Trial Outcomes & Findings for ENVISION: A Study to Evaluate the Efficacy and Safety of Givosiran (ALN-AS1) in Patients With Acute Hepatic Porphyrias (AHP) (NCT NCT03338816)

Last Updated: 2024-04-22

Results Overview

Porphyria attacks were defined as meeting all of the following criteria: an acute episode of neurovisceral pain in the abdomen, back, chest, extremities and/or limbs, no other medically determined cause, and required treatment with intravenous (IV) dextrose or hemin, carbohydrates, or analgesics, or other medications such as antiemetics at a dose or frequency beyond the participant's usual daily porphyria management. The annualized rate of porphyria attacks is a composite endpoint which included porphyria attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

94 participants

Primary outcome timeframe

6 months

Results posted on

2024-04-22

Participant Flow

Participants with acute hepatic porphyrias (AHP) were enrolled at thirty-six sites in Australia, Bulgaria, Canada, Germany, Denmark, Spain, Finland, France, United Kingdom, Italy, Japan, Korea (the Republic of), Mexico, Netherlands, Poland, Sweden, Taiwan and the United States.

Participant milestones

Participant milestones
Measure	Placebo 6-Month DB Matching placebo (normal saline \[0.9% NaCl\]) was administered subcutaneously (SC), monthly (QM), for 6 months during the 6-Month Double-blind (DB) Period.	Givosiran 2.5 mg/kg 6-Month DB Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.	Placebo/Givosiran Patients who received placebo during the 6-Month DB Period then entered the Open-Label Extension (OLE) Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly.	Givosiran/Givosiran Patients who received givosiran during the 6-Month DB Period then entered the OLE Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM mg/kg for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly.
6-Month Double-blind Period STARTED	46	48	0	0
6-Month Double-blind Period COMPLETED	46	48	0	0
6-Month Double-blind Period NOT COMPLETED	0	0	0	0
6-Month DB + Open-Label Extension Period STARTED	0	0	46	47
6-Month DB + Open-Label Extension Period COMPLETED	0	0	38	41
6-Month DB + Open-Label Extension Period NOT COMPLETED	0	0	8	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo/Givosiran Patients who received placebo during the 6-Month DB Period then entered the Open-Label Extension (OLE) Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly.	Givosiran/Givosiran Patients who received givosiran during the 6-Month DB Period then entered the OLE Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM mg/kg for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly.
6-Month DB + Open-Label Extension Period Adverse Event	2	0
6-Month DB + Open-Label Extension Period Death	0	1
6-Month DB + Open-Label Extension Period Lost to Follow-up	1	0
6-Month DB + Open-Label Extension Period Physician Decision	1	0
6-Month DB + Open-Label Extension Period Pregnancy	1	1
6-Month DB + Open-Label Extension Period Withdrawal by Subject	3	3
6-Month DB + Open-Label Extension Period Patient Desired Lower Dose	0	1

Baseline Characteristics

ENVISION: A Study to Evaluate the Efficacy and Safety of Givosiran (ALN-AS1) in Patients With Acute Hepatic Porphyrias (AHP)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=46 Participants Matching placebo (normal saline \[0.9% NaCl\]) was administered SC, QM, for 6 months during the 6-Month DB Period, followed by givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM for 29 months during the OLE period.	Givosiran n=48 Participants Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period, followed by givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM for 29 months during the OLE Period.	Total n=94 Participants Total of all reporting groups
Age, Continuous	37.4 years STANDARD_DEVIATION 10.5 • n=99 Participants	40.1 years STANDARD_DEVIATION 12.1 • n=107 Participants	38.8 years STANDARD_DEVIATION 11.4 • n=206 Participants
Sex: Female, Male Female	41 Participants n=99 Participants	43 Participants n=107 Participants	84 Participants n=206 Participants
Sex: Female, Male Male	5 Participants n=99 Participants	5 Participants n=107 Participants	10 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=99 Participants	5 Participants n=107 Participants	8 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	42 Participants n=99 Participants	42 Participants n=107 Participants	84 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=99 Participants	1 Participants n=107 Participants	2 Participants n=206 Participants
Race/Ethnicity, Customized Asian	7 Participants n=99 Participants	8 Participants n=107 Participants	15 Participants n=206 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 Participants n=99 Participants	0 Participants n=107 Participants	1 Participants n=206 Participants
Race/Ethnicity, Customized Black or African American	1 Participants n=99 Participants	0 Participants n=107 Participants	1 Participants n=206 Participants
Race/Ethnicity, Customized White	34 Participants n=99 Participants	39 Participants n=107 Participants	73 Participants n=206 Participants
Race/Ethnicity, Customized More than One Race	1 Participants n=99 Participants	0 Participants n=107 Participants	1 Participants n=206 Participants
Race/Ethnicity, Customized Unknown or Not Reported	2 Participants n=99 Participants	1 Participants n=107 Participants	3 Participants n=206 Participants

