Fundamental 2014a1

Methods	Prospective, double‐blind, multinational, randomised, placebo controlled phase II trial (CDEB025A2210; ClinicalTrials.gov NCT01183169) conducted between 30 August 2010 and 9 May 2013
Participants	459 eligible participants Sex: 278 men, 181 women Mean age: 50.6 years Countries: Europe, North America, Asia‐Pacific region Inclusion criteria: 9‐69 years with chronic hepatitis C genotype 1 infection and HCV RNA > = 1000 IU/mL and had failed to respond to or had relapse after prior P/R therapy; all participants had to have a liver biopsy within 3 years or transient elastography within 6 months of enrolment. Participants with compensated cirrhosis were eligible. Exclusion criteria: nongenotype 1 infection, presence or history of hepatic decompensation and haematological abnormalities, and recent treatment with any anti‐HCV drug, concomitant treatment with known substrates or inhibitors of cytochrome P450 3A, P‐gp, OATPs, MRP2 or BSEP was not permitted within 2 weeks of study entry. 459 participants randomised, 77% white, 25% compensated cirrhosis/transition to cirrhosis, 57% prior P/R‐non responders, 79% genotype IL28B 457 treated.
Interventions	Participants were randomised (1:1:1:1) Experimental group 1: alisporivir 600 mg once a day for 48 weeks. Experimental group 2: alisporivir 800 mg once a day for 48 weeks. Experimental group 3: alisporivir 400 mg twice a day for 48 weeks. Control group: placebo for 48 weeks. Co‐intervention: peg‐IFN‐α‐2a 180 lg/week plus RBV 1000 or 1200 mg/day based on body weight for 48 weeks.
Outcomes	eEVR (weeks 12 on treatment), SVR12, SVR24, all‐cause mortality, AEs.
Notes	Following a partial clinical hold imposed by FDA, alisporivir/placebo was discontinued in all participants; at that time, all active participants had received at least 31 weeks of triple therapy out of a total of 48 weeks. Analysis group 1 vs control. In the placebo arm, 57% of participants were switched in a blinded manner to alisporivir plus P/R after Week 16 due to failure to achieve the efficacy criterion (HCV RNA < limit of quantification) at Week 12. We could therefore not use the results from this trial.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	There was only missing data for 2 participants
Selective reporting (reporting bias)	High risk	The secondary outcomes were changed from the original secondary outcomes
Vested‐interest bias	High risk	The study was funded by Novartis
Other bias	Low risk	The trial appeared to be free of other components that could put it at risk of bias