Study	Reason for exclusion
Abd‐Elsalam 2016	Randomised clinical trial involving 262 participants with cirrhosis, ascites and a previous episode of spontaneous bacterial peritonitis assigned to receive either rifaximin or norfloxacin for 6 months. We excluded this study as the comparator was another antibiotic.
Ahire 2017	A prospective observational study involving 60 participants with cirrhosis and hepatic encephalopathy allocated to treatment with rifaximin plus lactulose (n = 32) or lactulose alone (n = 28) by physicians decision. We excluded the study because the treatment allocation was not randomised.
Ahluwalia 2014	Observational study involving 20 participants with cirrhosis and minimal hepatic encephalopathy who underwent cognitive testing before and after 8 week treatment with rifaximin. We excluded this study because it was uncontrolled.
Anon 2014a	Paper not retrievable. Springer Nature Group were contacted on 12 April 2021, but their response on 30 April 2021 was: "due to a technical error, it is unfortunately impossible to upload the missing pages".
Anon 2014b	Paper not retrievable. Springer Nature Group were contacted on 12 April 2021 but their response on 30 April 2021 was: "due to a technical error, it is unfortunately impossible to upload the missing pages".
Bajaj 2013	Observational study involving the same 20 participants with cirrhosis and minimal hepatic encephalopathy as Ahluwalia 2014; participants underwent cognitive testing, serum endotoxin analysis, urine/serum metabolomics, and faecal microbiome assessment before and after 8 week treatment with rifaximin. We excluded this study because it was uncontrolled.
Bajaj 2016b	Randomised, double‐blind, placebo controlled dose‐finding study in 518 people with early decompensated cirrhosis allocated to rifaximin at varying dose levels (n = 422) or placebo (n = 94). We excluded this study as its primary aim was to test the efficacy of a new formulation of rifaximin. The amount of extractable information was limited. In particular, we could not identify information on the proportion of participants with hepatic encephalopathy at baseline or how it was assessed.
Bajaj 2020a	Post hoc analysis of an open‐label randomised control trial involving 221 participants assigned to rifaximin (n = 113) or rifaximin plus lactulose (n = 108). The study end point was the number of episodes of hepatic encephalopathy in participants in whom lactulose was withdrawn before randomisation against those who continued lactulose. The study was excluded as both groups received rifaximin. Full data from the trial can be accessed on ClinicalTrials.gov site.
Bajaj 2020b	Randomised, placebo‐controlled, double‐blind, multi‐arm, dose‐ranging, parallel assignment, phase 2 trial in 71 people with overt hepatic encephalopathy at baseline or grade ll‐lll hepatic encephalopathy following 8 to 12 hr of intravenous fluids and lactulose. Participants received rifaximin immediate‐release soluble solid dispersion in combination with lactulose, or placebo. We excluded this study as there were no extractable data in the abstract or press releases (below). Information from Bausch Health America Inc, received on 2 September 2020, confirmed that the study was ongoing and that recruitment was complete. Last study update posted March 2021 as completed but with no reported data. Further information from Bausch Health America Inc on 19 April 2021: "The study in question is currently under review with the Food and Drug Administration for a separate indication, and the sponsor is not able to share data beyond what has already been presented in the press release." A press release (available at https://ir.bauschhealth.com/news‐releases/2020/03‐31‐2020‐120048038) [last accessed 8 May 2021], stated: "In the double‐blinded, placebo‐controlled multi‐arm, dose‐ranging study, the treatment arm evaluating 40 mg BID of rifaximin SSD IR plus standard of care therapy met its primary endpoint of time to resolution of overt hepatic encephalopathy using the Hepatic Encephalopathy Grading Instrument (HEGI) scale. The 40 mg BID rifaximin SSD IR in combination with standard of care therapy treatment arm was statistically significantly superior to the placebo plus standard of care therapy treatment arm with median time to resolution being 21.1 hours versus 62.7 hours, respectively. The rates of adverse events were comparable across all treatment arms of the study" This information was insufficient to allow inclusion of this trial at this time.
