Higuera‐de‐la‐Tijera 2018.

Study characteristics
Methods	Randomised, double‐blind, three‐arm clinical trial
Participants	The trial assessed the effects of rifaximin versus: (i) lactulose; (ii) L‐ornithine L‐aspartate; and, (iii) placebo for the prevention of hepatic encephalopathy in 88 people with cirrhosis admitted to hospital with an acute variceal bleed who had no evidence of minimal or overt hepatic encephalopathy at the time of admission. The comparisons assessed were (i) rifaximin versus placebo; (ii) rifaximin versus lactulose. There were 21 participants in the rifaximin group and 22 participants in both the lactulose and placebo groups. Age (mean ± SD) years Rifaximin 53.0 ± 10.9 Lactulose 50.5 ± 11.3 Placebo 49.3 ± 9.5 Proportion of men (n: %) Rifaximin 10 (47.6) Lactulose 14 (63.6) Placebo 17 (77.3) Aetiology of cirrhosis (n: %) Rifaximin Alcohol 9 (43) Hepatitis C 3 (14) Non‐alcoholic steatohepatitis 5 (24) Other 4(19) Lactulose Alcohol 8 (36) Hepatitis C 6 (27) Non‐alcoholic steatohepatitis 4 (18) Other 4 (18) Placebo Alcohol 11 (50) Hepatitis C 4 (18) Non‐alcoholic steatohepatitis 4 (18) Other 3 (12)
Interventions	Intervention: rifaximin: 400 mg thrice daily plus placebo lactulose (dextrose solution) 30 ml thrice daily (n = 21) Control intervention: lactulose 30 ml thrice daily, adjusted to achieve 2 to 3 semi‐soft stools per day plus placebo rifaximin (identically presented dextrose tablets) 2 thrice daily (n = 22) Control intervention: placebo, 30 ml placebo lactulose (dextrose solution) thrice daily plus placebo rifaximin (dextrose tablets) 2 thrice daily (n = 22) Co‐medications: intravenous quinolones or cephalosporins were given for primary prophylaxis of infections for 7 days in all groups except the rifaximin group Duration of therapy: 7 days, follow‐up extended to 28 days
Outcomes	Neuropsychiatric assessment Mental status: West Haven Criteria; PHES psychometric test battery and critical flicker frequency
Inclusion period	June 2014 to August 2016
Outcomes included in meta‐analyses	Mortality, serious adverse events, hepatic encephalopathy, non‐serious adverse events
Country of origin	Single centre in Mexico
Notes	Publication status: full paper Vested interests bias: the publication fee was supported by Alfasigma Inc. Additional information: authors contacted for further information on adverse events and our secondary outcomes. The request was made on 4 April 2021; still awaiting response. No information is available on whether participants had a history of hepatic encephalopathy prior to the trial.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated table of random numbers considering four groups of equal size.
Allocation concealment (selection bias)	Low risk	Allocating investigator did not have contact with participants, blinded to the drugs administered in each group (only lettered groups).
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participant, caregiver, and outcome assessors were blinded. All participants received treatment corresponding to the complementary placebos to ensure blinding of both investigator and participants.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessor was blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	One person in the rifaximin group withdrew from the study before receiving the treatment; this person was not included in the analysis. No participants were lost to follow‐up, and no participants discontinued the intervention.
Selective reporting (reporting bias)	Low risk	All outcomes listed on the trial registry have been included and reported in the full‐text paper.
Other bias	Low risk	No other bias detected.
Overall bias assessment (mortality)	Low risk	All domains were at a low risk of bias.
Overall bias assessment (non‐mortality outcomes)	Low risk	All domains were at a low risk of bias.