Bureau 2021.

Study characteristics
Methods	Randomised, double‐blind, placebo‐controlled clinical trial
Participants	This trial assessed the effects of rifaximin versus placebo for the prevention of hepatic encephalopathy in people with cirrhosis being considered for insertion of a transjugular intrahepatic portosystemic shunt (TIPS) to control resistant ascites (86%) or prevent variceal re‐bleeding (16%). A total of 197 participants were randomised, but 11 were either ineligible; did not receive a TIPS; did not receive the study drug; or withdrew consent. Data on the remaining 186 eligible participants were included in the efficacy analysis. There were 93 participants in both groups. Age (mean (SEM)) years Rifaximin 61 (9) Placebo 58 (8) Proportion of men (n: %) Rifaximin 73 (75) Placebo 79 (79) Aetiology of cirrhosis (n: %) Rifaximin group Alcohol 83 (86) Placebo group Alcohol 87 (87)
Interventions	Intervention: rifaximin capsules 600 mg twice daily Control: identically presented placebo capsules twice daily Co‐intervention: lactulose was co‐administered in the event of an episode of overt hepatic encephalopathy developing during follow‐up, at which point the participant was withdrawn from the study; lactulose was otherwise prohibited. Duration of treatment: 15 days before TIPS and for 6 months post‐TIPS; study medication was stopped in the event of 2 episodes of overt hepatic encephalopathy and open‐label rifaximin provided. Follow‐up period: 6 months post‐TIPS, at which point study medication was stopped; further follow‐up every 3 months for 1 year, death, or liver transplantation.
Outcomes	Neuropsychiatric assessment Mental status assessed using modified West Haven criteria and the presence of asterixis. Overt hepatic encephalopathy was defined as grade 2 or more change in mental status or isolated asterixis; psychometric hepatic encephalopathy score (PHES) measured in the absence of overt hepatic encephalopathy; minimal hepatic encephalopathy defined as a score of ‐4 or below.
Inclusion period	October 2013 to June 2016
Outcomes included in meta‐analyses	Mortality, hepatic encephalopathy post‐TIPS, adverse events
Country of origin	A total of 12 investigatory centres in France
Notes	Publication status: full paper Vested interests bias: The study was funded by the French ministry; they played no role in the conduct of the study or its subsequent publication. Dr Bureau received support from Alfa Wasserman outside this study; risk of bias unclear. Additional information: Participants with diabetes: rifaximin 43%; placebo 34%. In 24 participants with a history of overt hepatic encephalopathy (rifaximin = 12; placebo = 12), the cumulative incidence of overt encephalopathy post‐TIPS was 33% with rifaximin versus 83% with placebo (P < 0.05). In 162 participants without a history of previous overt encephalopathy, the cumulative incidence of overt encephalopathy post‐TIPS was 35% with rifaximin versus 51% with placebo (P = 0.070). A total of 23 participants had minimal hepatic encephalopathy at baseline; post‐TIPS insertion 39% of participants with and 44% without minimal encephalopathy at baseline developed overt encephalopathy. Rifaximin did not reduce the incidence of minimal encephalopathy (27% versus 29% in the rifaximin and placebo groups, respectively P = 0.74). Authors contacted for further information on the aetiology of cirrhosis and data on our secondary outcomes. Request sent on 13 April 2021; still awaiting response.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomly assigned to treatment groups in a 1:1 ratio using computer‐generated randomisation with random block sizes. Participants were stratified according to Child‐Pugh classification and history of overt hepatic encephalopathy.
Allocation concealment (selection bias)	Low risk	Investigators used a website which immediately sent the investigator the participant’s unique number in the study, the treatment group allocated to the participant and the number of the treatment bottle.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Randomised, double‐blind study, with the study drugs similar in size, shape and colour
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote from supplementary material: "Up until the end of the study, neither the investigating physicians, nor the patient will know the group to which the patient has been assigned by randomisation"
Incomplete outcome data (attrition bias) All outcomes	Low risk	197 participants were randomised, but 186 were analysed as the other 11 did not receive a TIPS, did not receive the study drug, withdrew consent or had a wrong indication for TIPS. For the remaining participants who received a TIPS, an intention‐to‐treat analysis was used.
Selective reporting (reporting bias)	Low risk	All outcomes outlined were fulfilled in results.
Other bias	Low risk	No other bias identified
Overall bias assessment (mortality)	Low risk	Low risk of bias in all domains
Overall bias assessment (non‐mortality outcomes)	Low risk	Low risk of bias in all domains