Block 2010	Unable to retrieve study. The publisher was contacted on 7 November 2020 and 13 April 2021; we still have not received a response.
Bohra 2020	Observational study involving 188 participants with cirrhosis and hepatic encephalopathy who were treated with rifaximin. Outcomes were assessed up to 48 months following admission, and included 12‐month survival. We excluded this study as it is observational; however, we included the information on adverse events in our review of harms.
Chang 2021	Retrospective cohort study involving 43 participants with previous hepatic encephalopathy allocated to rifaximin plus lactulose (n = 12) or lactulose alone (n = 31) for prevention of recurrence. We excluded this study as group allocation was not randomised, but we included information on adverse events in our review of harms.
Cobbold 2018	An open‐label pilot study in participants with biopsy‐proven NASH and elevated serum ALT activity who received 6 weeks rifaximin 400 mg twice daily, followed by a 6‐week observation period. The primary end point was change in serum ALT after 6 weeks and changes in hepatic lipid content and insulin sensitivity. We excluded this study because it was not randomised, none of the patients had cirrhosis and the endpoints did not include hepatic encephalopathy.
Crisafulli 2016	Randomised, dose‐comparison study in 77 participants with cirrhosis and acute hepatic encephalopathy allocated to high dose rifaximin plus lactulose (n = 39) or standard dose rifaximin plus lactulose (n = 38). We excluded the study as there was no control group.
CTRI/2019/05/018966	Randomised, double‐blind, study comparing lactulose plus rifaximin versus lactulose, rifaximin and L‐ornithine L‐aspartate for the treatment of overt grade lll‐lV hepatic encephalopathy in 124 people with cirrhosis. We excluded this study as rifaximin will be given to participants in both study arms. The trial is not yet recruiting.
Danulescu 2013	Non‐randomised, case‐control study involving 46 participants with severely decompensated cirrhosis and refractory ascites, followed over a period of 6 months. Of these 22 received rifaximin for the treatment of hepatic encephalopathy while 24 did not. The primary outcome was the development of spontaneous bacterial peritonitis. We excluded this trial because it was observational.
De Marco 1984	Randomised study involving 32 participants with cirrhosis and varying degrees of hepatic encephalopathy allocated to treatment with rifaximin (n = 18) or paromomycin (n = 14) over a 6 to 15‐day period. We excluded this study as the comparison was with another antibiotic.
Deshmukh 2016	Randomised, 6‐month open‐label study evaluating the efficacy and safety of rifaximin versus lactulose for the treatment of minimal/covert hepatic encephalopathy in an unspecified number of people with cirrhosis. The study is published in abstract form; quantitative and qualitative data were not provided. The study has not been published as a full paper and no response has been obtained from the trialists.
Di Piazza 1991	Randomised, double‐blind, cross‐over study involved 14 participants with chronic persistent or recurrent hepatic encephalopathy allocated to rifaximin or neomycin for one week with a one‐week washout. Concomitant treatment with lactulose was allowed. We excluded this study because the comparator was another antibiotic.
Diana‐Maria 2019	Randomised trial involving 66 participants with cirrhosis admitted with an episode of acute hepatic encephalopathy who were allocated equally to lactulose and rifaximin or lactulose plus rifaximin plus L‐ornithine L‐aspartate. We excluded this study as rifaximin was given in both treatment arms.
Dupont 2016	Randomised, 6‐month, open‐label study of the effect of rifaximin, with or without lactulose, on stool microbiota and antimicrobial susceptibility in people with cirrhosis and recurrent overt hepatic encephalopathy in remission. We excluded this study because there were no extractable data on hepatic encephalopathy.
