Trial Outcomes & Findings for Safety and Efficacy of Selonsertib in Adults With Nonalcoholic Steatohepatitis (NASH) and Bridging (F3) Fibrosis (NCT NCT03053050)

Last Updated: 2020-06-29

Results Overview

Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Worsening of NASH was defined as ≥ 1 point increase from baseline in hepatocellular ballooning or lobular inflammation according to the Non-Alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) criteria. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

808 participants

Primary outcome timeframe

Week 48

Results posted on

2020-06-29

Participant Flow

Participants were enrolled at study sites in North America, Asia, Europe, Australia, South America, Puerto Rico, and New Zealand. The first participant was screened on 13 February 2017. The last study visit occurred on 19 June 2019.

2250 participants were screened.

Participant milestones

Participant milestones
Measure	SEL 18 mg Randomized Phase: Selonsertib (SEL) 18 mg tablet orally once daily + placebo to match SEL 6 mg tablet orally once daily for 240 weeks.	SEL 6 mg Randomized Phase: SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks.	Placebo Randomized Phase: Placebo-to-match SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks.	Open-Label SEL 18 mg Open-Label (OL) Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.
Randomized Phase STARTED	324	323	161	0
Randomized Phase COMPLETED	0	0	0	0
Randomized Phase NOT COMPLETED	324	323	161	0
Open-label Phase STARTED	0	0	0	99
Open-label Phase COMPLETED	0	0	0	0
Open-label Phase NOT COMPLETED	0	0	0	99

Reasons for withdrawal

Reasons for withdrawal
Measure	SEL 18 mg Randomized Phase: Selonsertib (SEL) 18 mg tablet orally once daily + placebo to match SEL 6 mg tablet orally once daily for 240 weeks.	SEL 6 mg Randomized Phase: SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks.	Placebo Randomized Phase: Placebo-to-match SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks.	Open-Label SEL 18 mg Open-Label (OL) Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.
Randomized Phase Study Terminated by Sponsor	259	260	128	0
Randomized Phase Withdrew Consent	16	8	9	0
Randomized Phase Investigator's Discretion	6	6	3	0
Randomized Phase Lost to Follow-up	5	1	1	0
Randomized Phase Adverse Event	0	1	0	0
Randomized Phase Randomized but Never Treated	2	2	2	0
Randomized Phase Entered the Open-Label Phase	36	45	18	0
Open-label Phase Study Terminated by Sponsor	0	0	0	89
Open-label Phase Withdrew Consent	0	0	0	6
Open-label Phase Investigator's Discretion	0	0	0	4

