Manns 2014a

Methods	A phase III, randomised, double‐blind, placebo‐controlled, parallel‐design trial (QUEST‐2)(NCT01290679)
Participants	391 participants Location: 14 countries in Europe, North America, and South America Inclusion criteria: age ≥ 18 years. Chronic hepatitis C infection. HCV genotype 1. HCV RNA level at screening > 100,000 IU/mL. Treatment‐naive. An ultrasound performed within 6 months of enrolment showing no signs of HCC in participants with cirrhosis. Exclusion criteria: hepatic decompensation. Any non‐HCV‐related liver disease. HIV or HBV co‐infection. Non‐genotype 1 HCV infection. Significant laboratory abnormalities. Any other active disease. Male or female participants who had, or were planning to conceive. Simeprevir group: 257 participants Sex: 140 men, 117 women Median age: 46 years (range 18‐73) Race: 237 white (92%), 16 black or African American (6%), 2 Asian (< 1%), and 2 other (< 1%) HCV genotype 1a: 105 (41%), HCV genotype 1b: 150 (58%), other HCV genotype: 2 (< 1%) IL28B genotype CC: 75 (29%), IL28B genotype CT: 142 (55%), IL28B genotype TT: 40 (16%) METAVIR score F0‐F1: 130 (52%), METAVIR score F2: 65 (26%), METAVIR score F3: 36 (15%), METAVIR score F4: 17 (7%) HCV RNA > 800,000 IU/mL, n(%): 199(77). Placebo group: 134 participants Sex: 77 men, 57 women Median age: 47 years (range 18‐73) Race: 123 white (92%), 10 black or African‐American (10%), 1 Asian (< 1%), and 0 other HCV genotype 1a: 54 (41%), HCV genotype 1b: 77 (58%), other HCV genotype: 2 (2%) IL28B genotype CC: 42 (31%), IL28B genotype CT: 71 (53%), IL28B genotype TT: 21 (16%) METAVIR score, n(%): METAVIR score F0‐F1: 60 (45%), METAVIR score F2: 42 (31%), METAVIR score F3: 17 (13%), METAVIR score F4: 15 (11%) HCV RNA > 800,000 IU/mL, n(%): 98(73).
Interventions	Experimental group: oral simeprevir 150 mg once daily for 12 weeks. Control group: oral placebo 150 mg once daily for 12 weeks. Co‐interventions: Experimental group: peg‐IFN α‐2a 180 μg subcutaneously once weekly or peg‐IFN α‐2b 1.5 μg/kg body weight subcutaneously once weekly and oral weight‐based RBV 1000 mg to 1200 mg in 2 divided daily doses (1000 mg if body weight < 75 kg; 1200 mg if body weight ≥ 75 kg) for 24‐48 weeks Control group: peg‐IFN α‐2a 180 μg subcutaneously once weekly or peg‐IFN α‐2b 1.5 μg/kg body weight subcutaneously once weekly and oral weight‐based RBV 1000 to 1200 mg in 2 divided daily doses (1000 mg if body weight < 75 kg; 1200 mg if body weight ≥75 kg) for 48 weeks.
Outcomes	Primary outcome: proportion of participants achieving SVR12 (HCV RNA < 25 IU/mL undetectable at end of treatment and < 25 IU/mL detectable or undetectable 12 weeks after the planned end of treatment). Secondary outcomes: proportion of participants meeting criteria for response‐guided therapy to complete treatment at week 24. RVA (HCV RNA < 25 IU/mL undetectable at week 4). Activity, safety, and tolerability of simeprevir in the 2 subpopulations of participants who were given peg‐IFN α‐2a or 2b. On‐treatment failure (detectable HCV RNA at end of treatment). Incidence of viral relapse (HCV RNA ≥ 25 IU/mL during follow‐up or at the time of SVR assessments in participants with undetectable levels at end of treatment). Incidence of AEs. Incidence of laboratory abnormalities. Quality‐of‐life measures. SVR at 24 weeks after the planned end of treatment. Assessment of depression severity. Assessment of health status. Assessment of polymorphisms (HCV NS3 protease domain) at baseline and their correlation with efficacy of simeprevir plus peg‐IFN and RBV.
Notes	We emailed Manns and colleagues on 26 April 2016 for additional information blinding of outcome assessors but reply not received yet.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"A computer‐generated randomisation schedule that was prepared by or under the supervision of the sponsor before the study was used"
Allocation concealment (selection bias)	Low risk	Concealment of allocation was obtained by using an interactive web‐based or voice‐response system
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Authors stated that "patients, study personnel, and the sponsor were masked to the treatment group assignment", the blinding method was not adequately described. A matched placebo was used
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	It was not mentioned if the outcome assessors were blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Number and reasons for discontinuation were clearly reported on
Selective reporting (reporting bias)	Low risk	Protocol was available. All pre‐specified study outcomes were reported on
Vested‐interest bias	Unclear risk	"The sponsor (Janssen Infectious Diseases‐Diagnostics) was directly involved in trial design, data analyses and interpretation, and writing and reviewing the manuscript."
Other bias	Low risk	The trial seems to be free of other potential sources of bias