EUCTR2014‐001856‐51‐DK	A randomised double‐blind, placebo‐controlled, single‐centre trial involving participants with alcohol‐related liver injury and hepatic fibrosis classified, using the Ishak score, from F1‐F4, allocated to rifaximin or placebo. We excluded this study as the majority of the participants would not have established cirrhosis (F4) and because it is unclear whether outcomes of interest will be available as clinical data collection is not mentioned.
Frenette 2020a	Randomised, open‐label trial evaluating rifaximin versus rifaximin plus lactulose for 6 months in 64 participants with previous hepatic encephalopathy now in remission. The trial focused on colonic microbial cross‐resistance to other antibiotics in the people treated with rifaximin alone vs rifaximin plus lactulose. We excluded this trial as rifaximin was administered to both groups, and no data on hepatic encephalopathy were reported.
Frenette 2020b	Randomised, open‐label trial evaluating rifaximin versus rifaximin plus lactulose for 6 months in 66 participants with previous hepatic encephalopathy now in remission. The trial focused on the impact of rifaximin alone or rifaximin plus lactulose treatment on stool microbiota in people with a history of OHE. We excluded this trial as rifaximin was administered to both groups, and no data on hepatic encephalopathy were reported.
Gangarapu 2015	A prospective, open‐label, observational cohort study in participants with biopsy‐proven NAFLD/NASH in whom circulating endotoxins and cytokines were measures before and after 28 days of rifaximin. We excluded this study because it was not randomised or controlled and the participants did not have cirrhosis or hepatic encephalopathy.
Giacomo 1993	Randomised, double‐blind, double‐dummy clinical trial involving 40 participants with mild hepatic encephalopathy allocated to rifaximin (n = 20), or lactulose (n = 20). We have excluded this study as we were unable to extract quantitative data. We contacted Alfa Sigma for further information on 3 April 2021 but have b not received a response.
Gupta 2021	A prospective, open‐label, randomised clinical trial comparing rifaximin versus rifaximin plus norfloxacin for secondary prophylaxis of spontaneous bacterial peritonitis in 62 participants with cirrhosis and hepatic encephalopathy. We excluded this study because both trial groups received rifaximin.
Habib 2020	Randomised, dose‐comparison trial evaluating rifaximin 400 mg daily and rifaximin 1100 mg daily in 80 participants with cirrhosis and hepatic encephalopathy. We excluded this trial as there was no suitable comparator.
Hammond 2017	Retrospective cohort study in which participants who had experienced an episode of hepatic encephalopathy in the previous 6 months were reviewed and outcomes in those who had received lactulose plus rifaximin (n = 169) were compared with those receiving lactulose alone (n = 437). We excluded this study because it was not randomised.
Hotten 2003	Randomised trial involving 30 participants with compensated Child B cirrhosis allocated in equal numbers to receive 3‐week treatment with (i) lactitol; (ii) rifaximin; or (iii) the symbiotic SCM‐III. The primary objective was the effect of the three treatments on faecal organic acid excretion and gut flora changes. We excluded this study as none of the participants had hepatic encephalopathy at baseline and neuropsychiatric status was not monitored during the study.
Huang 2018	This abstract reports the results of an analysis of gut microbiome and its metabolites in participants with cirrhosis who had a variceal haemorrhage, underwent endoscopic intervention for prophylaxis of re‐bleeding and received 8‐week rifaximin treatment based on a randomised open‐label trial of rifaximin versus no antibiotic treatment; this trial appears to have two registrations on clinical trials.gov‐‐ NCT02991612 and NCT02964195. The only results reported to date appear to be those pertaining to the gut microbiome. We excluded this study as hepatic encephalopathy was not included as a primary or secondary end point.
Jain 2022	A double‐blind, randomized, placebo‐controlled trial, involving 140 participants with cirrhosis and acute hepatic encephalopathy who received a combination of L‐ornithine L‐aspartate, lactulose, and rifaximin or placebo, lactulose, and rifaximin. We excluded this study as both trials groups received rifaximin.
