Trial Outcomes & Findings for Cisplatin or Carboplatin, and Etoposide With or Without Sunitinib Malate in Treating Patients With Extensive-Stage Small Cell Lung Cancer (NCT NCT00453154)

Last Updated: 2023-04-04

Results Overview

The maximum tolerated dose is defined at the highest sunitinib dose at which less than one third of participants develop a dose limiting toxicity (DLT). A DLT is defined as: delay of beginning cycle 2 of chemotherapy by \> 7 days due to neutropenia, grade 4 hematologic toxicity lasting greater than 1 week (chemotherapy alone would be expected to cause significant grade 4 hematologic toxicity) or grade 3 or 4 nonhematologic toxicity (excluding grade 3 or 4 fatigue if the patient is found to be hypothyroid and responds to fatigue \< grade 3 with thyroid replacement therapy).

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

156 participants

Primary outcome timeframe

21 days

Results posted on

2023-04-04

Participant Flow

Between March 2007 and December 2011, 156 participants were recruited.

Participant milestones

Participant milestones
Measure	Phase 1B Participants will receive the following combination chemotherapy for 6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle Etoposide 100 mg/m\^2 by IV over 1 hour on days 1, 2, and 3 every cycle Sunitinib 25 mg oral, daily days 1-14 every cycle Maintenance: Following 6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.	Phase II Combination Chemotherapy Participants will receive the following combination chemotherapy for 4-6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle OR Carboplatin AUC = 5\* by IV Etoposide 100 mg/m\^2 by IVover 1 hour on days 1, 2, and 3 every cycle	Double Blind Placebo Maintenance With Optional Crossover Maintenance: Following 4-6 cycles of combination chemotherapy, start placebo at 150 mg on day 1, then 37.5 daily until disease progression. At progression, participants receiving placebo could cross over to receive open label sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.	Double Blind Sunitinib Maintenance Following 4-6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.
Combination Chemotherapy STARTED	12	144	0	0
Combination Chemotherapy COMPLETED	12	95	0	0
Combination Chemotherapy NOT COMPLETED	0	49	0	0
Double BIind Maintenance STARTED	0	0	46	49
Double BIind Maintenance COMPLETED	0	0	0	0
Double BIind Maintenance NOT COMPLETED	0	0	46	49
Open Label Sunitinib Crossover STARTED	0	0	18	0
Open Label Sunitinib Crossover COMPLETED	0	0	18	0
Open Label Sunitinib Crossover NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Double Blind Placebo Maintenance With Optional Crossover Maintenance: Following 4-6 cycles of combination chemotherapy, start placebo at 150 mg on day 1, then 37.5 daily until disease progression. At progression, participants receiving placebo could cross over to receive open label sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.	Double Blind Sunitinib Maintenance Following 4-6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.
Double BIind Maintenance Adverse Event	3	12
Double BIind Maintenance Death	2	1
Double BIind Maintenance Withdrawal by Subject	4	4
Double BIind Maintenance Progression	29	26
Double BIind Maintenance Medical Issues	3	1
Double BIind Maintenance Randomized, did not receive therapy	5	5

Baseline Characteristics

Cisplatin or Carboplatin, and Etoposide With or Without Sunitinib Malate in Treating Patients With Extensive-Stage Small Cell Lung Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I n=12 Participants Participants will receive the following combination chemotherapy for 6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle Etoposide 100 mg/m\^2 by IV over 1 hour on days 1, 2, and 3 every cycle Sunitinib 25 mg oral, daily days 1-14 every cycle Maintenance: Following 6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.	Arm I (Combination Chemotherapy + Sunitinib Maintenance) n=44 Participants Participants will receive the following combination chemotherapy for 4-6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle OR Carboplatin AUC = 5\* by IV Etoposide 100 mg/m\^2 by IV over 1 hour on days 1, 2, and 3 every cycle Maintenance: Following 4-6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.	Arm II (Combination Chemotherapy + Placebo Maintenance) n=41 Participants Participants will receive the following combination chemotherapy for 4-6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle OR Carboplatin AUC = 5\* by IV Etoposide 100 mg/m2 by IV over 1 hour on days 1, 2, and 3 every cycle Maintenance: Following 4-6 cycles of combination chemotherapy, start placebo at 150 mg on day 1, then 37.5 daily until disease progression.	Total n=97 Participants Total of all reporting groups
Age, Continuous	57 years n=99 Participants	60 years n=107 Participants	61 years n=206 Participants	60 years n=7 Participants
Sex: Female, Male Female	4 Participants n=99 Participants	26 Participants n=107 Participants	21 Participants n=206 Participants	51 Participants n=7 Participants
Sex: Female, Male Male	8 Participants n=99 Participants	18 Participants n=107 Participants	20 Participants n=206 Participants	46 Participants n=7 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Asian	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Black or African American	0 Participants n=99 Participants	3 Participants n=107 Participants	1 Participants n=206 Participants	4 Participants n=7 Participants
Race (NIH/OMB) White	12 Participants n=99 Participants	41 Participants n=107 Participants	40 Participants n=206 Participants	93 Participants n=7 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants
Region of Enrollment United States	12 participants n=99 Participants	44 participants n=107 Participants	41 participants n=206 Participants	97 participants n=7 Participants
Chemotherapy Agent Cisplatin	NA participants n=99 Participants	12 participants n=107 Participants	11 participants n=206 Participants	NA participants n=7 Participants
Chemotherapy Agent Carboplatin	NA participants n=99 Participants	32 participants n=107 Participants	30 participants n=206 Participants	NA participants n=7 Participants
Number of combination chemotherapy cycles < 6 cycles	NA participants n=99 Participants	12 participants n=107 Participants	9 participants n=206 Participants	NA participants n=7 Participants
Number of combination chemotherapy cycles 6 cycles	NA participants n=99 Participants	32 participants n=107 Participants	32 participants n=206 Participants	NA participants n=7 Participants

