Forns 2014

Methods	Randomised, multicenter, double‐blind, parallel‐group, placebo‐controlled, phase III clinical trial (PROMISE)(NCT01281839)
Participants	393 participants (260 in experimental group and 133 in control group) Sex: 258 men, 135 women Mean age: 52 years (range 20‐70 years) Location: Europe, North America, Australia, and New Zealand. Inclusion criteria: age ≥ 18 years. Confirmed chronic genotype 1 HCV infection. Screening plasma HCV RNA levels > 10,000 IU/mL. Treatment‐experienced participants who had relapsed after 24 weeks or more of IFN‐based therapy (undetectable HCV RNA at end of treatment or within 2 months after end of treatment, with documented relapse within 1 year after therapy). A liver biopsy specimen obtained within 3 years of screening showing histology consistent with chronic HCV infection (participants with bridging fibrosis (F3) or cirrhosis (F4) were eligible if they had an ultrasound performed within 6 months before screening (or between the screening and baseline visit) with no findings suspicious for HCC) Exclusion criteria: hepatic decompensation. Non–HCV‐related liver disease. HBV, HIV, or non‐genotype 1 HCV co‐infection. Defined laboratory abnormalities: platelets < 90,000/mm3, white blood cell count < 3000/μL, haemoglobin level < 12 g/dL for women and < 13 g/dL for men, creatinine level > 1.5 mg/dL, ALT and/or AST level > 10 times the upper limit and normal, total serum bilirubin level 1.5 times or more the ULN, and α‐fetoprotein level > 50 ng/mL in participants with cirrhosis. Any other active disease. Pregnant women or planning pregnancy were excluded
Interventions	Experimental group: oral simeprevir 150 mg once daily for 12 weeks Control group: placebo for 12 weeks Co‐interventions: Experimental group: peg‐IFN α‐2a 180 μg subcutaneously once weekly for 24 weeks (if HCV RNA < 25 IU/mL at week 4 and undetectable at week 12) or 48 weeks if not meeting these criteria. Oral weight‐based RBV 1000 to 1200 mg daily for 24 weeks (if HCV RNA < 25 IU/mL at week 4 and undetectable at week 12) or 48 weeks if not meeting these criteria Control group: peg‐IFN α‐2a 180 μg subcutaneously once weekly for 48 weeks. Oral weight‐based RBV 1000 to 1200 mg daily for 48 weeks
Outcomes	Primary outcome: proportion of participants achieving SVR 12 weeks after planned end of treatment (SVR12) Secondary outcomes: comparison of other virologic response rates at other time points. Rate of RVR. Proportion of simeprevir‐treated participants meeting response‐guided treatment criteria to complete treatment at week 24. Incidence of viral breakthrough. Incidence of on‐treatment failure. Incidence of viral relapse. Incidence of AEs. Laboratory abnormalities. Quality‐of‐life measures.
Notes	We sent an email to Forns and colleagues on 20 April 2016 for the following additional information. Reply received on 27 April 2016 with data on baseline number of participants with elevated AST/ALT and randomisation details.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information given
Allocation concealment (selection bias)	Unclear risk	Insufficient information given
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Stated that "participants, study personnel, and the sponsor were blinded to the treatment assignments"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Stated that "participants, study personnel, and the sponsor were blinded to the treatment assignments"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "The proportion of patients who discontinued simeprevir/placebo intake early was 3.5% and 72.2% in the simeprevir/PR and placebo/PR groups, respectively. The main reason for discontinuation was meeting the week 4 virologic stopping rule for simeprevir or placebo in both arms, with a large proportion of patients in the placebo group (69.9%) stopping placebo at week 4. The proportion of patients who completed PR treatment was 93.5% in the simeprevir/PR group (24 or 48 weeks) and 72.2% in the placebo/PR group (48 weeks)"
Selective reporting (reporting bias)	Low risk	A protocol was published before randomisation. Outcomes specified in the protocol are similar, but not completely equal to the ones stated in the article. Not all outcomes stated in the protocol were reported in the article, but results of all outcomes were reported and available on www.ClinicalTrials.gov.
Vested‐interest bias	High risk	Trial sponsored by Janssen
Other bias	Low risk	The trial appeared to be free of other bias domains that could put it at risk of bias.