Jiménez 2022	A multicentre, open, comparative pilot study exploring the use of rifaximin as an add‐on to standard therapy in a prospective cohort of 21 participants with severe alcoholic hepatitis; outcomes were compared with a matched historical cohort of 42 participants with severe alcoholic hepatitis from other countries; the primary outcome was the incidence of infection. We excluded this study because it was not randomised; the proportion of participants with underlying cirrhosis was not specified and hepatic encephalopathy, although monitored, was not one of the stated outcomes.
John 2018	Randomised trial involving participants with cirrhosis and overt hepatic encephalopathy randomised in groups of 20 to (i) rifaximin plus branched chain amino acids (BCAA); (ii) rifaximin plus bovine immunoglobulin (IG) or (iii) rifaximin plus BCAA plus bovine IG. The study was excluded as a non‐rifaximin control group was not included.
Jones 2020	Retrospective, data‐linked analysis of 4669 people with newly diagnosed hepatic encephalopathy treated with either rifaximin, lactulose or a combination of the two in primary care. Treatment was assumed to last for 28 days either side of the prescription date. We excluded this study from the main analyses as it was not randomised, but included survival data in our review of harms.
Kaji 2017	Observational study examining the effects of 4‐weeks' treatment with rifaximin in 20 participants with decompensated cirrhosis. The study was excluded from the quantitative analyses as it was not controlled, but data on the adverse events were included in our review of harms.
Kalambokis 2012a	Open‐label, observational study to assess the effects of 4 weeks of treatment with rifaximin on systemic haemodynamics and renal function in 13 participants with alcohol‐related cirrhosis and ascites. The study was excluded because it was observational and uncontrolled.
Kalambokis 2012b	Open‐label, observational study to assess the effects of 4 weeks of treatment with rifaximin on platelet counts, plasma endotoxin and serum interleukin‐1 (IL‐1), interleukin‐6 (IL‐6) and tumour necrosis factor‐α (TNF‐α) in 25 participants with alcohol‐related cirrhosis and thrombocytopenia. Four participants had hepatic encephalopathy at baseline (two in each group); no follow‐up data were provided on neuropsychiatric status; no adverse events were reported. We excluded this study as it was observational and did not report on our end points of interest.
Kalambokis 2012c	Open‐label, observational study to assess the effects of either 4 weeks treatment with rifaximin (n = 9) or no treatment (n = 7) on the occurrence of spontaneous bacterial peritonitis (SBP) in participants with cirrhosis and ascites but no history of previous SBP. The study was observational and did not include an assessment of neuropsychiatric status; no side effects of treatment were recorded.
Kalambokis 2012d	Open‐label, observational study to assess the effects of 8 weeks treatment with rifaximin on endotoxaemia, liver function and disease severity in nine liver transplant candidates with alcohol‐related cirrhosis. Hepatic encephalopathy was assessed as none (n = 4) or suppressed by medication (n = 5) both before and after treatment with rifaximin; it was unclear whether the participants with suppressed hepatic encephalopathy were receiving other anti‐encephalopathy medication. The trial was excluded as it was observational and uncontrolled; no adverse events were reported.
Kang 2017	Retrospective study comparing the effects of rifaximin plus lactulose versus lactulose alone in 1042 participants with a previous episode of hepatic encephalopathy. We excluded this trial as it was not randomised; however, we considered the data on adverse events in our assessment of harms.
Kawaratani 2022	A multicenter, retrospective, observational, cohort study of 215 consecutive participants with cirrhosis and at least Grade 1 hepatic encephalopathy treated with rifaximin for > 12 months. The primary outcome was the effectiveness of long‐term rifaximin treatment; the secondary outcome was the safety of long‐term rifaximin treatment. We excluded this study because it was uncontrolled and because no serious adverse events were reported.
Khokhar 2015	Randomised, 6‐month, dose‐comparison study involving 306 participants with cirrhosis with at least one previous episode of overt hepatic encephalopathy allocated to rifaximin 550 mg once daily (n = 128) or rifaximin 550 mg twice daily (n = 178). We excluded this study as there was no control arm.
