Trial Outcomes & Findings for A Study to Evaluate Chronic Hepatitis C Infection (NCT NCT01716585)

Last Updated: 2021-07-12

Results Overview

The percentage of participants with sustained virologic response (plasma Hepatitis C virus ribonucleic acid \[HCV RNA\] level less than the lower limit of quantitation \[\< LLOQ\]) 12 weeks after the last dose of study drug.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

636 participants

Primary outcome timeframe

12 weeks after the last actual dose of active study drug

Results posted on

2021-07-12

Participant Flow

Participant milestones

Participant milestones
Measure	ABT-450/r/ABT-267 and ABT-333, Plus RBV Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks	Placebo Followed by ABT-450/r/ABT-267 and ABT-333, Plus RBV Double-blind placebo for 12 weeks followed by open-label ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (RBV; dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks
Double-blind Treatment STARTED	477	159
Double-blind Treatment Randomized But Not Treated	4	1
Double-blind Treatment COMPLETED	464	157
Double-blind Treatment NOT COMPLETED	13	2
Open-label Treatment STARTED	0	157
Open-label Treatment COMPLETED	0	150
Open-label Treatment NOT COMPLETED	0	7

Reasons for withdrawal

Reasons for withdrawal
Measure	ABT-450/r/ABT-267 and ABT-333, Plus RBV Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks	Placebo Followed by ABT-450/r/ABT-267 and ABT-333, Plus RBV Double-blind placebo for 12 weeks followed by open-label ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (RBV; dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks
Double-blind Treatment Did Not Receive Study Drug	4	1
Double-blind Treatment Adverse Event	2	1
Double-blind Treatment Withdrawal by Subject	3	0
Double-blind Treatment Lost to Follow-up	2	0
Double-blind Treatment Subject Noncompliant	1	0
Double-blind Treatment Other	1	0
Open-label Treatment Adverse Event	0	2
Open-label Treatment Virologic Failure	0	2
Open-label Treatment Withdrawal by Subject	0	3

Baseline Characteristics

A Study to Evaluate Chronic Hepatitis C Infection

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	ABT-450/r/ABT-267 and ABT-333, Plus RBV n=473 Participants Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks	Placebo n=158 Participants Double-blind placebo for 12 weeks	Total n=631 Participants Total of all reporting groups
Age, Continuous	49.4 years STANDARD_DEVIATION 10.98 • n=5 Participants	51.2 years STANDARD_DEVIATION 10.23 • n=7 Participants	49.9 years STANDARD_DEVIATION 10.82 • n=5 Participants
Sex: Female, Male Female	202 Participants n=5 Participants	85 Participants n=7 Participants	287 Participants n=5 Participants
Sex: Female, Male Male	271 Participants n=5 Participants	73 Participants n=7 Participants	344 Participants n=5 Participants

PRIMARY outcome

Timeframe: 12 weeks after the last actual dose of active study drug

Population: Intent-to-treat (ITT) Population: All randomized participants who received at least 1 dose of blinded study drug.

Outcome measures

Outcome measures
Measure	ABT-450/r/ABT-267 and ABT-333, Plus RBV n=473 Participants Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks	Placebo Double-blind placebo for 12 weeks
Percentage of Participants With Sustained Virologic Response 12 Weeks After Treatment	96.4 percentage of participants	—

SECONDARY outcome

Timeframe: At 12 weeks

Population: Intent-to-treat (ITT) Population: All randomized participants who received at least 1 dose of blinded study drug and had ALT ≥ ULN of the reference range at baseline were included in the analysis.

Normalization is defined as alanine aminotransferase less than or equal to the upper limit of normal (ULN) at final treatment visit for participants with alanine aminotransferase greater than ULN at baseline.

Outcome measures

Outcome measures
Measure	ABT-450/r/ABT-267 and ABT-333, Plus RBV n=363 Participants Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks	Placebo n=114 Participants Double-blind placebo for 12 weeks
Percentage of Participants With Normalization of Alanine Aminotransferase (ALT) at Final Treatment Visit During the Double-Blind Treatment Period	97.0 percentage of participants	15.8 percentage of participants

SECONDARY outcome

Timeframe: 12 weeks after the last actual dose of active study drug

Population: Intent-to-treat (ITT) Population: All randomized participants in the Double-blind ABT-450/r/ABT-267 and ABT-333, plus RBV treatment arm with HCV genotype 1a who received at least 1 dose of blinded study drug.

