Trial Outcomes & Findings for Safety and Efficacy of Simtuzumab (SIM, GS-6624) in Adults With Advanced Liver Fibrosis But Not Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (NASH) (NCT NCT01672866)

NCT ID: NCT01672866

Last Updated: 2019-03-27

Results Overview

• Recruitment status: TERMINATED
• Study phase: PHASE2
• Target enrollment: 222 participants
• Primary outcome timeframe: Baseline to Week 96
• Results posted on: 2019-03-27

Participant Flow

Participants were enrolled at study sites in Europe and North America. The first participant was screened on 05 December 2012. The last study visit occurred on 29 December 2016.

631 participants were screened.

Participant milestones

Measure	SIM 75 mg Blinded Phase: Participants received simtuzumab (SIM) 75 mg via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks.	SIM 125 mg Blinded Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks.	Placebo Blinded Phase: Participants received placebo to match SIM via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks.
Blinded Phase (up to 240 Weeks) STARTED	74	74	74
Blinded Phase (up to 240 Weeks) COMPLETED	0	0	0
Blinded Phase (up to 240 Weeks) NOT COMPLETED	74	74	74
Open-Label Phase (up to 240 Weeks) STARTED	11	15	16
Open-Label Phase (up to 240 Weeks) COMPLETED	0	0	0
Open-Label Phase (up to 240 Weeks) NOT COMPLETED	11	15	16

Reasons for withdrawal

Measure	SIM 75 mg Blinded Phase: Participants received simtuzumab (SIM) 75 mg via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks.	SIM 125 mg Blinded Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks.	Placebo Blinded Phase: Participants received placebo to match SIM via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks.
Blinded Phase (up to 240 Weeks) Study Terminated by Sponsor	40	42	35
Blinded Phase (up to 240 Weeks) Withdrew Consent	9	8	12
Blinded Phase (up to 240 Weeks) Lost to Follow-up	3	3	5
Blinded Phase (up to 240 Weeks) Adverse Event	3	3	3
Blinded Phase (up to 240 Weeks) Investigator's Discretion	3	3	2
Blinded Phase (up to 240 Weeks) Protocol Violation	2	0	0
Blinded Phase (up to 240 Weeks) Death	0	0	1
Blinded Phase (up to 240 Weeks) Randomized but Never Treated	3	0	0
Blinded Phase (up to 240 Weeks) Met protocol-specified reason(s)	11	15	16
Open-Label Phase (up to 240 Weeks) Study Terminated by Sponsor	8	15	15
Open-Label Phase (up to 240 Weeks) Withdrew Consent	1	0	1
Open-Label Phase (up to 240 Weeks) Death	1	0	0
Open-Label Phase (up to 240 Weeks) Lost to Follow-up	1	0	0

Baseline Characteristics

Safety and Efficacy of Simtuzumab (SIM, GS-6624) in Adults With Advanced Liver Fibrosis But Not Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (NASH)