Kimer 2018	Randomised, placebo‐controlled, double‐blind clinical trial involving 54 participants with cirrhosis and ascites allocated to rifaximin (n = 36) or placebo (n = 18) for 28 days. No clinical data were reported in this publication but clinically relevant data were reported from the same dataset of participants in Kimer 2017.
Kimer 2022	An open‐label, randomised, clinical trial involving 32 participants with severe alcoholic hepatitis who were allocated to standard medical therapy (SMT) or SMT plus rifaximin. We excluded this study because it was unclear whether some or all of the participants had cirrhosis and because although neurocognitive status was assessed at baseline it did not appear to have been monitored during the study.
Kubota 2022	Randomised, open‐label study involving 83 people with cirrhosis and Grade I or II hepatic encephalopathy, refractory to non‐absorbable disaccharides, allocated to 12‐weeks treatment with rifaximin (n = 42) or rifaximin plus L‐carnitine (n = 41). Lactulose treatment was continued throughout. We excluded this study because there was no appropriate control group as rifaximin was given in both study arms.
Lauridsen 2018	Randomised, double‐blind, study comparing the effects of 3 months treatment with lactulose, branched‐chain amino acids and rifaximin versus triple placebo in 44 participants with cirrhosis none of whom had evidence of overt hepatic encephalopathy although 22 manifest features of minimal hepatic encephalopathy on testing. We excluded this study as participants receive other potentially active anti‐encephalopathy medication in addition to rifaximin.
Lighthouse 2004	Randomised open‐label trial comparing the effects of (i) rifaximin (2 weeks); (ii) SCM‐III (symbiotic) (2 weeks); and, (iii) rifaximin (1 week) followed by SCM‐III (5 weeks) on circulating benzodiazepine‐like substances, ammonia and endotoxin in 30 participants with viral‐related cirrhosis. All participants were taking low dose non‐absorbable disaccharide before the trial, but this was stopped 2 weeks before enrolment. We excluded this study as there was no appropriate control group and neuropsychiatric status was not assessed.
Miglio 1997	Randomised trial involving 49 people with cirrhosis allocated to either rifaximin or neomycin for 14 consecutive days each month, for a period of six months. We excluded this study as it compared rifaximin with another antibiotic.
Mohamed 2018	Randomised comparison of the effects of rifaximin (n = 60) versus metronidazole (n = 60) for the treatment of an acute episode of hepatic encephalopathy in participants with cirrhosis. We excluded this study as it compared rifaximin with another antibiotic.
Mostafa 2015	Randomised single‐blind comparison of the effects of 6‐months treatment with rifaximin (n = 40) or norfloxacin (n = 30) for the prevention of spontaneous bacterial peritonitis in participants with cirrhosis and ascites. The study was excluded because it compared rifaximin with another antibiotic; neuropsychiatric status was not evaluated or monitored.
Mullen 2014	A 24‐month, open label maintenance study of rifaximin in 392 participants with hepatic encephalopathy who had either participated in a prior randomised clinical trial or were newly enrolled. The primary outcome was safety, namely adverse events and clinical laboratory parameters. We excluded the trial as it was observational; however, we did include data on adverse events in our review of harms.
NCT00364689	A single‐centre, randomised, controlled trial evaluating the efficacy and safety of rifaximin, given alone or in combination with lactulose, as compared to lactulose given alone, in people in remission from prior acute episodes of HE. We excluded this trial as it was terminated before completion because of recruitment difficulties.
NCT00748904	A randomised, open label, single‐centre trial of rifaximin versus lactulose in hospital inparticipants with cirrhosis with progressive renal failure and stage 0 to 2 hepatic encephalopathy; the primary end points are progression to severe hepatic encephalopathy and severe adverse events (renal failure). Extractable data might have been available from this trial, once completed, but it has now been withdrawn.