Baseline Characteristics

Safety and Efficacy of Selonsertib in Adults With Nonalcoholic Steatohepatitis (NASH) and Bridging (F3) Fibrosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	SEL 18 mg n=322 Participants Randomized Phase: Selonsertib (SEL) 18 mg tablet orally once daily + placebo to match SEL 6 mg tablet orally once daily for 240 weeks Open-Label (OL) Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.	SEL 6 mg n=321 Participants Randomized Phase: SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks OL Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.	Placebo n=159 Participants Randomized Phase: Placebo to match SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks OL Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.	Total n=802 Participants Total of all reporting groups
Age, Continuous	57 years STANDARD_DEVIATION 9.1 • n=5 Participants	57 years STANDARD_DEVIATION 9.2 • n=7 Participants	57 years STANDARD_DEVIATION 9.0 • n=5 Participants	57 years STANDARD_DEVIATION 9.1 • n=4 Participants
Sex: Female, Male Female	181 Participants n=5 Participants	196 Participants n=7 Participants	76 Participants n=5 Participants	453 Participants n=4 Participants
Sex: Female, Male Male	141 Participants n=5 Participants	125 Participants n=7 Participants	83 Participants n=5 Participants	349 Participants n=4 Participants
Race/Ethnicity, Customized Race · American Indian or Alaska Native	5 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	8 Participants n=4 Participants
Race/Ethnicity, Customized Race · Asian	88 Participants n=5 Participants	84 Participants n=7 Participants	41 Participants n=5 Participants	213 Participants n=4 Participants
Race/Ethnicity, Customized Race · Black	8 Participants n=5 Participants	5 Participants n=7 Participants	2 Participants n=5 Participants	15 Participants n=4 Participants
Race/Ethnicity, Customized Race · White	219 Participants n=5 Participants	227 Participants n=7 Participants	113 Participants n=5 Participants	559 Participants n=4 Participants
Race/Ethnicity, Customized Race · Other	2 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	6 Participants n=4 Participants
Race/Ethnicity, Customized Race · Not Permitted	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Ethnicity · Not Hispanic or Latino	269 Participants n=5 Participants	269 Participants n=7 Participants	137 Participants n=5 Participants	675 Participants n=4 Participants
Race/Ethnicity, Customized Ethnicity · Hispanic or Latino	52 Participants n=5 Participants	48 Participants n=7 Participants	22 Participants n=5 Participants	122 Participants n=4 Participants
Race/Ethnicity, Customized Ethnicity · Not Permitted	1 Participants n=5 Participants	4 Participants n=7 Participants	0 Participants n=5 Participants	5 Participants n=4 Participants
Region of Enrollment United States	161 Participants n=5 Participants	172 Participants n=7 Participants	80 Participants n=5 Participants	413 Participants n=4 Participants
Region of Enrollment Japan	38 Participants n=5 Participants	23 Participants n=7 Participants	19 Participants n=5 Participants	80 Participants n=4 Participants
Region of Enrollment Canada	16 Participants n=5 Participants	14 Participants n=7 Participants	8 Participants n=5 Participants	38 Participants n=4 Participants
Region of Enrollment France	14 Participants n=5 Participants	10 Participants n=7 Participants	5 Participants n=5 Participants	29 Participants n=4 Participants
Region of Enrollment South Korea	8 Participants n=5 Participants	13 Participants n=7 Participants	7 Participants n=5 Participants	28 Participants n=4 Participants
Region of Enrollment Australia	9 Participants n=5 Participants	12 Participants n=7 Participants	3 Participants n=5 Participants	24 Participants n=4 Participants
Region of Enrollment Hong Kong	10 Participants n=5 Participants	8 Participants n=7 Participants	6 Participants n=5 Participants	24 Participants n=4 Participants
Region of Enrollment Spain	9 Participants n=5 Participants	10 Participants n=7 Participants	4 Participants n=5 Participants	23 Participants n=4 Participants
Region of Enrollment Taiwan	7 Participants n=5 Participants	14 Participants n=7 Participants	0 Participants n=5 Participants	21 Participants n=4 Participants
Region of Enrollment United Kingdom	8 Participants n=5 Participants	5 Participants n=7 Participants	7 Participants n=5 Participants	20 Participants n=4 Participants
Region of Enrollment India	7 Participants n=5 Participants	4 Participants n=7 Participants	4 Participants n=5 Participants	15 Participants n=4 Participants
Region of Enrollment Germany	4 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	11 Participants n=4 Participants
Region of Enrollment Singapore	4 Participants n=5 Participants	5 Participants n=7 Participants	2 Participants n=5 Participants	11 Participants n=4 Participants
Region of Enrollment Brazil	3 Participants n=5 Participants	4 Participants n=7 Participants	2 Participants n=5 Participants	9 Participants n=4 Participants
Region of Enrollment Israel	2 Participants n=5 Participants	4 Participants n=7 Participants	3 Participants n=5 Participants	9 Participants n=4 Participants
Region of Enrollment Belgium	3 Participants n=5 Participants	3 Participants n=7 Participants	2 Participants n=5 Participants	8 Participants n=4 Participants
Region of Enrollment Mexico	5 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	8 Participants n=4 Participants
Region of Enrollment Italy	2 Participants n=5 Participants	4 Participants n=7 Participants	0 Participants n=5 Participants	6 Participants n=4 Participants
Region of Enrollment Argentina	3 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	5 Participants n=4 Participants
Region of Enrollment Austria	2 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	4 Participants n=4 Participants
Region of Enrollment Poland	2 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	4 Participants n=4 Participants
Region of Enrollment Puerto Rico	2 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants
Region of Enrollment Switzerland	1 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	3 Participants n=4 Participants
Region of Enrollment Malaysia	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Region of Enrollment Portugal	0 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Region of Enrollment Netherlands	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Region of Enrollment New Zealand	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants

PRIMARY outcome

Timeframe: Week 48

Population: The Full Analysis Set included all participants who were randomized into the study and received at least 1 dose of study drug.

