Vierling 2011

Methods	Randomised clinical trial
Participants	111 participants Sex: 64 men, 47 women Mean age: 46 years Inclusion criteria: adults with chronic hepatitis C genotype 1 with no previous treatment for chronic hepatitis C, 18‐55 years of age, weight between 40 kg and 125 kg, liver biopsy within 2 years of screening with histology consistent with chronic hepatitis C and no evidence of bridging fibrosis or cirrhosis, participant and participant's partner(s) must each agree to use acceptable methods of contraception for at least 2 weeks prior to Day 1 and continue until at least 6 months after last dose of study drugs and participants must be willing to give written informed consent. Exclusion criteria: prior treatment for hepatitis C other than herbal remedies, HIV‐positive or known to be co‐infected with hepatitis B, medically significant gallbladder or hepatobiliary findings on screening ultrasound, use of any known significant inducers or substrates of CYP3A4 2 weeks prior to start of study medications, use of herbal supplements (milk thistle permitted), diabetic and hypertensive participants with clinically significant ocular examination findings, current moderate or severe depression, history of depression associated with any of the following: hospitalisation for depression, electroconvulsive therapy for depression, depression that resulted in a prolonged absence from work and/or significant disruption of daily functions, suicidal or homicidal ideation and/or attempt, history of severe psychiatric disorders, past history or current use of lithium, clinical diagnosis of substance abuse of alcohol, intravenous drugs, inhalational (not including marijuana), psychotropics, narcotics, cocaine use, prescription or over‐the‐counter drugs within 5 years of Day 1, past or current use of opiate agonist substitution therapy, any known pre‐existing medical condition (CNS, cardiac, pulmonary, immune mediated) that could interfere with the participant's participation in and completion of the study, active clinical gout within the last year, haemoglobinopathy or coagulopathy, myelodysplastic syndromes, organ transplants other than cornea and hair, poor venous access that precluded routine peripheral blood sampling or an indwelling venous catheter, participants with a history of gastric surgery (e.g. stapling, banding, bypass) or participants with a history of malabsorption disorders (e.g. celiac sprue disease), evidence of active or suspected malignancy, or a history of malignancy, within the last 5 years (except adequately treated basal cell carcinoma of the skin). Participants under evaluation for malignancy were not eligible, participants who were pregnant or nursing, participants who intended to become pregnant during the study period and male participants with partners who were, or intended to become, pregnant during the study period.
Interventions	Experimental group: narlaprevir 100 mg twice a day and ritonavir 100 mg. narlaprevir 200 mg once a day and ritonavir 100 mg. narlaprevir 400 mg once a day and ritonavir 100 mg. narlaprevir 200 mg once a day and ritonavir 100 mg. There was a 4‐week run in with peg‐IFN and RBV. narlaprevir 400 mg once a day and ritonavir 100 mg. There was a 4‐week run in with peg‐IFN and RBV. Control group: no intervention. Co‐intervention: peg‐IFN α‐2b (1.5 μg/kg subcutaneously, weekly) and RBV (600 mg‐1400 mg/d based on weight) for 48 weeks.
Outcomes	Antiviral effects, pharmacokinetics, safety.
Notes	Participants from the control group were allowed to cross over to the experimental group after 12 weeks of treatment. We could therefore only use results from the first 12 weeks. We contacted trial authors about allocation sequence generation and concealment, how was missing data accounted for, SAE, number randomised to each group.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias) All outcomes	High risk	Described as open‐label
Blinding of outcome assessment (detection bias) All outcomes	High risk	Described as open‐label
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Above 5% dropouts in the control group and it was unclear how the trial handled missing data
Selective reporting (reporting bias)	Low risk	All outcomes stated in the protocol were reported on (NCT00797745)
Vested‐interest bias	High risk	The trial was funded by a company that might have an interest in a given result (Merck Sharp & Dohme Corp.)
Other bias	Low risk	The trial appeared to be free of other components that could put it at risk of bias