Thursz 2015

Methods	Multicentre, randomised trial with a 2‐by‐2 factorial design (09/MRE09/59) Country: UK (65 hospitals). January 2011‐February 2014 Analyses were performed according to intention‐to‐treat basis Sample size calculation was reported.
Participants	Demographic characteristics Age: (mean) + SD: glucocorticosteroids group/control group 49.3 ± 10.6; 48.6 ± 9.8/47.9 ± 10.2; 48.8 ± 10.3 Sex (male (%)): glucocorticosteroids group/control group 359 (65,6%)/326 (59,8%) Hepatic encephalopathy (%): 152/143 (28%/26%) Inclusion criteria and degree of severity "all patients were alcohol abusers with a clinical diagnosis of severe alcoholic hepatitis manifested by hepatomegaly, leukocytosis, and a serum‐bilirubin greater than 5 mg/dL, spontaneous hepatic encephalopathy" Age of ≥ 18 years Clinical diagnosis of alcoholic hepatitis Average alcohol consumption of > 80 g/d for men and > 60 g/d for women, Serum bilirubin level > 80 μmol/L (4.7 mg/dL) Discriminant function of ≥ 32 Exclusion criteria Jaundice for > 3 months Cessation of alcohol consumption for > 2 months before randomisation Presence of other causes of liver disease Serum aspartate aminotransferase level > 500 IU/L or serum alanine transaminase level > 300 IU/L Previous entry into the study within the preceding 6 months Randomisation procedure "...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." Number of participants randomised n = 1103 ("...1103 patients underwent randomisation (data from 1053 were available for the primary end‐point analysis..") Prednisolone group: 274 + 277 Control group: 276 + 276
Interventions	Experimental groups: "the second group receiving 40 mg of prednisolone daily and a pentoxifylline‐matched placebo (n = 277), the fourth group receiving 40 mg of prednisolone daily, and 400 mg of pentoxifylline three times daily (n = 274) Dose: 40 mg Control groups: "one group receiving a pentoxifylline matched placebo and a prednisolone matched placebo, placebo (n = 276). The third group receiving 400 mg of pentoxifylline three times daily and prednisolone matched placebo (n = 274)". Additional treatment: "Standard supportive care and nutritional support were given to each patient. The clinician responsible for each patient made the decision regarding other treatments, such as terlipressin for patients in whom hepatorenal failure was developing, acid suppression for prophylaxis against gastrointestinal haemorrhage, antibiotics, and vitamin supplementation. Patients with renal failure (defined as a creatinine level > 500 μmol per liter [> 5.7 mg per decilitre] or the requirement for renal‐replacement therapy), active gastrointestinal bleeding, or untreated sepsis, and patients requiring inotropic support with epinephrine or norepinephrine, were excluded unless the condition stabilized within the first 7 days after admission to the hospital." Duration of treatment: 28 days Duration of follow‐up: 1 year
Outcomes	The trial outcomes were Mortality Adverse events Quality of life (using the European quality of life ‐5 dimensions (EQ ‐5D) score registered to Eudra CT 2009‐ 013897‐42 and ISRCTN 88782125)
Notes	The "European Quality of Life Five Dimension Five Level Scale (EQ‐5D‐5L): The EQ‐5D‐5L is a self‐report, multiple choice questionnaire that provides a simple descriptive profile and a single index value for health status. The EQ‐5D‐5L essentially consists of 2 pages – the EQ‐5D descriptive system (page 2) and the EQ visual analogue scale (EQ VAS) (page 3). The descriptive system comprises the following 5 dimensions: 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, visual analogue scale. The EQ‐5D‐5L takes only a few minutes to complete. A summary index with a maximum score of 1 can be derived from these five 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 visual analogue scale (VAS) to indicate the general health status with 100 indicating the best health status." "The study was approved by the Multicenter Research Ethics Committee (reference number 09/MRE09/59), and clinical trial authorization was 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.)" "The trial was conducted and reported with fidelity 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	"A web‐based computer system (Tenalea, Forms‐Vision) was used to enrol eligible patients and randomly assign them to study groups."
Allocation concealment (selection bias)	Low risk	"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‐blinded "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	"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	High risk	"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."
Selective reporting (reporting bias)	Low risk	All‐cause mortality, serious adverse events, liver‐related mortality, and quality of life were reported.
For‐profit bias	Low risk	"Owing to limitations on funding, the trial was stopped after all enrolled patients had completed at least 28 days of follow‐up." "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."
Other bias	Low risk	None suspected

INH = isoniazid; PAS = para‐aminosalicylic acid; PPD = purified protein derivative; PTX = pentoxifylline