NCT01676597	Randomised, double‐blind trial to evaluate the effects of pentoxifylline in participants with clinical or subclinical hepatopulmonary syndrome; those not responding will continue treatment with pentoxifylline but will also be randomised to either rifaximin or placebo. We excluded this trials as neuropsychiatric status will not be monitored. The trial's current status is unknown.
NCT01846806	Observational study examining the effects of 14 days treatment with rifaximin on bacterial overgrowth and delayed intestinal transit in 10 participants with cirrhosis. The trial was terminated but would have been excluded as it was observational and uncontrolled.
NCT01897051	Randomised study comparing the effects of propranolol plus rifaximin versus propranolol plus placebo on the hepatic vein pressure gradient and the occurrence of upper gastrointestinal bleeding in 140 participants with cirrhosis and portal hypertension. The trial's current status is unknown. However, we excluded the trial as propranolol can have adverse effects on hepatic encephalopathy.
NCT01951209	A pilot study of the effect of rifaximin on B‐cell dysregulation in cirrhosis. The study was terminated due to failed recruitment but would have been excluded as it did not appear that relevant clinical data would be collected.
NCT02011841	Randomised study to compare the effects of rifaximin and ciprofloxacin for the secondary prevention of spontaneous bacterial peritonitis in participants with cirrhosis. This trial was terminated early because of poor recruitment but would have been excluded as it involved comparison with another antibiotic, and it was unclear if data on hepatic encephalopathy would be collected.
NCT02485106	Randomised, open‐label study to evaluate the effect of rifaximin as an adjuvant to treatment with steroids or pentoxifylline in 170 participants with severe alcoholic hepatitis. The current status of this study is unknown, but it would be excluded as participants may or may not have coexisting cirrhosis and hepatic encephalopathy was not one of the stated outcomes.
NCT03712280	A randomised, open‐label, completed comparator study to assess the pharmacodynamics, safety and pharmacokinetics of 3 different dose regimes of L‐ornithine phenylacetate versus rifaximin over a 5‐day period in 50 people with cirrhosis and a history of previous episodes of hepatic encephalopathy. The trial is completed, and the results posted on the clinicaltrials.gov website. We excluded this study as the comparator was not one of those stipulated for this review.
NCT04159870	Randomised, open‐label trial comparing rifaximin versus norfloxacin for the primary prophylaxis of spontaneous bacterial peritonitis in 322 adults with cirrhosis and ascites. The study is active but not recruiting. We excluded this trial as the comparator was another antibiotic, and we were uncertain if relevant clinical data on hepatic encephalopathy would be collected.
Oey 2019	Observational study involving 127 people with cirrhosis and overt hepatic encephalopathy allocated to rifaximin, with or without concomitant lactulose who were followed for at least 6 months or until death, liver transplantation, or permanent discontinuation of rifaximin. We excluded this study as it is observational; however, we included the reported adverse events in our review of harms.
Orr 2016	Observational study involving 326 participants with cirrhosis receiving rifaximin for the secondary prevention of hepatic encephalopathy. We excluded this study as it was observational; however, we included the data on adverse events in out review of harms.
Parini 1992	Randomised trial involving 30 adults with cirrhosis and an acute episode of hepatic encephalopathy allocated to rifaximin (n = 15) or paromomycin (n = 15) for 15 days. We excluded this trial as the comparator was another antibiotic.
Pedretti 1991	Randomised, double‐blind study involving 30 participants with cirrhosis and an acute episode of hepatic encephalopathy allocated to rifaximin (n = 15) or neomycin (n = 15) for 21 days. We excluded this study as the comparator was another antibiotic.
Ponziani 2016	An open‐label, observational study aimed at exploring the correlation between gut microbiota modulation and symptoms improvement in participants undergoing rifaximin treatment, including a small number with cirrhosis and hepatic encephalopathy (n = 4). We excluded this study as it was observational and did not provide quantifiable data.
