Bruix 2011

Methods	Randomized trial comparing pegylated interferon with no therapy in 626 patients who were still hepatitis C positive after prior therapy. Intention to treat analysis ‐ unclear (Dropouts who had not had an event were assumed not to have had one afterward (modified ITT); however, 116 and 118 patients in the treatment and control arms failed to complete the trial.  Even so, not all of the patients could be counted because 5 were excluded from the analyses because of the failure of the two sites to comply with "Good Clinical Practice"; according to an abstract published in Gastroenterology in 2009, there were actually 631 patients randomized.) (All of the tables indicated that 626 were analysed.) Sample size calculation ‐ yes (Trial was to stop when 98 events had occurred (90% power to detect hazard ratio of 2.0); however, the trial was stopped after 5 years when only 63 patients had experienced a clinical event, as the other decision to stop was after 5 years.)
Participants	Countries: Spain, France, Italy, United States, Canada, Germany, Mexico, Brazil, Argentina Participants ‐ Both nonresponders and relapsers included. Previous lack of sustained viral response was to combination therapy (pegylated interferon plus ribavirin). ‐ Previous relapse or nonresponse: Virologic. ‐ Groups (interferon/interferon): 311/315 ‐ Excluded: 0/0 ‐ Mean age (y): 52.3 (7.5 SD)/52.0 (7.6 SD) ‐ Male (%): 66/68 ‐ Transfusion (%): N/A ‐ Drug abuse (%): N/A ‐ Genotype 1 (%): 89/90 ‐ Cirrhosis (%): 100/100 Inclusion criteria: HCV‐RNA positive, age 18‐65, biopsy confirmed cirrhosis that was clinically compensated (Childs‐Pugh A), failure to respond to combination therapy in past, no hepatocellular carcinoma (AFP < 100 ng/ml and no evidence of HCC on ultrasound).  Some patients failed treatment with combination therapy just prior to randomisation; these patients had to have neutrophil count > 750 and platelet count > 50,000 at end of treatment.  The remaining patients were directly enrolled into the trial; this cohort had to have hemoglobin > 9 gm%, neutrophil count > 1200, WBC count > 2500, and platelet count > 70,000. Exclusion criteria: Hepatitis B HIV coinfection, status post liver transplant, decompensated cirrhosis,hepatocellular carcinoma, prothrombin time prolonged > 3 seconds over control, ascites, encephalopathy, other liver disease, “certain pre‐existing psychiatric conditions, use of medications known to decrease portal hypertension.
Interventions	‐ Schedule: Experimental 1: Pegylated Interferon alfa‐2b, 0.5 mcg weekly up to 5 years (up to 130 mcg) (average duration of exposure 31.4 months) Experimental 2: No treatment (average duration of "exposure" 30.2 months) ‐ Follow‐up (F/U): Up to 5 years.
Outcomes	‐ Mortality (all‐cause and hepatic) ‐ Liver morbidity (ascites, variceal bleeding, encephalopathy, hepatocellular carcinoma) ‐ Liver transplantation ‐ Childs‐Pugh‐Turcotte score ‐ Adverse events ‐ Noninvasive markers of necroinflammation.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated code stratified according to age (more than 50 or not) and retreatment/direct enrollee status).
Allocation concealment (selection bias)	Low risk	Centralized.
Blinding (performance bias and detection bias) Objective outcomes (Biochemical or virologic response)	Low risk	Trial was not blinded, but outcomes were objective.
Blinding (performance bias and detection bias) Subjective outcomes (Clinical events other than mortality, Histology)	Low risk	Committee of experts adjudicated outcomes; they were blinded to the treatment arm. (The same was true for the clinical outcomes.)
Blinding (performance bias and detection bias) Adverse effects	Low risk	Committee of experts adjudicated outcomes; they were blinded to the treatment arm.
Incomplete outcome data (attrition bias) All outcomes	Low risk	See comments above regarding intention‐to‐treat analysis.
Selective reporting (reporting bias)	Low risk	Pertinent clinical outcomes reported.
Other bias	Unclear risk	Sample size calculation performed, no baseline differences between groups, and no apparent academic bias. Study sponsored by Schering‐Plough.