Baseline characteristics by cohort

Measure	SIM 75 mg n=71 Participants Blinded Phase: Participants received SIM 75 mg via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks.	SIM 125 mg n=74 Participants Blinded Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks.	Placebo n=74 Participants Blinded Phase: Participants received placebo to match SIM via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks.	Total n=219 Participants Total of all reporting groups
Age, Continuous	54 years STANDARD_DEVIATION 8.8 • n=5 Participants	53 years STANDARD_DEVIATION 9.4 • n=7 Participants	53 years STANDARD_DEVIATION 8.4 • n=5 Participants	53 years STANDARD_DEVIATION 8.8 • n=4 Participants
Sex: Female, Male Female	43 Participants n=5 Participants	47 Participants n=7 Participants	48 Participants n=5 Participants	138 Participants n=4 Participants
Sex: Female, Male Male	28 Participants n=5 Participants	27 Participants n=7 Participants	26 Participants n=5 Participants	81 Participants n=4 Participants
Race/Ethnicity, Customized Race · American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Race · Asian	1 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	5 Participants n=4 Participants
Race/Ethnicity, Customized Race · Black or African American	2 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Race/Ethnicity, Customized Race · Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Race · White	66 Participants n=5 Participants	71 Participants n=7 Participants	69 Participants n=5 Participants	206 Participants n=4 Participants
Race/Ethnicity, Customized Race · Other	2 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Race/Ethnicity, Customized Ethnicity · Hispanic or Latino	9 Participants n=5 Participants	14 Participants n=7 Participants	11 Participants n=5 Participants	34 Participants n=4 Participants
Race/Ethnicity, Customized Ethnicity · Not Hispanic or Latino	62 Participants n=5 Participants	60 Participants n=7 Participants	63 Participants n=5 Participants	185 Participants n=4 Participants
Region of Enrollment Canada	5 Participants n=5 Participants	6 Participants n=7 Participants	1 Participants n=5 Participants	12 Participants n=4 Participants
Region of Enrollment Belgium	1 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants	6 Participants n=4 Participants
Region of Enrollment United States	51 Participants n=5 Participants	58 Participants n=7 Participants	54 Participants n=5 Participants	163 Participants n=4 Participants
Region of Enrollment Italy	2 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	6 Participants n=4 Participants
Region of Enrollment United Kingdom	3 Participants n=5 Participants	0 Participants n=7 Participants	5 Participants n=5 Participants	8 Participants n=4 Participants
Region of Enrollment France	4 Participants n=5 Participants	4 Participants n=7 Participants	4 Participants n=5 Participants	12 Participants n=4 Participants
Region of Enrollment Germany	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants	8 Participants n=4 Participants
Region of Enrollment Spain	2 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	4 Participants n=4 Participants
Morphometric Quantitative Collagen (MQC)	7.0 percentage of liver collagen STANDARD_DEVIATION 4.18 • n=5 Participants	7.2 percentage of liver collagen STANDARD_DEVIATION 4.62 • n=7 Participants	6.7 percentage of liver collagen STANDARD_DEVIATION 3.78 • n=5 Participants	7.0 percentage of liver collagen STANDARD_DEVIATION 4.19 • n=4 Participants

PRIMARY outcome

Timeframe: Baseline to Week 96

Population: Participants in the Full Analysis Set (all enrolled participants who were randomized and received at least 1 dose of study drug) with available data were analyzed.

Outcome measures

Measure	SIM 75 mg n=46 Participants Blinded Phase: Participants received SIM 75 mg via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks.	SIM 125 mg n=49 Participants Blinded Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks.	Placebo n=55 Participants Blinded Phase: Participants received placebo to match SIM via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks.
Change From Baseline in MQC on Liver Biopsy	-3.1 percentage of liver collagen Standard Deviation 4.83	-2.5 percentage of liver collagen Standard Deviation 5.11	-1.9 percentage of liver collagen Standard Deviation 4.28

PRIMARY outcome

Timeframe: Baseline up to the time of progression to cirrhosis or last dose date (maximum: 240 weeks in the Blinded Phase), which ever occurred first

Population: Participants in the Full Analysis Set were analyzed.

The EFS was the primary clinical efficacy endpoint and was assessed by the time to progression to cirrhosis. Participants were considered to have become cirrhotic if they had a post-baseline biopsy consistent with cirrhosis or developed overt signs and symptoms of cirrhosis. All overt signs and symptoms went through an adjudication process and were confirmed before they were considered for the EFS analysis.

Outcome measures

Measure	SIM 75 mg n=71 Participants Blinded Phase: Participants received SIM 75 mg via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks.	SIM 125 mg n=74 Participants Blinded Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks.	Placebo n=74 Participants Blinded Phase: Participants received placebo to match SIM via subcutaneous injection weekly for up to 240 weeks. Open-Label Phase: Participants received SIM 125 mg via subcutaneous injection weekly for up to an additional 240 weeks.
Event Free Survival (EFS) Using Kaplan-Meier	NA months Data was not estimable as more than 50% of participants were censored.	NA months Data was not estimable as more than 50% of participants were censored.	NA months Interval 38.4 to Data was not estimable as more than 50% of participants were censored.