PRIMARY outcome

Timeframe: 6 months

Population: AIP participants in the Full Analysis Set (FASAIP): All randomized AIP participants (with identified mutation in the hydroxymethylbilane synthase \[HMBS\] gene) who received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Matching placebo (normal saline \[0.9% NaCl\]) was administered SC, QM, for 6 months during the 6-Month DB Period.	Givosiran 2.5 mg/kg n=46 Participants Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.
Annualized Rate of Porphyria Attacks in Participants With Acute Intermittent Porphyria (AIP)	12.52 annualized attack rate Interval 9.35 to 16.76	3.22 annualized attack rate Interval 2.25 to 4.59

SECONDARY outcome

Timeframe: 3 and 6 months

Population: FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

The PD effect of givosiran was evaluated by spot urine ALA levels normalized to spot urine creatinine levels.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Matching placebo (normal saline \[0.9% NaCl\]) was administered SC, QM, for 6 months during the 6-Month DB Period.	Givosiran 2.5 mg/kg n=46 Participants Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.
The Pharmacodynamic (PD) Effect of Givosiran on Urine Levels of Delta-aminolevulinic Acid (ALA) in Participants With AIP Month 3	19.965 mmol/mol creatinine (Cr) Standard Error 1.475	1.756 mmol/mol creatinine (Cr) Standard Error 1.413
The Pharmacodynamic (PD) Effect of Givosiran on Urine Levels of Delta-aminolevulinic Acid (ALA) in Participants With AIP Month 6	23.150 mmol/mol creatinine (Cr) Standard Error 2.534	4.013 mmol/mol creatinine (Cr) Standard Error 2.352

SECONDARY outcome

Timeframe: 6 months

Population: FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

The PD effect of givosiran was evaluated by spot urine PBG levels normalized to spot urine creatinine levels.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Matching placebo (normal saline \[0.9% NaCl\]) was administered SC, QM, for 6 months during the 6-Month DB Period.	Givosiran 2.5 mg/kg n=46 Participants Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.
The PD Effect of Givosiran on Urine Levels of Porphobilinogen (PBG) in Participants With AIP	49.110 mmol/mol Cr Standard Error 4.959	12.906 mmol/mol Cr Standard Error 4.642

SECONDARY outcome

Timeframe: 6 months

Population: FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

Annualized rate of hemin doses was evaluated as annualized days of hemin use.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Matching placebo (normal saline \[0.9% NaCl\]) was administered SC, QM, for 6 months during the 6-Month DB Period.	Givosiran 2.5 mg/kg n=46 Participants Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.
Annualized Rate of Hemin Administration in Participants With AIP	29.71 annualized rate of use Interval 18.41 to 47.94	6.77 annualized rate of use Interval 4.2 to 10.92

SECONDARY outcome

Timeframe: 6 months

Population: Full Analysis Set (FAS): All randomized patients who received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Placebo n=46 Participants Matching placebo (normal saline \[0.9% NaCl\]) was administered SC, QM, for 6 months during the 6-Month DB Period.	Givosiran 2.5 mg/kg n=48 Participants Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.
Annualized Rate of Porphyria Attacks in Participants With AHP	12.26 annualized attack rate Interval 9.22 to 16.29	3.35 annualized attack rate Interval 2.37 to 4.74

