Tanwar 2012

Methods	Randomized trial comparing pegylated interferon for 48 weeks with no treatment Intention‐to‐treat analysis ‐ Yes for most outcomes, no for QOL and adverse events Sample size calculation ‐ yes, but trial stopped early by Safety Committee because of results from HALT‐C and EPIC‐3 trials.
Participants	Country: UK Participants ‐ Both nonresponders and relapsers included (9/18 nonresponders and 7/18 relapsers in treatment arm with an additional 2 patients in treatment arm who were treatment naive/13/22 nonresponder and 9/22 relapsers in control arm. Previous lack of sustained viral response was to any therapy and not specified ‐ Previous relapse or nonresponse: Virologic in the 38 who were previously treated ‐ Groups (interferon/no treatment): 18/22 ‐ Excluded: 0/0 (1 patient in interferon arm withdrew before any treatment received, but appears to have been accounted for in most of outcomes ‐ Mean age (y): 54.9 (8.5 SD) in interferon arm, 52.1 (8.5 SD) in controls ‐ Male (%): 72/77 ‐ Transfusion (%): N/A ‐ Drug abuse (%): N/A ‐ Genotype 1 (%): 50/54.9 ‐ Cirrhosis (%): 100 (16 Child A/2 Child B)/100 (19 Child A/3 Child B) Inclusion criteria: Anti‐HCV and HCV‐RNA positive, age > 18 years, previous failure to therapy or unwilling take ribavirin or were believed not to be able to tolerate ribavirin, Child’s A or B cirrhosis (see above), no evidence hepatocellular carcinoma on imaging of AFP monitoring. Exclusion criteria: Other forms of liver disease, hepatitis B infection, severe pre‐existing depression or other conditions preventing se of interferon (including psychiatric disease, cardiac disease, renal disease, seizure disorders, pregnancy, severe retinopathy), neutrophil count < 1000, platelet count < 60,000.
Interventions	Interferon arm: Peginterferon α‐2a 90 mcg/week on weeks 1‐4, then dose escalated to 135 mcg/week X 4 weeks, then 180 mcg/week for 40 additional weeks (a total of 48 weeks) – If intolerant, dose decreased by 45 mcg/week intervals until tolerated. Patients then followed for 48 weeks in formal trial, but total follow‐up almost 4 years. Controls ‐ Standard care (unclear if seen as often during the first 48 weeks or if monitored as closely for toxicity‐like events).
Outcomes	Primary outcomes: SVR, all‐cause and hepatic mortalities. Secondary outcomes: Liver related events (variceal hemorrhage, new ascites and SBP, HCC and, although not listed in Methods, "decompensated cirrhosis"), quality of life scores (SF‐36 and Fatigue Severity Scale).
Notes	RLK sent an e‐mail to the first author at sudeep.tanwar@nhs.net on 4/12/12 with following questions:1. What were outcomes in two patients who were treatment naive [since plan was to eliminate those two from data]; 2. How was decompensation defined in Child B patients; 3. How often were controls seen, especially in first 48 weeks; 4‐6. How was randomisation sequence generated, allocation concealed, and any blinding performed; 7. Obtaining copy of protocol; 8. Details about support from Roche. A response was received on 4/16/12 indicating that records were all in storage and that it would be a few days before Dr Tanwar could get answers. We responded back to him on 4/16/12 asking a further question about how the patient who dropped out before receiving any treatment was followed so long‐term data could be obtained (or if it was just a matter of the last observation being carried forward). Upon rereading the protocol on 4/17/12, RLK was reminded of the provision that patients with decompensated cirrhosis also were to be excluded, and 5 patients in this trial were Childs B; an email was sent to Dr Tanwar requesting the outcome details on these five patients as well. Dr Tanwar responded back on 4/17/12; he sent us a protocol for the trial as well as information that allowed us to consider both the generation of the randomisation sequence and the concealment of allocation to be adequate. The details about the excluded patients are in the text.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randmization was stratified on the basis of HCV genotype. Patients were randomised..." Further details indicated that the sequence was constructed using a random number generator.
Allocation concealment (selection bias)	Low risk	Subsequent details from the investigator indicated that patients were assigned via a central computer, and the allocation was concealed from the investigator and patient.
Blinding (performance bias and detection bias) Objective outcomes (Biochemical or virologic response)	Low risk	Trial was not blinded to investigators or subjects, but outcomes were objective.
Blinding (performance bias and detection bias) Subjective outcomes (Clinical events other than mortality, Histology)	High risk	No blinding done (confirmed by investigator in his response to us).
Blinding (performance bias and detection bias) Adverse effects	High risk	No blinding done (confirmed by the investigator in his response to us).
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Alhough there was one dropout in treatment arm, that patient was still followed in accordance with the protocol. Most of data presented as outcomes in all randomized patients; high risk of bias for quality of life scores and adverse events, as the data were incomplete and patients in the treatment arm were seen more frequently than the patients in the control group for the first 48 weeks of the trial. Most importantly, the trial was not limited to previously‐treated patients with compensated cirrhosis (see text), resulting in the removal of 6 patients from the original database, with an unknown effect on the randomisation.
Selective reporting (reporting bias)	Low risk	All pertinent outcomes were reported (as documented in the trial protocol provided by the investigator).
Other bias	Unclear risk	Sample size calculation done, but trial stopped early by Safety Committee after HALT‐C and EPIC3 trials available. No important differences in baseline characteristics. As noted earlier, there was more intense follow up of the treated patients than the controls during the first year. Some support from Roche was obtained but, according to the information received from the author, it did not appear to be such that there was any industry influence.