Outcome measures

Outcome measures
Measure	ABT-450/r/ABT-267 and ABT-333, Plus RBV n=322 Participants Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks	Placebo Double-blind placebo for 12 weeks
Percentage of HCV Genotype 1a-infected Participants With Sustained Virologic Response 12 Weeks After Treatment	95.7 percentage of participants	—

SECONDARY outcome

Timeframe: 12 weeks after the last actual dose of active study drug

Population: Intent-to-treat (ITT) Population: All randomized participants in the Double-blind ABT-450/r/ABT-267 and ABT-333, plus RBV treatment arm with HCV genotype 1b who received at least 1 dose of blinded study drug.

Outcome measures

Outcome measures
Measure	ABT-450/r/ABT-267 and ABT-333, Plus RBV n=151 Participants Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks	Placebo Double-blind placebo for 12 weeks
Percentage of HCV Genotype 1b-infected Participants With Sustained Virologic Response 12 Weeks After Treatment	98.0 percentage of participants Interval 95.8 to 100.0	—

SECONDARY outcome

Timeframe: 12 weeks after the last actual dose of active study drug

Population: Intent-to-treat (ITT) Population: All randomized participants who received at least 1 dose of blinded study drug in the Double-blind ABT-450/r/ABT-267 and ABT-333, plus RBV treatment arm.

Virologic failure was defined as rebound (hepatitis C virus ribonucleic acid \[HCV RNA\] ≥ lower limit of quantification \[LLOQ\] after HCV RNA \< LLOQ or increase in HCV RNA of at least 1 log10 IU/mL) or failure to suppress (all on-treatment values of plasma HCV RNA ≥ LLOQ with at least 36 days of treatment) during treatment.

Outcome measures

Outcome measures
Measure	ABT-450/r/ABT-267 and ABT-333, Plus RBV n=473 Participants Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks	Placebo Double-blind placebo for 12 weeks
Percentage of Participants With On-treatment Virologic Failure During the Double-blind Treatment Period: ABT-450/r/ABT-267 and ABT-333, Plus RBV Arm	0.2 percentage of participants Interval 0.0 to 0.6	—

SECONDARY outcome

Timeframe: Within 12 weeks post-treatment

Population: Intent-to-treat (ITT) Population: All randomized participants who received at least 1 dose of blinded study drug with HCV RNA \< LLOQ at the final treatment visit who completed treatment in the Double-blind ABT-450/r/ABT-267 and ABT-333, plus RBV treatment arm.

Participants were considered to have virologic relapse after treatment if they had confirmed quantifiable plasma hepatitis C virus ribonucleic acid (HCV RNA) greater than or equal to the lower limit of quantification (≥ LLOQ) between the end of treatment and 12 weeks after the last dose of study drug among participants who completed treatment with HCV RNA \< LLOQ at the end of treatment.

Outcome measures

Outcome measures
Measure	ABT-450/r/ABT-267 and ABT-333, Plus RBV n=463 Participants Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks	Placebo Double-blind placebo for 12 weeks
Percentage of Participants With Virologic Relapse After Treatment: ABT-450/r/ABT-267 and ABT-333, Plus RBV Arm	1.5 percentage of participants Interval 0.4 to 2.6	—

Adverse Events

Double Blind ABT-450/r/ABT-267 and ABT-333, Plus RBV

Serious events: 10 serious events

Other events: 391 other events

Deaths: 0 deaths

Double Blind Placebo

Serious events: 0 serious events

Other events: 108 other events

Deaths: 0 deaths

Open Label ABT-450/r/ABT-267 and ABT-333, Plus RBV

Serious events: 2 serious events

Other events: 117 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Global Medical Information

AbbVie (prior sponsor, Abbott)

Phone: 800-633-9110

Results disclosure agreements

Principal investigator is a sponsor employee AbbVie requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. AbbVie requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if AbbVie needs to secure patent or proprietary protection.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Double Blind ABT-450/r/ABT-267 and ABT-333, Plus RBV n=473 participants at risk Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks	Double Blind Placebo n=158 participants at risk Double-blind placebo for 12 weeks	Open Label ABT-450/r/ABT-267 and ABT-333, Plus RBV n=157 participants at risk Open-label ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (RBV; dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks
Blood and lymphatic system disorders ANAEMIA	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Cardiac disorders SINUS TACHYCARDIA	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Cardiac disorders VENTRICULAR EXTRASYSTOLES	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Gastrointestinal disorders ABDOMINAL PAIN	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Gastrointestinal disorders DIARRHOEA	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Gastrointestinal disorders NAUSEA	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Gastrointestinal disorders VOMITING	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
General disorders CHILLS	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
General disorders NON-CARDIAC CHEST PAIN	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Hepatobiliary disorders BILIARY COLIC	0.00% 0/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.64% 1/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Hepatobiliary disorders CHOLECYSTITIS	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Infections and infestations APPENDICITIS	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Infections and infestations LOBAR PNEUMONIA	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Infections and infestations POSTOPERATIVE WOUND INFECTION	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Infections and infestations SUBCUTANEOUS ABSCESS	0.00% 0/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.64% 1/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Injury, poisoning and procedural complications LUMBAR VERTEBRAL FRACTURE	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Injury, poisoning and procedural complications OVERDOSE	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) NON-SMALL CELL LUNG CANCER	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Nervous system disorders ENCEPHALOPATHY	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Respiratory, thoracic and mediastinal disorders ACUTE RESPIRATORY FAILURE	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Respiratory, thoracic and mediastinal disorders HYPOXIA	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Respiratory, thoracic and mediastinal disorders MEDIASTINAL MASS	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Vascular disorders AORTIC STENOSIS	0.21% 1/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).