Pose 2020	Randomised, double‐blind, placebo‐controlled, dose‐safety study in 50 people with decompensated cirrhosis and moderate‐to‐severe liver failure assigned to simvastatin 20 mg/day plus rifaximin 1200 mg/day (n = 18), simvastatin 40 mg/day plus rifaximin 1200 mg/day (n = 16), or double placebo (n = 16). The primary end points were liver and muscle toxicity, estimated by changes in circulating enzyme activities. This study was excluded because no relevant clinical data were collected. This is the preliminary safety study for an efficacy study registered as ClinicalTrials.gov NCT03780673 which is currently recruiting.
Praharaj 2022	Randomised, open‐label 6‐month study of rifaximin versus norfloxacin for the primary (n = 59) and secondary (n = 59) prevention of spontaneous bacterial peritonitis in participants with cirrhosis and ascites. Participants with prior overt or recurrent hepatic encephalopathy were excluded. We excluded this study as the comparator was another antibiotic and hepatic encephalopathy was not one of the primary outcomes.
Saboo 2021	Cross‐sectional study of sex‐differences in gut microbial function and composition in participants with cirrhosis and hepatic encephalopathy receiving rifaximin plus lactulose (n = 170,) participants with cirrhosis and hepatic encephalopathy receiving lactulose alone (n = 130), participants with cirrhosis and no evidence of hepatic encephalopathy (n = 319) and healthy controls (n = 142). We excluded this study as it was not randomised and did not report clinically relevant outcomes.
Salehi 2019	A retrospective analysis of 101 participants with at least two episodes of overt hepatic encephalopathy resulting in hospitalisation, or else encephalopathy at the time of assessment. Rifaximin‐treated or rifaximin‐naive participants were analysed. We excluded this study as it was not randomised; however, we included the data on adverse events in our review of harms.
Sama 2004	Observational, open‐label study involving 26 participants with cirrhosis and hepatic encephalopathy previously intolerant or non‐responsive to treatment with lactulose who were treated with rifaximin for a 10‐day period. We excluded this trial as it was not controlled but considered the data on adverse events in our review of harms.
Sarwar 2019	Randomised, double‐blind, quasi‐experimental trial involving 75 participants with decompensated cirrhosis but no history of hepatic encephalopathy allocated to rifaximin 400 mg (n = 34), or 1100 mg (n = 41) daily. We excluded this study as it was essentially dose ‐finding exercise with no control group.
Schulz 2019	Observational study to characterise the active bacterial assemblages in the upper gut and stool samples in participants with cirrhosis and minimal hepatic encephalopathy before, during and after long‐term treatment with rifaximin. The participants comprised a subset of 5 of the 60 individuals recruited to the “RiMINI” trial; they were allocated to either 3‐months of rifaximin monotherapy (n = 1) or to 3‐months of rifaximin plus lactulose (n = 4). We excluded this trial as rifaximin was used in both study arms and no relevant outcomes were reported.
Seifert 2021	A retrospective study looking at the prevention of hepatic encephalopathy post insertion of a transjugular intrahepatic portosystemic shunt; participants either received no treatment (n = 83) lactulose (n = 85), rifaximin (n = 6), rifaximin plus lactulose (n = 59) with or without L‐ornithine L‐aspartate. We excluded this study as it was a retrospective and treatment was not randomised.
Song 2021	A pilot, multicentre, open‐label, randomised clinical trial in 42 participants with severe alcoholic hepatitis receiving corticosteroids or pentoxifylline; participants were randomized to rifaximin or control stratified by treatment for the underlying condition. We excluded this study because the participants did not have cirrhosis and hepatic encephalopathy was not an end point.
Suzuki 2019	Retrospective 'real‐world' cohort study involving 65 participants with cirrhosis and hepatic encephalopathy on long‐term treatment with rifaximin. Participants were allowed to take other potentially active anti‐encephalopathy medications such as non‐absorbable disaccharides and branched‐chain amino acids. We excluded this study as it was not randomised or controlled; however, we considered the data on adverse events in our review of harms.