Adverse Events

Blinded Phase: SIM 75 mg

Serious events: 17 serious events

Other events: 65 other events

Deaths: 0 deaths

Blinded Phase: SIM 125 mg

Serious events: 17 serious events

Other events: 69 other events

Deaths: 0 deaths

Blinded Phase: Placebo

Serious events: 14 serious events

Other events: 72 other events

Deaths: 0 deaths

Open-Label Phase: SIM 125 mg

Serious events: 11 serious events

Other events: 29 other events

Deaths: 0 deaths

Serious adverse events

Measure	Blinded Phase: SIM 75 mg n=71 participants at risk Adverse events reported in this group occurred during the Blinded Phase. Participants received SIM 75 mg via subcutaneous injection weekly for up to 240 weeks.	Blinded Phase: SIM 125 mg n=74 participants at risk Adverse events reported in this group occurred during the Blinded Phase. Participants received SIM 125 mg via subcutaneous injection weekly for up to 240 weeks.	Blinded Phase: Placebo n=74 participants at risk Adverse events reported in this group occurred during the Blinded Phase. Participants received placebo to match SIM via subcutaneous injection weekly for up to 240 weeks.	Open-Label Phase: SIM 125 mg n=42 participants at risk All participants who completed the Blinded Phase through the Week 240 visit, or were ongoing at the time the study stopped, or who had progressed cirrhosis of the liver, were offered the opportunity to receive open-label SIM for up to 240 additional weeks. Additionally, participants who developed confirmed progression to cirrhosis prior to completing the Blinded Phase were eligible to roll over into the open-label phase. Adverse events reported in this group occurred during the Open-Label Phase. All participants received fixed-dose open-label SIM 125 mg via subcutaneous injection every week for up to 240 weeks.
Blood and lymphatic system disorders Pancytopenia	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Cardiac disorders Acute myocardial infarction	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Cardiac disorders Coronary artery occlusion	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Cardiac disorders Myocardial infarction	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Cardiac disorders Ventricular tachycardia	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Ear and labyrinth disorders Vertigo	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Endocrine disorders Hyperadrenocorticism	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Abdominal pain	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.8% 2/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Abdominal pain lower	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Colitis	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Diverticular perforation	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Duodenitis	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Gastritis	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Haemorrhoids	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Impaired gastric emptying	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Intestinal obstruction	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Melaena	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Nausea	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
General disorders Chest pain	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.1% 3/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
General disorders Death	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
General disorders Non-cardiac chest pain	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
General disorders Pyrexia	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Hepatobiliary disorders Biliary dilatation	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Hepatobiliary disorders Cholecystitis	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Hepatobiliary disorders Cholelithiasis	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Hepatobiliary disorders Perforation bile duct	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Abscess soft tissue	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Appendicitis	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Bacteraemia	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Cellulitis	4.2% 3/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Device related infection	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Gastroenteritis	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Gastroenteritis viral	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Groin abscess	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Infective exacerbation of chronic obstructive airways disease	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Mastoiditis	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Sepsis	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Injury, poisoning and procedural complications Procedural pain	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Injury, poisoning and procedural complications Seroma	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Injury, poisoning and procedural complications Upper limb fracture	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Investigations Blood glucose increased	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Investigations Weight increased	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Metabolism and nutrition disorders Dehydration	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Metabolism and nutrition disorders Diabetes mellitus inadequate control	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Metabolism and nutrition disorders Metabolic acidosis	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Metabolism and nutrition disorders Metabolic disorder	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Musculoskeletal and connective tissue disorders Joint instability	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Musculoskeletal and connective tissue disorders Osteonecrosis	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma gastric	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian adenoma	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal adenocarcinoma	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Nervous system disorders Carpal tunnel syndrome	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Nervous system disorders Depressed level of consciousness	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Nervous system disorders Epilepsy	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Nervous system disorders Hepatic encephalopathy	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Nervous system disorders Syncope	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Nervous system disorders Transient ischaemic attack	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Psychiatric disorders Anxiety	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Psychiatric disorders Depression	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Psychiatric disorders Major depression	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Renal and urinary disorders Acute kidney injury	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Renal and urinary disorders Bladder prolapse	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Renal and urinary disorders Nephrolithiasis	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Renal and urinary disorders Proteinuria	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Renal and urinary disorders Urinary retention	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Vascular disorders Hypertension	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Vascular disorders Hypotension	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.

