Thursz 2015.

Methods	Multicentre, randomised trial with a 2 × 2 factorial design (09/MRE09/59). Country: UK (65 hospitals) Dates: January 2011 to February 2014 Intention‐to‐treat analysis: yes Sample size calculation: reported
Participants	Demographic characteristics Age (mean): prednisolone plus placebo (n = 274) 49.3 ± 10.6); prednisolone plus pentoxifylline (n = 277) 48.6 ± 9.8; control group: placebo plus pentoxifylline (276) 47.9 ± 10.2; placebo plus placebo (276) 48.8 ± 10.3 Sex: glucocorticosteroid groups: 359 (65.6%) men; control groups: 326 (59.8%) men Hepatic encephalopathy: glucocorticosteroid groups: 152 (28%); control groups: 143 (26%) Inclusion criteria and degree of severity People abusing alcohol with a clinical diagnosis of severe alcoholic hepatitis manifested by hepatomegaly, leukocytosis, serum bilirubin > 5 mg/dL, spontaneous hepatic encephalopathy; aged ≥ 18 years; clinical diagnosis of alcoholic hepatitis; mean alcohol consumption > 80 g/day for men and > 60 g/day for women; serum bilirubin > 80 μmol/L (4.7 mg/dL); discriminant function ≥ 32 Exclusion criteria Jaundice for > 3 months; cessation of alcohol consumption for > 2 months before randomisation; presence of other causes of liver disease; serum AST > 500 IU/L or serum ALT > 300 IU/L; previous entry into the study within the preceding 6 months Randomisation procedure Web‐based computer system Number of participants randomised: 1103; data from 1053 were available for the primary end‐point analysis
Interventions	Participants randomised to 1 of 4 groups: pentoxifylline‐matched placebo + prednisolone‐matched placebo; pentoxifylline‐matched placebo + prednisolone; pentoxifylline + prednisolone‐matched placebo; or pentoxifylline + prednisolone Experimental groups: group 2 received prednisolone 40 mg daily + pentoxifylline‐matched placebo (n = 277); group 4 received prednisolone 40 mg daily + pentoxifylline 400 mg 3 times daily (n = 274) Control groups: group 1 received pentoxifylline‐matched placebo + prednisolone‐matched placebo (n = 276); group 3 received pentoxifylline 400 mg 3 times daily + prednisolone matched placebo (n = 276) Additional interventions to the trial groups: standard supportive care and nutritional support. Clinician made decision regarding other treatments, such as terlipressin for people with developing hepatorenal failure, acid suppression for prophylaxis against gastrointestinal haemorrhage, antibiotics, and vitamin supplementation. People with renal failure (defined as creatinine level > 500 μmol/L (> 5.7 mg/dL) or requirement for renal‐replacement therapy), active gastrointestinal bleeding, or untreated sepsis, and people requiring inotropic support with adrenaline or noradrenaline, were excluded unless the condition stabilised within the first 7 days after admission to hospital. Duration of treatment: 28 days Duration of follow‐up: 1 year
Outcomes	Mortality Adverse events Quality of life (using the EQ‐5D score registered to Eudra CT 2009‐013897‐42 and ISRCTN 88782125)
Notes	European Quality of Life – 5 Dimension – 5 Level Scale (EQ‐5D‐5L): self‐report, multiple choice questionnaire that provides a simple descriptive profile and a single index value for health status. Essentially consists of 2 pages: the EQ‐5D descriptive system (page 2) and the EQ VAS (page 3). The descriptive system comprises: mobility, self‐care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS records the respondent's self‐rated health on a vertical, VAS. The EQ‐5D‐5L takes a few minutes to complete. A summary index with a maximum score of 1 can be derived from these 5 dimensions by conversion with a table of scores. The maximum score of 1 indicates the best health state, by contrast with the scores of individual questions, where higher scores indicate more severe or frequent problems. In addition, there is a VAS to indicate the general health status with 100 indicating the best health status. Study approved by the Multicenter Research Ethics Committee (reference number 09/MRE09/59), and clinical trial authorisation received from the Medicines and Healthcare Products Regulatory Agency (funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009‐013897‐42, and Current Controlled Trials number, ISRCTN88782125. Trial was conducted and reported according to the protocol, the Medicines for Human Use (Clinical Trials) Regulations 2004, as amended in 2006, the European Union Clinical Trials Directive (Directive 2001/20/EC) guidelines, the principles of the International Conference on Harmonisation Good Clinical Practice under the oversight of University Hospital Southampton NHS Foundation Trust, and the provisions of the Declaration of Helsinki. Letter sent to M Thursz 12 October 2016. No reply received yet
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "… A web‐based computer system (Tenalea, Forms‐Vision) was used to enrol eligible patients and randomly assign them to study groups. The randomization schedule was created with the use of Stata software, version 11 (StataCorp). Randomization was performed with a block size of four, with stratification according to geographic area and risk category. The high‐risk category consisted of patients who had an occurrence of gastrointestinal bleeding, renal impairment, or sepsis before randomisation. All other patients were assigned to the intermediate‐risk category."