Tatsumi 2021	Observational study involving 37 participants with cirrhosis and hepatic encephalopathy who were switched from treatment with kanamycin sulphate to rifaximin. We excluded this study as it was observational; however, we considered the reported adverse events in our review of harms.
Testa 1985	Observational study involving 20 people with cirrhosis and minimal hepatic encephalopathy who were pretreated for one week with lactulose and were then randomly allocated to treatment with rifaximin or paromomycin for a further 5 days. We excluded this study as the comparator was another antibiotic.
Uchida 2020	Retrospective, observational study involving 95 participants with decompensated cirrhosis. Those with unmanageable overt hepatic encephalopathy and/or hyperammonaemia received rifaximin, with or without a concomitant non‐absorbable disaccharides. We excluded this study as it was not randomised; however, we included data on adverse events in our review of harms.
UMIN000036998	A randomised, open‐label controlled trial comparing zinc‐rifaximin combination therapy with zinc monotherapy in participants with hypozincaemia and minimal hepatic encephalopathy. This study has been terminated but would have been excluded because there was no inert control group.
UMIN000038487	Randomised, open‐label trial comparing the effects of rifaximin for 12 weeks versus standard treatment for the prevention of hepatorenal syndrome in 94 participants with cirrhosis and ascites. The trial is ongoing but would be excluded as it does not appear that participants' neuropsychiatric status will not be assessed.
Venturini 2005	Randomised study involving 18 participants with cirrhosis with no evidence of hepatic encephalopathy allocated, in groups of six, to either rifaximin, lactulose or placebo for 7 days to assess the effects on serum benzodiazepine‐like compounds. The study was excluded as none of the participants had hepatic encephalopathy and no information was provided on relevant outcomes.
Vittitow 2018	Pharmacokinetic study of two formulations of rifaximin in healthy volunteers.
Vlachogiannakos 2013	Assessment of the effects of long‐term rifaximin on outcomes in 23 participants with decompensated alcohol‐related cirrhosis who had shown improved liver haemodynamics while taking rifaximin and in 46 (pair matched) participants who did not receive rifaximin; both groups were followed for up to 5 years, death, or liver transplantation. We excluded this study as treatment allocation was not randomised, although we included the data on adverse events in our review of harms.
Walker 2020	Observational study involving 389 adults with cirrhosis and persistent hepatic encephalopathy. Outcomes were assessed for a minimum of 12 months, and compared between those receiving rifaximin (n = 280) and those receiving standard care (n = 89). We excluded this study as it was not randomised; however, we included the data on adverse events in our review of harms.
Williams 2000	Randomised, double‐blind, dose‐finding study involving 54 participants with cirrhosis and mild to moderate hepatic encephalopathy allocated to rifaximin 600 mg daily (n = 18), 1200 mg daily (n = 19) or 2400 mg daily (n = 17). We excluded this study as it lacked a control group.
Yang 2016	Randomised, trial comparing the effects of (i) L‐ornithine L‐aspartate; (ii) rifaximin and (iii) L‐ornithine L‐aspartate plus rifaximin in 80 participants with cirrhosis and an acute episode of hepatic encephalopathy. We excluded this study as no suitable control group was included, and hepatic encephalopathy outcomes were not reported.
Zeng 2015	Randomised open‐label study involving 43 participants with decompensated cirrhosis free of overt hepatic encephalopathy allocated, for a period of 2 weeks, to low‐dose rifaximin (800 mg daily; n = 14); high‐dose rifaximin (1200 mg/day; n = 14) or no treatment (n = 15). We excluded the trial from our main analyses as no information was provided on neuropsychiatric status during or following treatment, but we included data on adverse events in our review of harms.

ALT: serum alanine aminotransferase; NAFLD/NASH: non‐alcoholic fatty liver disease/non‐alcoholic steatohepatitis; OHE: overt hepatic encephalopathy