin Kelly, DO

Thomas Jefferson University

Phone: 215-955-8874

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place