Other adverse events
Measure	Double Blind ABT-450/r/ABT-267 and ABT-333, Plus RBV n=473 participants at risk Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks	Double Blind Placebo n=158 participants at risk Double-blind placebo for 12 weeks	Open Label ABT-450/r/ABT-267 and ABT-333, Plus RBV n=157 participants at risk Open-label ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (RBV; dosed 1,000 or 1,200 mg daily divided twice a day) for 12 weeks
Blood and lymphatic system disorders ANAEMIA	5.1% 24/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	8.9% 14/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
General disorders ASTHENIA	12.5% 59/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	3.8% 6/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	6.4% 10/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Gastrointestinal disorders ABDOMINAL PAIN UPPER	6.1% 29/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	3.2% 5/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	5.1% 8/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Gastrointestinal disorders DIARRHOEA	13.7% 65/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	7.0% 11/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	12.1% 19/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Gastrointestinal disorders DRY MOUTH	4.0% 19/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	5.7% 9/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	0.00% 0/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Gastrointestinal disorders DYSPEPSIA	5.5% 26/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	4.4% 7/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	3.8% 6/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Gastrointestinal disorders NAUSEA	23.7% 112/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	13.9% 22/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	15.3% 24/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Gastrointestinal disorders VOMITING	4.9% 23/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	3.8% 6/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	5.7% 9/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
General disorders FATIGUE	34.7% 164/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	28.5% 45/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	22.3% 35/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
General disorders IRRITABILITY	5.5% 26/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	2.5% 4/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	3.8% 6/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Infections and infestations NASOPHARYNGITIS	7.0% 33/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	6.3% 10/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	7.0% 11/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	4.7% 22/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	5.1% 8/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	6.4% 10/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Metabolism and nutrition disorders DECREASED APPETITE	7.8% 37/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	3.2% 5/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	7.0% 11/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Musculoskeletal and connective tissue disorders ARTHRALGIA	4.9% 23/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	5.7% 9/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	5.7% 9/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Musculoskeletal and connective tissue disorders MYALGIA	4.4% 21/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	5.1% 8/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	3.8% 6/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Musculoskeletal and connective tissue disorders BACK PAIN	4.7% 22/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	4.4% 7/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	5.7% 9/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Nervous system disorders DIZZINESS	8.0% 38/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	3.8% 6/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	3.2% 5/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Nervous system disorders HEADACHE	33.0% 156/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	26.6% 42/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	16.6% 26/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Psychiatric disorders ANXIETY	4.7% 22/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	3.2% 5/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	5.1% 8/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Psychiatric disorders INSOMNIA	14.2% 67/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	7.6% 12/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	13.4% 21/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Psychiatric disorders SLEEP DISORDER	5.1% 24/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	2.5% 4/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	2.5% 4/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Respiratory, thoracic and mediastinal disorders COUGH	7.2% 34/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	5.1% 8/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	4.5% 7/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Respiratory, thoracic and mediastinal disorders DYSPNOEA	8.0% 38/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	2.5% 4/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	7.6% 12/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Respiratory, thoracic and mediastinal disorders DYSPNOEA EXERTIONAL	5.1% 24/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	1.9% 3/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	5.1% 8/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Skin and subcutaneous tissue disorders DRY SKIN	5.7% 27/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	1.3% 2/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	4.5% 7/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Skin and subcutaneous tissue disorders PRURITUS	16.9% 80/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	4.4% 7/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	10.2% 16/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).
Skin and subcutaneous tissue disorders RASH	10.8% 51/473 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	5.7% 9/158 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).	5.1% 8/157 • Adverse events (AEs) were collected from the start of active study drug administration (double-blind [DB]/open-label, OL active) to 30 days after the last dose of active study drug 16 weeks. DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AES collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total up to 72 weeks).