McHutchison 2010

Methods	A phase II, randomised, partially placebo‐controlled, partially double‐blind, parallel‐group trial (PROVE‐3)(NCT00420784)
Participants	453 participants Sex: 306 men, 147 women Mean age: 51 years Inclusion criteria: age between 18 and 70 years, chronic hepatitis C infection, HCV genotype 1, previously treated, but without achieving SVR. Seronegative for hepatitis B surface antigen and antibodies against HIV‐1 and HIV‐2, absolute neutrophil count ≥ 1500 cells/mm3, platelet count ≥ 100,000 cell/mm3, normal bilirubin values. Exclusion criteria: decompensated liver disease, HCC, other clinically significant liver disease. Country: Canada, Germany, the Netherlands, Puerto Rico and USA. Group 1: 115 participants (T12PR24) Sex: 78 men, 37 women Median age: 51 years (range 22‐65) Race, n(%): white: 103(90), black: 9(8), Asian: 2(2), other: 1(1) HCV genotype, n(%): 1a: 69(60), 1b: 33(29), unknown: 13(11) HCV RNA ≥ 800,000 IU/mL, n(%): 106(92) Stage of fibrosis or cirrhosis, n(%): none or minimal: 26(23), portal fibrosis: 44(38), bridging fibrosis: 26(23), cirrhosis. 19(17) Group 2: 113 participants (T24PR48) Sex: 80 men, 33 women Median age: 52 years (range 31‐66) Race, n(%): white: 99(88), black: 11(10), Asian: 0, other: 3(3) HCV genotype, n(%): 1a: 61(54), 1b: 42(37), unknown: 10(9) HCV RNA ≥ 800,000 IU/mL, n(%): 104(92) Stage of fibrosis or cirrhosis, n(%): None or minimal: 20(18), portal fibrosis: 40(35), bridging fibrosis: 33(29), cirrhosis. 20(18) Group 3: 111 participants (T24PR24) Sex: 72 men, 39 women Median age: 53 years (range 19‐69) Race, n(%): white: 100(90), black: 10(9), Asian: 1(1), other: 0. HCV genotype, n(%): 1a: 64(58), 1b: 36(32), unknown: 11(10) HCV RNA ≥ 800,000 IU/mL, n(%): 104(94) Stage of fibrosis or cirrhosis, n(%): none or minimal: 17(15), portal fibrosis: 40(36), bridging fibrosis: 32(29), cirrhosis. 22(20) Group 4: 114 participants (PR48) Sex: 76 men, 38 women Median age: 50 years (range 18‐65) Race, n(%): white: 100(88), black: 10(9), Asian: 2(2), other: 2(2) HCV genotype, n(%): 1a: 71(62), 1b: 34(30), unknown: 9(8) HCV RNA ≥ 800,000 IU/mL, n(%): 104(91) Stage of fibrosis or cirrhosis, n(%): none or minimal: 33(29), portal fibrosis: 37(32), bridging fibrosis: 31(27), cirrhosis 13(11).
Interventions	Experimental group: 1: oral telaprevir given in a single initial dose of 1125 mg, followed by 750 mg every 8 h for 12 weeks (T12). 2 and 3: oral telaprevir given in a single initial dose of 1125 mg, followed by 750 mg every 8 h for 24 weeks (T24). Control group: 1: placebo from Week 13 to Week 24. 4: placebo for 24 weeks. Co‐intervention: 1 and 3: peg‐IFN α‐2a 180 μg subcutaneously once weekly plus oral weight‐based RBV 1000 mg to 1200 mg daily in 2 divided doses for 24 weeks (PR24). 2 and 4: peg‐IFN α‐2a 180 μg subcutaneously once weekly plus oral weight‐based RBV 1000 mg to 1200 mg daily in 2 divided doses for 48 weeks (PR48).
Outcomes	Primary outcome: SVR defined as undetectable HCV RNA level 24 weeks after the last dose of study drugs. Secondary outcome measures: proportion of participants with undetectable HCV RNA at completion of study drug dosing. Number of participants with AEs and SAE. Number of participants with viral relapse. Maximum, minimum, and average plasma concentration of telaprevir.
Notes	We emailed McHutchinson and colleagues on 27 April 2016 for additional information on generation of random sequence, allocation concealment, description of blinding but reply not received yet.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The method of sequence generation was not specified
Allocation concealment (selection bias)	Unclear risk	Insufficient information was provided on allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	The method of blinding was insufficiently described
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Data management and interim analyses were conducted by the Duke Clinical Research Institute, without revealing the unblinded data"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Number and reasons for discontinuation of treatment were clearly reported. Most participants discontinued treatment due to meeting pre‐specified stopping rules
Selective reporting (reporting bias)	Low risk	Protocol was available and all pre‐specified outcomes were reported on
Vested‐interest bias	High risk	The sponsor (Vertex Pharmaceuticals) was directly involved in trial design, protocol development, study co‐ordination, drafting and reviewing the manuscript
Other bias	Low risk	The trial appeared to be free of other potential sources of bias