Allocation concealment (selection bias)	Low risk	Quote: "The randomization schedule was created with the use of Stata software, version 11 (StataCorp). Randomization was performed with a block size of four, with stratification according to geographic area and risk category. Treatment allocation was blinded to site staff and the patient by providing each patient with a unique four‐digit patient pack number."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind Quote: "The treatment arm was also concealed to investigators and researchers. Only the study statisticians were unblinded and this was for analysis purposes only."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "An independent data monitoring and ethics committee, whose members were aware of the group assignments, was convened to review the conduct of the trial and to analyze primary end‐point data, using prespecified stopping guidelines, after the recruitment of 200, 400, and 800 patients, to avoid continued recruitment in the event that a definitive result had been achieved. Data collected by site investigative teams were submitted to the clinical trials unit and analysed by study statisticians. The first author wrote the first draft of the manuscript, with substantial contributions from the coauthors. All the authors vouch for the accuracy and completeness of the data and analyses."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Outcome data at the specific time points were reported. Quote: "At the time the trial was stopped, 33 patients who underwent randomization during the last 90 days of the trial could not be included in the 90‐day or 12‐month analyses. In addition, there were 159 patients who underwent randomization within 90 days to 12 months before the end of trial who could not be included in 12‐month analyses. The four groups were well matched with regard to their baseline characteristics, including laboratory values (See Table 1 in the published article). At 28 days, 16% of the patients had died, 1% had been lost to follow‐up, and 2% had withdrawn from the study. At 90 days, 29% of the patients (285 of 968 patients) had died, 5% had been lost to follow‐up, 3% had withdrawn, and 4% had not completed follow‐up owing to cessation of the study. At 1 year, 56% of the patients (421 of 747 patients) had died or undergone liver transplantation (the latter were 3 patients), 8% had been lost to follow‐up, 4% had withdrawn, and 20% had not completed follow‐up owing to cessation of the study due to limitations on funding." Quote: "Owing to limitations on funding, the trial was stopped after all enrolled patients had completed at least 28 days of follow‐up." Quote: "This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme. The NIHR Clinical Research Network provided research nurse support and the Imperial College Biomedical Research Centre also provided funding."
Selective reporting (reporting bias)	Low risk	Protocol was available, and data on all protocol outcomes such as all‐cause mortality, serious adverse events, liver‐related mortality, and quality of life were reported.
Other bias	Low risk	None suspected

ALT: alanine aminotransferase; AST: aspartate aminotransferase; EQ‐5D: European Quality of Life‐5 dimensions; GAHS: Glasgow alcoholic hepatitis score; MDF: Maddrey's Discriminant Function; MELD: model for end‐stage liver disease; n: number of participants; PPD: purified protein derivative; SD: standard deviation; VAS: visual analogue scale.