Outcome measures

Outcome measures
Measure	SEL 18 mg n=322 Participants Randomized Phase: Selonsertib (SEL) 18 mg tablet orally once daily + placebo to match SEL 6 mg tablet orally once daily for 240 weeks Open-Label (OL) Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.	SEL 6 mg n=321 Participants Randomized Phase: SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks OL Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.	Placebo n=159 Participants Randomized Phase: Placebo to match SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks OL Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.
Percentage of Participants Who Achieved a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH at Week 48	9.6 percentage of participants Interval 6.6 to 13.4	12.1 percentage of participants Interval 8.8 to 16.2	13.2 percentage of participants Interval 8.4 to 19.5

PRIMARY outcome

Timeframe: Week 240

Population: No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.

EFS was assessed by the time to the first clinical event, including progression to cirrhosis on liver biopsy, liver decompensation events, liver transplantation, and all-cause mortality.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 48

Population: Participants in the Full Analysis Set were analyzed.

Progression to cirrhosis was defined as a change in NASH CRN fibrosis stage from \< 4 at baseline to 4 at Week 48.

Outcome measures

Outcome measures
Measure	SEL 18 mg n=322 Participants Randomized Phase: Selonsertib (SEL) 18 mg tablet orally once daily + placebo to match SEL 6 mg tablet orally once daily for 240 weeks Open-Label (OL) Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.	SEL 6 mg n=321 Participants Randomized Phase: SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks OL Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.	Placebo n=159 Participants Randomized Phase: Placebo to match SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks OL Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.
Percentage of Participants Who Had Progression to Cirrhosis at Week 48	13.0 percentage of participants Interval 9.6 to 17.2	15.6 percentage of participants Interval 11.8 to 20.0	15.7 percentage of participants Interval 10.4 to 22.3

SECONDARY outcome

Timeframe: Week 240

Population: No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.

Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Worsening of NASH was defined as ≥ 1 point increase from baseline in hepatocellular ballooning or lobular inflammation according to the NAS criteria. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 48

Population: Participants in the Full Analysis Set were analyzed.

Outcome measures

Outcome measures
Measure	SEL 18 mg n=322 Participants Randomized Phase: Selonsertib (SEL) 18 mg tablet orally once daily + placebo to match SEL 6 mg tablet orally once daily for 240 weeks Open-Label (OL) Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.	SEL 6 mg n=321 Participants Randomized Phase: SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks OL Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.	Placebo n=159 Participants Randomized Phase: Placebo to match SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks OL Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.
Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 48	12.7 percentage of participants Interval 9.3 to 16.9	13.7 percentage of participants Interval 10.1 to 18.0	16.4 percentage of participants Interval 11.0 to 23.0

SECONDARY outcome

Timeframe: Week 240

Population: No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 48

Population: Participants in the Full Analysis Set with available data were analyzed.

NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning of 1 from a value ≥ 1 at baseline; both criteria were necessary conditions. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1. Worsening of Fibrosis was defined by an increase in Fibrosis stage from 3 to 4 as defined by NASH CRN.

Outcome measures

Outcome measures
Measure	SEL 18 mg n=322 Participants Randomized Phase: Selonsertib (SEL) 18 mg tablet orally once daily + placebo to match SEL 6 mg tablet orally once daily for 240 weeks Open-Label (OL) Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.	SEL 6 mg n=321 Participants Randomized Phase: SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks OL Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.	Placebo n=158 Participants Randomized Phase: Placebo to match SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks OL Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.
Percentage of Participants Who Had NASH Resolution Without Worsening of Fibrosis at Week 48	5.0 percentage of participants Interval 2.9 to 7.9	4.4 percentage of participants Interval 2.4 to 7.2	8.9 percentage of participants Interval 4.9 to 14.4

SECONDARY outcome

Timeframe: Week 240

Population: No data was analyzed as the study was terminated and no participants reached the Week 240 timepoint.