SECONDARY outcome

Timeframe: Baseline and 6 months

Population: FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

Participants rated worst daily pain score in an eDiary using the 11-point BPI-SF NRS, in which 0=no pain and 10=worst pain. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the post baseline weekly mean score minus the baseline score. Lower scores indicate an improvement. The 6-month AUC was calculated based on change from baseline in weekly mean scores.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Matching placebo (normal saline \[0.9% NaCl\]) was administered SC, QM, for 6 months during the 6-Month DB Period.	Givosiran 2.5 mg/kg n=46 Participants Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.
Area Under the Curve (AUC) of the Change From Baseline in Weekly Mean Score of Daily Worst Pain as Measured by the Brief Pain Inventory-Short Form (BPI-SF) Numeric Rating Scale (NRS) in Participants With AIP	5.286 score on a scale*week Interval -23.048 to 11.145	-11.514 score on a scale*week Interval -29.181 to 3.04

SECONDARY outcome

Timeframe: Baseline and 6 months

Population: FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

Participants rated worst daily pain score in an eDiary using the 11-point BPI-SF NRS, in which 0=no pain and 10=worst pain. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the postbaseline weekly mean score minus the baseline score. Lower scores indicate an improvement.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Matching placebo (normal saline \[0.9% NaCl\]) was administered SC, QM, for 6 months during the 6-Month DB Period.	Givosiran 2.5 mg/kg n=46 Participants Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.
Average Change From Baseline in Weekly Mean Score of Daily Worst Pain as Measured by the Brief Pain Inventory-Short Form (BPI-SF) Numeric Rating Scale (NRS) in Participants With AIP	0.245 score on a scale Interval -1.02 to 0.47	-0.506 score on a scale Interval -1.309 to 0.143

SECONDARY outcome

Timeframe: Baseline and 6 months

Population: FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

Participants rated daily worst fatigue score in an eDiary using the 11-point BFI-SF NRS, in which 0=no fatigue and 10=worst fatigue. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the post baseline weekly mean score minus the baseline score. Lower scores indicate an improvement. The 6-month AUC was calculated based on change from baseline in weekly mean scores.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Matching placebo (normal saline \[0.9% NaCl\]) was administered SC, QM, for 6 months during the 6-Month DB Period.	Givosiran 2.5 mg/kg n=46 Participants Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.
AUC of the Change From Baseline in Weekly Mean Score of Daily Worst Fatigue Score as Measured by the Brief Fatigue Inventory-Short Form (BFI-SF) NRS in Participants With AIP	-4.208 score on a scale*week Standard Error 4.689	-11.148 score on a scale*week Standard Error 4.501

SECONDARY outcome

Timeframe: Baseline and 6 months

Population: FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

Participants rated daily worst fatigue score in an eDiary using the 11-point BFI-SF NRS, in which 0=no fatigue and 10=worst fatigue. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the postbaseline weekly mean score minus the baseline score. Lower scores indicate an improvement.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Matching placebo (normal saline \[0.9% NaCl\]) was administered SC, QM, for 6 months during the 6-Month DB Period.	Givosiran 2.5 mg/kg n=46 Participants Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.
Average Change From Baseline in Weekly Mean Score of Daily Worst Fatigue Score as Measured by the Brief Fatigue Inventory-Short Form (BFI-SF) NRS in Participants With AIP	-0.182 score on a scale Standard Error 0.209	-0.502 score on a scale Standard Error 0.200

SECONDARY outcome

Timeframe: Baseline and 6 months

Population: FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

Participants rated worst daily nausea score in an eDiary using an 11-point NRS, in which 0=no nausea and 10=worst nausea. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the postbaseline weekly mean score minus the baseline score. Lower scores indicate an improvement. The 6-month AUC was calculated based on change from baseline in weekly mean scores.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Matching placebo (normal saline \[0.9% NaCl\]) was administered SC, QM, for 6 months during the 6-Month DB Period.	Givosiran 2.5 mg/kg n=46 Participants Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.
AUC of the Change From Baseline in Weekly Mean Score Daily Worst Nausea Score as Measured by NRS in Participants With AIP	-4.011 score on a scale Standard Error 3.453	1.481 score on a scale Standard Error 3.310