PRIMARY outcome

Timeframe: 21 days

Population: Due to safety concerns, the study committee discontinued sunitinib from combination chemotherapy to study single agent sunitinib in the maintenance setting.

Outcome measures

Outcome measures
Measure	Cohort 1 n=12 Participants Participants will receive the following combination chemotherapy for 6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle Etoposide 100 mg/m\^2 by IV over 1 hour on days 1, 2, and 3 every cycle Sunitinib 25 mg oral, daily days 1-14 every cycle Maintenance: Following 6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.	Cohort 2 Participants will receive the following combination chemotherapy for 6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle Etoposide 100 mg/m\^2 by IV over 1 hour on days 1, 2, and 3 every cycle Sunitinib 37.5 mg oral, daily days 1-14 every cycle Maintenance: Following 6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.	Cohort 3 Participants will receive the following combination chemotherapy for 6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle Etoposide 100 mg/m\^2 by IV over 1 hour on days 1, 2, and 3 every cycle Sunitinib 50 mg oral, daily days 1-14 every cycle Maintenance: Following 6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.
Maximum Tolerated of Sunitinib Combined With Cisplatin and Etoposide (Phase I)	25 mg/day	—	—

PRIMARY outcome

Timeframe: Up to 3 years

Population: Participants who were randomized to maintenance were analyzed.

Progression free survival (PFS) was defined as the time from maintenance randomization to progression or death of any cause. Progression free and alive patients were censored at the date of last follow-up. The median PFS with 95% CI was estimated using the Kaplan Meier method.

Outcome measures

Outcome measures
Measure	Cohort 1 n=44 Participants Participants will receive the following combination chemotherapy for 6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle Etoposide 100 mg/m\^2 by IV over 1 hour on days 1, 2, and 3 every cycle Sunitinib 25 mg oral, daily days 1-14 every cycle Maintenance: Following 6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.	Cohort 2 n=41 Participants Participants will receive the following combination chemotherapy for 6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle Etoposide 100 mg/m\^2 by IV over 1 hour on days 1, 2, and 3 every cycle Sunitinib 37.5 mg oral, daily days 1-14 every cycle Maintenance: Following 6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.	Cohort 3 Participants will receive the following combination chemotherapy for 6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle Etoposide 100 mg/m\^2 by IV over 1 hour on days 1, 2, and 3 every cycle Sunitinib 50 mg oral, daily days 1-14 every cycle Maintenance: Following 6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.
Progression-free Survival (Phase II)	3.7 months Interval 1.8 to 4.3	2.1 months Interval 1.6 to 2.6	—

SECONDARY outcome

Timeframe: Up to 3 years

Population: Participants who were randomized to maintenance were analyzed.

Overall survival (OS) was defined as the time from randomization to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% CI was estimated using the Kaplan Meier method.

Outcome measures

Outcome measures
Measure	Cohort 1 n=44 Participants Participants will receive the following combination chemotherapy for 6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle Etoposide 100 mg/m\^2 by IV over 1 hour on days 1, 2, and 3 every cycle Sunitinib 25 mg oral, daily days 1-14 every cycle Maintenance: Following 6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.	Cohort 2 n=41 Participants Participants will receive the following combination chemotherapy for 6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle Etoposide 100 mg/m\^2 by IV over 1 hour on days 1, 2, and 3 every cycle Sunitinib 37.5 mg oral, daily days 1-14 every cycle Maintenance: Following 6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.	Cohort 3 Participants will receive the following combination chemotherapy for 6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle Etoposide 100 mg/m\^2 by IV over 1 hour on days 1, 2, and 3 every cycle Sunitinib 50 mg oral, daily days 1-14 every cycle Maintenance: Following 6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.
Overall Survival	9.0 months Interval 8.0 to 12.7	6.9 months Interval 5.4 to 11.8	—

SECONDARY outcome

Timeframe: Up to 3 years

Population: Participants who were randomized to maintenance were analyzed.

Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): disappearance of all target lesions; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD): 20% increase in sum of longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria. Overall tumor response is the total number of CR and PRs.

Outcome measures

Outcome measures
Measure	Cohort 1 n=44 Participants Participants will receive the following combination chemotherapy for 6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle Etoposide 100 mg/m\^2 by IV over 1 hour on days 1, 2, and 3 every cycle Sunitinib 25 mg oral, daily days 1-14 every cycle Maintenance: Following 6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.	Cohort 2 n=41 Participants Participants will receive the following combination chemotherapy for 6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle Etoposide 100 mg/m\^2 by IV over 1 hour on days 1, 2, and 3 every cycle Sunitinib 37.5 mg oral, daily days 1-14 every cycle Maintenance: Following 6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.	Cohort 3 Participants will receive the following combination chemotherapy for 6 cycles (21 days): Cisplatin 80 mg/m\^2 by IV over 1 hour on day 1 every cycle Etoposide 100 mg/m\^2 by IV over 1 hour on days 1, 2, and 3 every cycle Sunitinib 50 mg oral, daily days 1-14 every cycle Maintenance: Following 6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.
Number of Participants With Overall Tumor Response Complete Response	3 participants	0 participants	—
Number of Participants With Overall Tumor Response Partial Response	4 participants	5 participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline to within 7 days of sunitinib/placebo therapy discontinuation

The frequency of tumor response by the optimally dichotomized VEGF levels will be tabulated and their association will be tested by Fisher's exact test as well as the maximally selected rank test. The association of the VEGF levels as continuous predictor with tumor response will be tested by Wilcoxon rank sum test. Further assessments of the association of the VEGF levels as\> continuous or binary variables and the tumor response will be implemented in a logistic regression while adjusting for other covariates such as performance status, weight loss and age

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline to within 7 days of sunitinib/placebo therapy discontinuation

Correlated with clinical outcome (response and survival).

Outcome measures

Outcome data not reported

Adverse Events

Arm I (Combination Chemotherapy + Sunitinib Maintenance)

Serious events: 12 serious events

Other events: 41 other events

Deaths: 0 deaths

Arm II (Combination Chemotherapy + Placebo Maintenance)

Serious events: 9 serious events

Other events: 38 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Dr. Neal Ready

