Bacon 2011a1

Methods	Parallel‐group, randomised, placebo‐controlled, double‐blind study (RESPOND‐2)(NCT00708500)
Participants	403 participants Inclusion criteria: chronic hepatitis C infection genotype 1 HCV RNA ≥ 10,000 IU/mL, demonstrated responsiveness to IFN (minimum duration of therapy 12 weeks); non‐response defined as a decrease in HCV RNA of at least 2 log10 IU/mL by week 12, but with detectable HCV RNA during the therapy period; relapse defined as an undetectable HCV RNA at end of treatment, but without subsequent attainment of SVR. A liver biopsy with histology consistent with chronic hepatitis C, age ≥ 18 years, weight between 40‐125 kg, signed informed consent, acceptable method of contraception for the participant and participant's partner(s) for at least 2 weeks before day 1 and continue until at least 6 months after treatment termination. Exclusion criteria: Hepatitis B infection, HIV infection, other causes of liver disease, decompensated liver disease, uncontrolled diabetes mellitus, a severe psychiatric disorder, active substance abuse, active or suspected malignancy, or a history of malignancy within last 5 years, pregnant or nursing women, severe AE during prior treatment, seizure disorder, cerebrovascular diseases, cardiovascular disease, autoimmune diseases, prior organ transplantation, haemoglobinopathies, coagulopathies, abnormal levels of serum bilirubin, albumin, and creatinine, haemoglobin < 120 g/L (women) and < 130 g/L (men), neutrophil count < 1500/mm3, platelet count < 100,000/mm3. Group 1: 80 participants Age, mean (years): 52.9 Sex: 58 men (72%), 22 women (28%) Race, n(%): white: 62(84), black: 12(15), other: 1(1) Region, n(%): North America: 51(64), European Union: 29(36). Latin America: 0. BMI, mean ± SD (kg/m2): 28.2 ± 4.3 HCV subtype, n(%): 1a: 46(58), 1b: 34(42), missing data: 0 HCV RNA > 800,000 IU/mL, n(%): 65(81) METAVIR fibrosis score, n(%): 0, 1, or 2: 61(76), 3 or 4: 15(19) Cirrhosis, n(%): 10(12) Previous therapy, n(%): peg‐IFN alpha‐2a: 42(53), peg‐IFN alpha‐2b: 38(48) Prior non‐response, n(%): 29(36) Prior relapse, n(%): 51(64) Group 2: 162 participants Age, mean (years): 52.9 Sex: 98 men (60%), 64 women (40%) Race, n(%): white: 142(88), black: 18(11), other: 2(1). Region, n(%): North America: 115(71), European Union: 46(28), Latin America: 1(1). BMI, mean ± SD (kg/m2): 28.8 ± 4.6 HCV subtype, n(%): 1a: 94(58), 1b: 66(41), missing data: 2(1) HCV RNA > 800,000 IU/mL, n(%): 147(91) METAVIR fibrosis score, n(%): 0, 1, or 2: 117(72), 3 or 4: 32(20) Cirrhosis, n(%): 17(10) Previous therapy, n(%): peg‐IFN alpha‐2a: 79(49), peg‐IFN alpha‐2b: 83(51) Prior non‐response, n(%): 57(35) Prior relapse, n(%): 105(65) Group 3: 161 participants Age, mean (yr.): 52.3 Sex: 112 men (70%), 49 women (30%) Race, n(%): white: 135(84), black: 19(12), other: 7(4) Region, n(%): North America: 119(74), European Union: 42(26), Latin America: 0. BMI, mean ± SD (kg/m2): 28.2 ± 4.6 HCV subtype, n(%): 1a: 96(60), 1b: 61(38), missing data, 4(2) HCV RNA > 800,000 IU/mL, n(%): 141(88) METAVIR fibrosis score, n(%): 0, 1, or 2: 119(74), 3 or 4: 31(20) Cirrhosis, n(%): 17(10) Previous therapy, n(%): pegIFN alpha‐2a: 79(49), peg‐IFN alpha‐2b: 83(51) Prior non‐response, n(%): 57(35) Prior relapse, n(%): 105(65)
Interventions	Experimental group: Group 2: oral boceprevir 800 mg thrice‐daily to be taken in with food and with an interval of 7‐9 h, in 4 capsules of 200 mg each, beginning at week 5 for a total of 32 weeks (if HCV RNA undetectable at week 8 and 12, treatment was terminated at week 36; if HCV RNA detectable at week 8 participants received placebo + peg‐IFN + RBV for an additional 12 weeks). Group 3: oral boceprevir 800 mg thrice‐daily to be taken in with food and with an interval of 7‐9 h, in 4 capsules of 200 mg each, beginning at week 5 for a total of 44 weeks Control group: Group 1: boceprevir‐matched placebo beginning at week 5 for a total of 44 weeks. Co‐interventions: Group 1 and 3: peg‐IFN alpha‐2b 1.5 μg/kg body weight subcutaneously once weekly and weight‐based oral RBV at a divided daily dose of 600 to 1400 mg for a total of 48 weeks Group 2: peg‐IFN alpha‐2b 1.5 μg/kg body weight subcutaneously once weekly and weight‐based oral RBV at a divided daily dose of 600 to 1400 mg for 36 weeks (if HCV RNA undetectable at week 8 and 12), and for 48 weeks if (HCV RNA detectable at week 8, but undetectable at week 12).
Outcomes	Primary outcome: achievement of SVR (undetectable HCV RNA at week 24). Secondary outcome: achievement of SVR in randomised participants who received at least 1 dose of experimental study drug or placebo. Proportion of participants with EVR (undetectable HCV RNA at week 2, 4, 8, or 12) who achieved SVR. Proportion of participants with undetectable HCV RNA at week 12. Proportion of participants with undetectable HCV RNA at 72 weeks after randomisation.
Notes	Group 2 received a similar, but not equal co‐intervention as Groups 1 and 3.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random sequence
Allocation concealment (selection bias)	Low risk	Allocation of participants through interactive voice‐response system in a 1:2:2 ratio
Blinding of participants and personnel (performance bias) All outcomes	Low risk	A boceprevir‐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	Treatment discontinuation due to AE was 2% to 12%. Seems no other drop‐outs occurred.
Selective reporting (reporting bias)	Low risk	A study protocol was published prior to randomisation (NCT00708500). All pre‐specified outcomes were reported on.
Vested‐interest bias	High risk	Trial was sponsored by a pharmaceutical company (Schering‐Plough/Merck). The company was directly involved in trial design and managing, data analysis, and writing of article.
Other bias	Low risk	Seems there were no other potential sources of bias.