Other adverse events

Measure	Blinded Phase: SIM 75 mg n=71 participants at risk Adverse events reported in this group occurred during the Blinded Phase. Participants received SIM 75 mg via subcutaneous injection weekly for up to 240 weeks.	Blinded Phase: SIM 125 mg n=74 participants at risk Adverse events reported in this group occurred during the Blinded Phase. Participants received SIM 125 mg via subcutaneous injection weekly for up to 240 weeks.	Blinded Phase: Placebo n=74 participants at risk Adverse events reported in this group occurred during the Blinded Phase. Participants received placebo to match SIM via subcutaneous injection weekly for up to 240 weeks.	Open-Label Phase: SIM 125 mg n=42 participants at risk All participants who completed the Blinded Phase through the Week 240 visit, or were ongoing at the time the study stopped, or who had progressed cirrhosis of the liver, were offered the opportunity to receive open-label SIM for up to 240 additional weeks. Additionally, participants who developed confirmed progression to cirrhosis prior to completing the Blinded Phase were eligible to roll over into the open-label phase. Adverse events reported in this group occurred during the Open-Label Phase. All participants received fixed-dose open-label SIM 125 mg via subcutaneous injection every week for up to 240 weeks.
Gastrointestinal disorders Dyspepsia	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Dry mouth	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Blood and lymphatic system disorders Anaemia	2.8% 2/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	6.8% 5/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Abdominal distension	8.5% 6/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	6.8% 5/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Abdominal pain	18.3% 13/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	10.8% 8/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	14.9% 11/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	7.1% 3/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Abdominal pain lower	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	6.8% 5/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Abdominal pain upper	15.5% 11/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	25.7% 19/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	23.0% 17/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.8% 2/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Abdominal tenderness	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Constipation	8.5% 6/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	10.8% 8/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Diarrhoea	26.8% 19/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	25.7% 19/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	28.4% 21/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Nausea	22.5% 16/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	27.0% 20/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	29.7% 22/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	11.9% 5/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Gastrointestinal disorders Vomiting	15.5% 11/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	18.9% 14/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	13.5% 10/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.8% 2/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
General disorders Chest pain	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	8.1% 6/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
General disorders Fatigue	26.8% 19/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	25.7% 19/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	32.4% 24/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	9.5% 4/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
General disorders Influenza like illness	2.8% 2/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
General disorders Injection site bruising	12.7% 9/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.1% 3/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	6.8% 5/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
General disorders Injection site erythema	4.2% 3/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	6.8% 5/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
General disorders Injection site pain	5.6% 4/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
General disorders Oedema peripheral	9.9% 7/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.1% 3/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	8.1% 6/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.8% 2/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
General disorders Pain	4.2% 3/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	6.8% 5/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
General disorders Pyrexia	8.5% 6/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	8.1% 6/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	6.8% 5/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Hepatobiliary disorders Hepatomegaly	2.8% 2/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Bronchitis	22.5% 16/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	9.5% 7/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	10.8% 8/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Cellulitis	5.6% 4/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Gastroenteritis	5.6% 4/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Gastroenteritis viral	1.4% 1/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	6.8% 5/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Influenza	11.3% 8/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	10.8% 8/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	13.5% 10/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.8% 2/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Localised infection	5.6% 4/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Nasopharyngitis	7.0% 5/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	10.8% 8/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	21.6% 16/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Sinusitis	14.1% 10/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	10.8% 8/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	18.9% 14/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.8% 2/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Tooth abscess	8.5% 6/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Upper respiratory tract infection	15.5% 11/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	16.2% 12/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	13.5% 10/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.8% 2/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Infections and infestations Urinary tract infection	14.1% 10/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	9.5% 7/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	