Duke University Medical Center

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Arm I (Combination Chemotherapy + Sunitinib Maintenance) n=43 participants at risk Maintenance: Following 4-6 cycles of combination chemotherapy, start sunitinib at 150 mg on day 1, then 37.5 daily until disease progression.	Arm II (Combination Chemotherapy + Placebo Maintenance) n=41 participants at risk Maintenance: Following 4-6 cycles of combination chemotherapy, start placebo at 150 mg on day 1, then 37.5 daily until disease progression.
Blood and lymphatic system disorders Hemoglobin decreased	11.6% 5/43 • Number of events 5 84 participants were evaluable for adverse events.	17.1% 7/41 • Number of events 7 84 participants were evaluable for adverse events.
Cardiac disorders Atrial fibrillation	0.00% 0/43 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Cardiac disorders Cardiac disorder	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Cardiac disorders Supraventricular tachycardia	0.00% 0/43 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Ear and labyrinth disorders Ear disorder	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Endocrine disorders Hypothyroidism	0.00% 0/43 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 3 84 participants were evaluable for adverse events.
Gastrointestinal disorders Abdominal distension	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Gastrointestinal disorders Abdominal pain	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Gastrointestinal disorders Colitis	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Gastrointestinal disorders Constipation	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	4.9% 2/41 • Number of events 2 84 participants were evaluable for adverse events.
Gastrointestinal disorders Diarrhea	11.6% 5/43 • Number of events 6 84 participants were evaluable for adverse events.	7.3% 3/41 • Number of events 3 84 participants were evaluable for adverse events.
Gastrointestinal disorders Dry mouth	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Gastrointestinal disorders Dyspepsia	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Gastrointestinal disorders Dysphagia	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Gastrointestinal disorders Fecal incontinence	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Gastrointestinal disorders Gastrointestinal disorder	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Gastrointestinal disorders Nausea	7.0% 3/43 • Number of events 3 84 participants were evaluable for adverse events.	4.9% 2/41 • Number of events 2 84 participants were evaluable for adverse events.
Gastrointestinal disorders Pancreatic hemorrhage	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Gastrointestinal disorders Pancreatitis	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Gastrointestinal disorders Upper gastrointestinal hemorrhage	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Gastrointestinal disorders Vomiting	4.7% 2/43 • Number of events 2 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
General disorders Chills	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
General disorders Death NOS	0.00% 0/43 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
General disorders Disease progression	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
General disorders Fatigue	16.3% 7/43 • Number of events 8 84 participants were evaluable for adverse events.	12.2% 5/41 • Number of events 7 84 participants were evaluable for adverse events.
General disorders Fever	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Infections and infestations Appendicitis	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Infections and infestations Pneumonia	7.0% 3/43 • Number of events 3 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Investigations ADH abnormal	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Investigations Alanine aminotransferase increased	9.3% 4/43 • Number of events 4 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Investigations Alkaline phosphatase increased	11.6% 5/43 • Number of events 5 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Investigations Aspartate aminotransferase increased	11.6% 5/43 • Number of events 5 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Investigations Blood bilirubin increased	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Investigations Creatinine increased	4.7% 2/43 • Number of events 2 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Investigations Lipase increased	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Investigations Lymphocyte count decreased	4.7% 2/43 • Number of events 2 84 participants were evaluable for adverse events.	4.9% 2/41 • Number of events 2 84 participants were evaluable for adverse events.
Investigations Neutrophil count decreased	4.7% 2/43 • Number of events 2 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Investigations Platelet count decreased	14.0% 6/43 • Number of events 6 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Investigations Weight loss	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Metabolism and nutrition disorders Anorexia	4.7% 2/43 • Number of events 2 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Metabolism and nutrition disorders Blood glucose increased	14.0% 6/43 • Number of events 6 84 participants were evaluable for adverse events.	4.9% 2/41 • Number of events 2 84 participants were evaluable for adverse events.
Metabolism and nutrition disorders Dehydration	4.7% 2/43 • Number of events 2 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Metabolism and nutrition disorders Serum albumin decreased	4.7% 2/43 • Number of events 2 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Metabolism and nutrition disorders Serum calcium decreased	9.3% 4/43 • Number of events 4 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Metabolism and nutrition disorders Serum calcium increased	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Metabolism and nutrition disorders Serum glucose decreased	0.00% 0/43 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Metabolism and nutrition disorders Serum magnesium decreased	4.7% 2/43 • Number of events 2 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Metabolism and nutrition disorders Serum potassium decreased	7.0% 3/43 • Number of events 3 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Metabolism and nutrition disorders Serum sodium decreased	11.6% 5/43 • Number of events 5 84 participants were evaluable for adverse events.	4.9% 2/41 • Number of events 2 84 participants were evaluable for adverse events.
Metabolism and nutrition disorders Serum sodium increased	0.00% 0/43 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Musculoskeletal and connective tissue disorders Back pain	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/43 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Musculoskeletal and connective tissue disorders Chest wall pain	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	4.9% 2/41 • Number of events 2 84 participants were evaluable for adverse events.
Musculoskeletal and connective tissue disorders Neck pain	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/43 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Nervous system disorders Ataxia	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Nervous system disorders Dizziness	4.7% 2/43 • Number of events 2 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Nervous system disorders Headache	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Nervous system disorders Memory impairment	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Nervous system disorders Mini mental status examination abnormal	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	4.9% 2/41 • Number of events 2 84 participants were evaluable for adverse events.
Nervous system disorders Peripheral motor neuropathy	4.7% 2/43 • Number of events 2 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Nervous system disorders Peripheral sensory neuropathy	0.00% 0/43 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Nervous system disorders Seizure	4.7% 2/43 • Number of events 2 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Nervous system disorders Syncope	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Psychiatric disorders Confusion	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Renal and urinary disorders Proteinuria	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.00% 0/43 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Cough	11.6% 5/43 • Number of events 5 84 participants were evaluable for adverse events.	4.9% 2/41 • Number of events 2 84 participants were evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Dyspnea	11.6% 5/43 • Number of events 5 84 participants were evaluable for adverse events.	12.2% 5/41 • Number of events 6 84 participants were evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Hiccups	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Hypoxia	4.7% 2/43 • Number of events 2 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 2 84 participants were evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Pleuritic pain	0.00% 0/43 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Pneumonitis	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Respiratory disorder	0.00% 0/43 84 participants were evaluable for adverse events.	4.9% 2/41 • Number of events 2 84 participants were evaluable for adverse events.
Respiratory, thoracic and mediastinal disorders Respiratory tract hemorrhage	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Skin and subcutaneous tissue disorders Alopecia	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Skin and subcutaneous tissue disorders Dry skin	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.
Skin and subcutaneous tissue disorders Rash desquamating	0.00% 0/43 84 participants were evaluable for adverse events.	2.4% 1/41 • Number of events 1 84 participants were evaluable for adverse events.
Skin and subcutaneous tissue disorders Skin hyperpigmentation	2.3% 1/43 • Number of events 1 84 participants were evaluable for adverse events.	0.00% 0/41 84 participants were evaluable for adverse events.