Forestier 2011a1

Methods	Randomised clinical trial
Participants	50 participants Sex: 40 men, 10 women Mean age: 48 years Inclusion criteria: men and women between 18 and 65 years of age with a history of chronic HCV genotype 1 infection and detectable plasma HCV RNA (> 1 104 IU/mL) at the study screening visit. Additional enrolment criteria included a BMI between 18 and 30, minimum body weight of 45 kg, and a liver biopsy or non‐invasive procedure (liver scan) within the previous 2 years showing no evidence of cirrhosis. In addition, participants in Part A were required to have no history of prior therapy with IFN‐based regimens; participants in Part B were required to have had failed previous IFN‐alfa and RBV‐based therapy as defined above. Exclusion criteria: participants were excluded from the study if they met any of the following criteria: decompensated liver disease; impaired liver function; clinical or histopathologic evidence of cirrhosis; history of non‐hepatitis C chronic liver disease; positive screening for hepatitis B surface antigen or HIV infection; history of active malignancy within the preceding 5 years; history of clinically significant cardiovascular or cerebrovascular disease; treatment with peg‐IFN‐α and RBV (Part A) or treatment with peg‐IFN‐α and RBV within 3 months before screening (Part B); treatment with growth factors within 3 months before screening; history of drug abuse within the previous year; regular consumption of more than 1 glass of alcohol per day for women or 2 glasses of alcohol per day for men; participation in an investigational drug study within 3 months of screening or any prior participation in a study of an experimental HCV therapy; and selected laboratory abnormalities, including serum ALT > 5 times the upper limit of the reference range, creatinine clearance < 30 mL/min, or total bilirubin P26 lmol/L. Pregnant or lactating women, women of childbearing potential, and male partners of pregnant or lactating women were excluded from enrolment. Additionally, anyone who, in the opinion of the investigator, was not a suitable candidate for enrolment or was unlikely to comply with the requirements of the study was also excluded from enrolment.
Interventions	Experimental group: Group 1: danoprevir was administered orally in soft gelatin capsule form in total daily doses of 200, 300, 400 and 600 mg in treatment‐naive participants. Group 2: a single dose level of danoprevir (600 mg daily) was explored in a cohort of non‐responders (NR) Control intervention: placebo
Outcomes	Safety assessments, pharmacokinetics, viral kinetics
Notes	4 cohorts of 10 participants each were randomised (8:2) to treatment with danoprevir or placebo equivalent. In Part A, treatment‐naive (Cohorts 1–5) were permitted but not required to begin standard of care (SOC) treatment with peg‐IFN‐α/RBV anytime after 24 h following the last dose of the study drug. 3 treatment‐naive participants in the 200 mg every‐12‐h cohort who were mis‐dosed at a single study site were excluded from the efficacy analysis. We sent an email was sent to Forestier and colleagues on 20 April 2016 for additional information but reply not received yet.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised using an interactive voice‐response system that assigned a participant identification number that corresponded to treatment assignment (danoprevir or placebo) according to the randomisation code.
Allocation concealment (selection bias)	Low risk	Participants were randomised using an interactive voice‐response system that assigned a participant identification number that corresponded to treatment assignment (danoprevir or placebo) according to the randomisation code.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	The study was described as double‐blinded, but it was unclear how the blinding was maintained
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	The study was described as double‐blinded but it was unclear how the blinding was maintained and who performed the outcome assessment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	3 participants excluded. Clearly stated reason
Selective reporting (reporting bias)	Unclear risk	No protocol was found
Vested‐interest bias	High risk	The study was sponsored by InterMune, Inc. and Roche
Other bias	Low risk	The trial appeared to be free of other components that could put it at risk of bias