SECONDARY outcome

Timeframe: Baseline and 6 months

Population: FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Matching placebo (normal saline \[0.9% NaCl\]) was administered SC, QM, for 6 months during the 6-Month DB Period.	Givosiran 2.5 mg/kg n=46 Participants Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.
Average Change From Baseline in Weekly Mean Score Daily Worst Nausea Score as Measured by NRS in Participants With AIP	-0.181 score on a scale Standard Error 0.154	0.067 score on a scale Standard Error 0.147

SECONDARY outcome

Timeframe: Baseline and 6 months

Population: FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

The SF-12 is a survey designed for use in patients with multiple chronic conditions. This 12-item scale can be used to assess the physical and mental health of respondents. 10 of the 12 questions are answered on a 5 point likert scale and 2 are answered on a 3 point likert scale. The questions are then scored and weighted into 2 subscales, physical health and mental health. Respondents can have a score that ranges from 0-100 with 100 being the best score and indicating high physical or mental health. A 3 point change in SF-12 score reflects a meaningful difference. A higher score indicates improvement.

Outcome measures

Outcome measures
Measure	Placebo n=43 Participants Matching placebo (normal saline \[0.9% NaCl\]) was administered SC, QM, for 6 months during the 6-Month DB Period.	Givosiran 2.5 mg/kg n=46 Participants Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.
Change From Baseline in the Physical Component Summary (PCS) of the 12-Item Short Form Survey (SF-12) in Participants With AIP	1.431 score on a scale Standard Error 1.220	5.369 score on a scale Standard Error 1.169