18.9% 14/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	7.1% 3/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Injury, poisoning and procedural complications Contusion	5.6% 4/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	8.1% 6/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Injury, poisoning and procedural complications Fall	7.0% 5/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Injury, poisoning and procedural complications Laceration	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Injury, poisoning and procedural complications Ligament sprain	5.6% 4/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.1% 3/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Injury, poisoning and procedural complications Procedural pain	11.3% 8/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	8.1% 6/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	9.5% 7/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Investigations Blood glucose increased	5.6% 4/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Metabolism and nutrition disorders Decreased appetite	4.2% 3/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.1% 3/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	6.8% 5/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Metabolism and nutrition disorders Diabetes mellitus	8.5% 6/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.1% 3/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Metabolism and nutrition disorders Hyperglycaemia	5.6% 4/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.1% 3/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Metabolism and nutrition disorders Vitamin D deficiency	2.8% 2/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Musculoskeletal and connective tissue disorders Arthralgia	22.5% 16/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	14.9% 11/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	24.3% 18/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	7.1% 3/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Musculoskeletal and connective tissue disorders Back pain	15.5% 11/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	8.1% 6/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	27.0% 20/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Musculoskeletal and connective tissue disorders Muscle spasms	7.0% 5/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	12.2% 9/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	6.8% 5/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.8% 2/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	9.9% 7/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	9.5% 7/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	6.8% 5/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Musculoskeletal and connective tissue disorders Myalgia	9.9% 7/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	6.8% 5/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	8.1% 6/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	18.3% 13/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	10.8% 8/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	10.8% 8/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Nervous system disorders Carpal tunnel syndrome	5.6% 4/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Nervous system disorders Dizziness	11.3% 8/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	8.1% 6/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	9.5% 7/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.8% 2/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Nervous system disorders Headache	16.9% 12/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	21.6% 16/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	21.6% 16/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.8% 2/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Psychiatric disorders Anxiety	4.2% 3/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	6.8% 5/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.1% 3/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Psychiatric disorders Depression	5.6% 4/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	6.8% 5/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	9.5% 7/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.8% 2/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Psychiatric disorders Insomnia	2.8% 2/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.1% 3/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Respiratory, thoracic and mediastinal disorders Cough	9.9% 7/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	14.9% 11/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	13.5% 10/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.6% 4/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	1.4% 1/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.6% 4/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	10.8% 8/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	6.8% 5/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Skin and subcutaneous tissue disorders Alopecia	4.2% 3/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Skin and subcutaneous tissue disorders Palmar erythema	2.8% 2/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Skin and subcutaneous tissue disorders Pruritus	9.9% 7/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	5.4% 4/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	9.5% 7/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Skin and subcutaneous tissue disorders Rash	11.3% 8/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	9.5% 7/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	10.8% 8/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Skin and subcutaneous tissue disorders Urticaria	5.6% 4/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.7% 2/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	0.00% 0/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	2.4% 1/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.
Vascular disorders Hypertension	4.2% 3/71 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	6.8% 5/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	9.5% 7/74 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.	4.8% 2/42 • Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 weeks) Safety Analysis Set included all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set included all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.

Additional Information

Gilead Clinical Study Information Center

Gilead Sciences

Phone: 1-833-445-3230 (GILEAD-0)

Email: GileadClinicalTrials@gilead.com

Results disclosure agreements

• Principal investigator is a sponsor employee After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: * The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or * The study has been completed at all study sites for at least 2 years
• Publication restrictions are in place

Restriction type: OTHER