Wedemeyer 2013

Methods	A phase IIb, randomised, double‐blind, active‐controlled, parallel‐group trial (PROPEL) (NCT00869661)
Participants	424 participants Sex: 255 men (60.1%), 169 women (39.9%) Location: North America, Europe, and Australia. Inclusion criteria: participants with chronic hepatitis C infection genotype 1 or 4, age 18‐65 years, treatment‐naive, serum HCV RNA level of at least 50,000 IU/mL, liver biopsy consistent with chronic hepatitis C obtained within 24 calendar months before first dose of study drug (36 months for participants with cirrhosis or incomplete/transition to cirrhosis, fibrosis score 3‐4). Participants with fibrosis score 3‐4 were required to have had an abdominal ultrasound, computerised tomography scan, or magnetic resonance imaging scan without evidence of HCC (within 2 months prior to randomisation) and a serum alfa‐fetoprotein < 100 ng/mL. Exclusion criteria: hepatitis A or B co‐infection, HIV co‐infection, history or evidence of other chronic liver disease other than HCV, history or evidence of decompensated liver disease, absolute neutrophil count < 1.5 x 109 cells/L, haemoglobin concentration < 12 g/dL in women and < 13 g/dL in men. Platelet count < 90 x 109 cells/L, history of renal disease, serum creatinine > 1.5 times the ULN, BMI < 18 or ≥ 36 kg/m2. Pregnant or breastfeeding women and male partners of pregnant women, inadequate forms of contraception in women of childbearing age and men with female partners of childbearing age (2 forms of contraception required). Group A: 80 participants Mean age: 47 years (range 18‐62) Race, n(%): white: 70(88), black: 8(10), other: 2(3) HCV genotype, n(%): 1a: 44(55), 1b: 28(35), 4: 8(10) Cirrhosis, n(%): 17(21) Group B: 81 participants Mean age: 47 years (range 23‐62) Race, n(%): white: 69(85), black: 9(11), other: 3(4) HCV genotype, n(%): 1a: 51(63), 1b: 26(32), 4: 4(5) Cirrhosis, n(%): 18(22) Group C: 82 participants Mean age: 47 years (range 21‐65) Race, n(%): white: 70(85), black: 9(11), other: 3(4) HCV genotype, n(%): 1a. 50(61), 1b: 26(32), 4: 6(7) Cirrhosis, n(%): 18(22) Group D: 81 participants Mean age: 48 years (range 23‐60) Race, n(%): white: 71(88), black: 6(7), other: 4(5) HCV genotype, n(%): 1a: 56(69), 1b: 22(27), 4: 3(4) Cirrhosis, n(%): 23(28) Group E: 84 participants Mean age: 48 years (range 22‐65) Race, n(%): white: 75(89), black: 3(4), other: 6(7) HCV genotype, n(%): 1a: 52(62), 1b: 25(30), 4: 7(8) Cirrhosis, n(%): 19(23).
Interventions	Experimental group: Group A: oral mericitabine 500 mg twice daily for 12 weeks. Group B: oral mericitabine 1000 mg twice daily for 8 weeks. Group C: oral mericitabine 1000 mg twice daily for 12 weeks. Group D: oral mericitabine 1000 mg twice daily for 12 weeks. Control group: Group E: matched placebo orally twice daily for 12 weeks. Co‐interventions: Groups A, B, and C: peg‐IFN alfa‐2a 180 μg subcutaneously once weekly for 24 weeks ifeRVR achieved, or for 48 weeks if eRVR not achieved. Weight‐based oral RBV 1000 mg1‐200 mg daily in 2 divided doses for 24 weeks if eRVR achieved, or for 48 weeks if eRVR not achieved (eRVR was defined as undetectable HCV RNA (< 15 IU/mL) by week 4 and maintained through week 22). Groups D and E: peg‐IFN α‐2a 180 μg subcutaneously once weekly for 48 weeks. Weight‐based oral RBV 1000 mg‐1200 mg daily in 2 divided doses for 48 weeks.
Outcomes	Primary outcome: SVR at week 24 after the last dose of study medication. Secondary outcomes: viral responses at clinic visits (HCV RNA was determined at baseline and at weeks 1, 2, 4, 6, 8, 10, 12, 14, 18, 24, 30, 36, 42, 48 of treatment and at weeks 4, 12, and 24 of follow‐up). Proportion of participants with relapse.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was stratified by geographical region and the randomization sequence was generated centrally by the sponsor...The randomization list was not available to personnel at the study centers or to the sponsor’s monitors during the study."
Allocation concealment (selection bias)	Low risk	Quote: "...were randomized in enrollment order by central interactive voice‐response system or interactive web response system."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	A mericitabine‐matched placebo was used. Quote: "Patients and investigators remained blinded to individual treatment assignments during 24/48 weeks of study treatment and 24 weeks of study follow‐up."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The randomization list was made available to selected individuals from the sponsor at the time of Data Monitoring Committee review of ˜50% of patients in Cohort 2 at week 12, an independent statistician at the sponsor for analysis of ongoing safety data and an independent medical officer to review interim analysis data."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Number and reasons for withdrawal have been clearly stated.
Selective reporting (reporting bias)	Low risk	The protocol was published prior to randomisation and all pre‐specified outcomes were reported on.
Vested‐interest bias	High risk	Trial funded by Hoffmann‐LaRoche Ltd.
Other bias	Low risk	The trial appeared to be free of other bias domains that could put it at risk of bias.