Adverse Events

Placebo 6-Month DB

Serious events: 4 serious events

Other events: 37 other events

Deaths: 0 deaths

Givosiran 2.5 mg/kg 6-Month DB

Serious events: 10 serious events

Other events: 43 other events

Deaths: 0 deaths

Placebo/Givosiran

Serious events: 17 serious events

Other events: 44 other events

Deaths: 0 deaths

Givosiran/Givosiran

Serious events: 20 serious events

Other events: 47 other events

Deaths: 1 deaths

All Givosiran

Serious events: 37 serious events

Other events: 91 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	Placebo 6-Month DB n=46 participants at risk Matching placebo (normal saline \[0.9% NaCl\]) was administered SC, QM, for 6 months during the 6-Month DB Period.	Givosiran 2.5 mg/kg 6-Month DB n=48 participants at risk Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.	Placebo/Givosiran n=46 participants at risk Patients who received placebo during the 6-Month DB Period then entered the Open-Label Extension (OLE) Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly.	Givosiran/Givosiran n=48 participants at risk Patients who received givosiran during the 6-Month DB Period then entered the OLE Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM mg/kg for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly.	All Givosiran n=94 participants at risk All participants treated with any amount of givosiran.
General disorders Pyrexia	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Device related infection	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Escherichia urinary tract infection	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Gastroenteritis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Sepsis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Septic shock	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Injury, poisoning and procedural complications Fractured sacrum	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Investigations Liver function test abnormal	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Psychiatric disorders Major depression	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Renal and urinary disorders Chronic kidney disease	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.2% 2/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 2/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Surgical and medical procedures Pain management	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Blood and lymphatic system disorders Lymphadenitis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Blood and lymphatic system disorders Splenic vein thrombosis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Eye disorders Retinal vein occlusion	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Gastrointestinal disorders Abdominal pain	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Gastrointestinal disorders Duodenal ulcer	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Gastrointestinal disorders Gastritis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Gastrointestinal disorders Haematemesis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Gastrointestinal disorders Hiatus hernia	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Gastrointestinal disorders Nausea	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Gastrointestinal disorders Obstructive pancreatitis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Gastrointestinal disorders Pancreatitis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Gastrointestinal disorders Vomiting	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
General disorders Administration site extravasation	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
General disorders Asthenia	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
General disorders Drug withdrawal syndrome	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
General disorders Injection site reaction	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
General disorders Oedema	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Hepatobiliary disorders Cholelithiasis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Bronchitis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations COVID-19 pneumonia	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 2/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Catheter bacteraemia	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Clostridium difficile infection	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Helicobacter gastritis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Influenza	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Kidney infection	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Lower respiratory tract infection	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Pyelonephritis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Urinary tract infection	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 2/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Viral infection	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Injury, poisoning and procedural complications Post procedural fever 1	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Injury, poisoning and procedural complications Post procedural inflammation	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Investigations Blood homocysteine increased	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 2/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 2/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Investigations Transaminases increased	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Metabolism and nutrition disorders Electrolyte imbalance	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Musculoskeletal and connective tissue disorders Trismus	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon neoplasm	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Invasive breast carcinoma	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Invasive ductal breast carcinoma	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tonsil cancer	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Nervous system disorders Cerebral venous sinus thrombosis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Nervous system disorders Headache	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Nervous system disorders Migraine with aura	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Nervous system disorders Tremor	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Product Issues Device breakage	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 2/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Psychiatric disorders Drug dependence	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Psychiatric disorders Panic attack	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Renal and urinary disorders Nephropathy	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Reproductive system and breast disorders Pelvic pain	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Respiratory, thoracic and mediastinal disorders Nasal polyps	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 4/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Surgical and medical procedures Hysterosalpingo-oophorectomy	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Surgical and medical procedures Intrathecal pump insertion	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Vascular disorders Aortic dissection	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Vascular disorders Deep vein thrombosis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Vascular disorders Subclavian vein occlusion	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Vascular disorders Subclavian vein thrombosis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Vascular disorders Thrombophlebitis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	1.1% 1/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).