Outcome measures

Outcome data not reported

Adverse Events

SEL 18 mg

Serious events: 47 serious events

Other events: 248 other events

Deaths: 0 deaths

SEL 6 mg

Serious events: 36 serious events

Other events: 254 other events

Deaths: 0 deaths

Placebo

Serious events: 17 serious events

Other events: 130 other events

Deaths: 0 deaths

Open-Label SEL 18 mg

Serious events: 6 serious events

Other events: 48 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Gilead Clinical Study Information Center

Gilead Sciences

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

Email: [email protected]

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

Measure	SEL 18 mg n=322 participants at risk Randomized Phase: Selonsertib (SEL) 18 mg tablet orally once daily + placebo to match SEL 6 mg tablet orally once daily for 240 weeks.	SEL 6 mg n=321 participants at risk Randomized Phase: SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks.	Placebo n=159 participants at risk Randomized Phase: Placebo to match SEL 6 mg tablet orally once daily + placebo to match SEL 18 mg tablet orally once daily for 240 weeks.	Open-Label SEL 18 mg n=99 participants at risk Open-Label (OL) Phase: Participants who experienced a hepatic clinical event or have biopsy confirmed progression to cirrhosis during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks inclusive of the randomized phase.
Gastrointestinal disorders Abdominal distension	4.0% 13/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	3.7% 12/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	5.0% 8/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	2.0% 2/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal pain	6.8% 22/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	8.4% 27/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	9.4% 15/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	3.0% 3/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Gastrointestinal disorders Abdominal pain upper	10.2% 33/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	8.1% 26/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	10.1% 16/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	5.1% 5/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Gastrointestinal disorders Constipation	12.4% 40/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	13.4% 43/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	11.9% 19/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	4.0% 4/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Gastrointestinal disorders Diarrhoea	16.1% 52/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	14.6% 47/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	18.9% 30/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	8.1% 8/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Gastrointestinal disorders Nausea	9.9% 32/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	12.1% 39/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	8.8% 14/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	6.1% 6/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Gastrointestinal disorders Vomiting	5.9% 19/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	5.6% 18/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	5.0% 8/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	1.0% 1/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
General disorders Fatigue	10.9% 35/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	10.3% 33/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	7.5% 12/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	3.0% 3/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
General disorders Oedema peripheral	5.6% 18/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	2.8% 9/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	2.5% 4/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	3.0% 3/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Hepatobiliary disorders Hepatic cirrhosis	13.0% 42/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	15.6% 50/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	15.7% 25/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	0.00% 0/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Infections and infestations Bronchitis	7.1% 23/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	6.5% 21/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	3.8% 6/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	1.0% 1/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Infections and infestations Influenza	5.9% 19/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	6.2% 20/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	8.8% 14/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	4.0% 4/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Infections and infestations Nasopharyngitis	14.3% 46/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	12.5% 40/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	13.2% 21/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	0.00% 0/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Infections and infestations Sinusitis	6.5% 21/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	6.5% 21/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	7.5% 12/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	5.1% 5/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Infections and infestations Upper respiratory tract infection	12.7% 41/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	14.3% 46/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	13.2% 21/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	6.1% 6/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Infections and infestations Urinary tract infection	4.3% 14/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	8.4% 27/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	8.2% 13/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	3.0% 3/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Contusion	3.1% 10/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	1.6% 5/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	5.0% 8/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	0.00% 0/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	10.2% 33/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	9.3% 30/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	11.3% 18/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	3.0% 3/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Back pain	10.2% 33/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	8.4% 27/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	6.9% 11/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	3.0% 3/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Muscle spasms	5.0% 16/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	5.3% 17/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	4.4% 7/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	2.0% 2/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	4.3% 14/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	5.6% 18/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	5.0% 8/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	2.0% 2/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	6.2% 20/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	4.7% 15/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	6.9% 11/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	5.1% 5/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Nervous system disorders Dizziness	5.0% 16/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	9.3% 30/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	1.3% 2/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	2.0% 2/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Nervous system disorders Headache	11.2% 36/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	11.8% 38/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	11.3% 18/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	5.1% 5/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Cough	8.7% 28/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	5.6% 18/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	8.8% 14/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	3.0% 3/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Pruritus	7.1% 23/322 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	6.2% 20/321 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	6.9% 11/159 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.	3.0% 3/99 • First dose date up to last dose (maximum: 111.4 weeks) plus 30 days The Safety Analysis Set included all participants who received at least 1 dose of study drug.