Other adverse events

Other adverse events
Measure	Placebo 6-Month DB n=46 participants at risk Matching placebo (normal saline \[0.9% NaCl\]) was administered SC, QM, for 6 months during the 6-Month DB Period.	Givosiran 2.5 mg/kg 6-Month DB n=48 participants at risk Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.	Placebo/Givosiran n=46 participants at risk Patients who received placebo during the 6-Month DB Period then entered the Open-Label Extension (OLE) Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly.	Givosiran/Givosiran n=48 participants at risk Patients who received givosiran during the 6-Month DB Period then entered the OLE Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM mg/kg for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly.	All Givosiran n=94 participants at risk All participants treated with any amount of givosiran.
Gastrointestinal disorders Abdominal pain	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	17.4% 8/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	12.5% 6/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	14.9% 14/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Gastrointestinal disorders Constipation	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.7% 4/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	12.5% 6/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	10.6% 10/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Gastrointestinal disorders Dyspepsia	8.7% 4/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Gastrointestinal disorders Nausea	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	26.1% 12/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	45.8% 22/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	36.2% 34/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Gastrointestinal disorders Vomiting	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	17.4% 8/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	14.6% 7/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	16.0% 15/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
General disorders Asthenia	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.7% 4/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	10.4% 5/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	9.6% 9/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
General disorders Fatigue	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	28.3% 13/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	25.0% 12/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	26.6% 25/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
General disorders Injection site reaction	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	30.4% 14/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	33.3% 16/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	31.9% 30/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
General disorders Pyrexia	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	13.0% 6/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	12.5% 6/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	12.8% 12/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Nasopharyngitis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	23.9% 11/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	29.2% 14/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	26.6% 25/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Tooth infection	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.3% 4/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 4/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Upper respiratory tract infection	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	26.1% 12/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	14.6% 7/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	20.2% 19/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Urinary tract infection	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	21.7% 10/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	18.8% 9/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	20.2% 19/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Investigations Alanine aminotransferase increased	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.7% 4/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.3% 4/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.5% 8/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Investigations Aspartate aminotransferase increased	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.5% 3/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.3% 4/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	7.4% 7/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Investigations Glomerular filtration rate decreased	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 2/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	10.4% 5/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	7.4% 7/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Investigations Lipase increased	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	13.0% 6/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	14.6% 7/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	13.8% 13/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	13.0% 6/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	14.6% 7/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	13.8% 13/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.7% 4/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	7.4% 7/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Nervous system disorders Dizziness	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 4/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Nervous system disorders Headache	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	15.2% 7/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	27.1% 13/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	21.3% 20/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Nervous system disorders Hypoaesthesia	8.7% 4/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Product Issues Device occlusion	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	10.4% 5/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.4% 6/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Psychiatric disorders Anxiety	6.5% 3/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Renal and urinary disorders Chronic kidney disease	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	10.4% 5/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.4% 6/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Skin and subcutaneous tissue disorders Rash	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	10.4% 5/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	5.3% 5/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Blood and lymphatic system disorders Anaemia	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.5% 3/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 4/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Cardiac disorders Palpitations	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.5% 3/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 4/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Eye disorders Eye pruritus	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	3.2% 3/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Gastrointestinal disorders Abdominal pain upper	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.7% 4/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.3% 4/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.5% 8/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Gastrointestinal disorders Diarrhoea	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	15.2% 7/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	16.7% 8/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	16.0% 15/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.7% 4/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	7.4% 7/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
General disorders Influenza like illness	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	10.4% 5/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.4% 6/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
General disorders Injection site pain	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	3.2% 3/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
General disorders Oedema peripheral	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.5% 3/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.2% 2/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	5.3% 5/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
General disorders Pain	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.7% 4/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	7.4% 7/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Immune system disorders Drug hypersensitivity	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.5% 3/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 4/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Bronchitis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.7% 4/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.2% 2/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.4% 6/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations COVID-19	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 2/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	5.3% 5/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Conjunctivitis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	3.2% 3/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Cystitis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.5% 3/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.4% 6/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Gastroenteritis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	10.9% 5/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.5% 8/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Influenza	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	10.9% 5/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.3% 4/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	9.6% 9/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Infections and infestations Pharyngitis	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.5% 3/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.4% 6/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Injury, poisoning and procedural complications Contusion	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	10.9% 5/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.2% 2/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	7.4% 7/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Injury, poisoning and procedural complications Fall	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.7% 4/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	5.3% 5/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Injury, poisoning and procedural complications Ligament sprain	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.5% 3/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.4% 6/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Investigations Amylase increased	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.5% 3/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.3% 4/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	7.4% 7/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Investigations Blood creatinine increased	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 2/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	10.4% 5/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	7.4% 7/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Investigations Blood homocysteine increased	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 4/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Investigations Gamma-glutamyltransferase increased	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 2/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	5.3% 5/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Investigations Weight increased	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 4/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Metabolism and nutrition disorders Hyperhomocysteinaemia	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	13.0% 6/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	9.6% 9/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Metabolism and nutrition disorders Iron overload	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 4/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.5% 3/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	10.4% 5/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.5% 8/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.5% 3/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.3% 4/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	7.4% 7/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	10.4% 5/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.4% 6/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 2/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	10.4% 5/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	7.4% 7/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Nervous system disorders Migraine	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	12.5% 6/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	7.4% 7/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Nervous system disorders Paraesthesia	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.5% 3/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.1% 1/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 4/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Nervous system disorders Tremor	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 2/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	5.3% 5/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Psychiatric disorders Depression	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.7% 4/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	7.4% 7/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 4/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	2.2% 1/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 4/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.3% 2/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.3% 4/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.4% 6/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Skin and subcutaneous tissue disorders Eczema	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.5% 3/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	4.2% 2/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	5.3% 5/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	10.9% 5/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.5% 8/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).
Vascular disorders Hypertension	0.00% 0/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	0.00% 0/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	8.7% 4/46 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	6.2% 3/48 • From the first dose of study drug through completion of the OLE Period (up to 39 months).	7.4% 7/94 • From the first dose of study drug through completion of the OLE Period (up to 39 months).

Additional Information

Chief Medical Officer

Alnylam Pharmaceuticals Inc

Phone: 866-330-0326

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60