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. 2023 Jul 19;7(7):CD011585.
doi: 10.1002/14651858.CD011585.pub2.

Rifaximin for prevention and treatment of hepatic encephalopathy in people with cirrhosis

Harry D Zacharias  1 , Fady Kamel  1 , Jaclyn Tan  1 , Nina Kimer  2 , Lise Lotte Gluud  2 , Marsha Y Morgan  1
Affiliations

Rifaximin for prevention and treatment of hepatic encephalopathy in people with cirrhosis

Harry D Zacharias et al. Cochrane Database Syst Rev. .

Abstract

Background: Hepatic encephalopathy describes the spectrum of neuropsychiatric changes that may complicate the course of cirrhosis and detrimentally affect outcomes. Ammonia plays a key role in its development. Rifaximin is a non-absorbable antibiotic that inhibits urease-producing bacteria and reduces absorption of dietary and bacterial ammonia.

Objectives: To evaluate the beneficial and harmful effects of rifaximin versus placebo, no intervention, or non-absorbable disaccharides for: (i) the prevention of hepatic encephalopathy, and (ii) the treatment of minimal and overt hepatic encephalopathy, in people with cirrhosis, both when used alone and when combined with a non-absorbable disaccharide.

Search methods: We searched the Cochrane Hepato-Biliary Group Clinical Trials Register, CENTRAL, MEDLINE, Embase, three other databases, the reference lists of identified papers, and relevant conference proceedings. We wrote to authors and pharmaceutical companies for information on other published, unpublished, or ongoing trials. Searches were performed to January 2023.

Selection criteria: We included randomised clinical trials assessing prevention or treatment of hepatic encephalopathy with rifaximin alone, or with a non-absorbable disaccharide, versus placebo/no intervention, or a non-absorbable disaccharide alone.

Data collection and analysis: Six authors independently searched for studies, extracted data, and validated findings. We assessed the design, bias risk, and participant/intervention characteristics of the included studies. We assessed mortality, serious adverse events, health-related quality of life, hepatic encephalopathy, non-serious adverse events, blood ammonia, Number Connection Test-A, and length of hospital stay.

Main results: We included 41 trials involving 4545 people with, or at risk for, developing hepatic encephalopathy. We excluded 89 trials and identified 13 ongoing studies. Some trials involved participants with more than one type of hepatic encephalopathy or more than one treatment comparison. Hepatic encephalopathy was classed as acute (13 trials), chronic (7 trials), or minimal (8 trials), or else participants were considered at risk for its development (13 trials). The control groups received placebo (12 trials), no/standard treatment (1 trial), or a non-absorbable disaccharide (14 trials). Eighteen trials assessed rifaximin plus a non-absorbable disaccharide versus a non-absorbable disaccharide alone. We classified 11 trials as at high risk of overall bias for mortality and 28 for non-mortality outcomes, mainly due to lack of blinding, incomplete outcome data, and selective reporting. Compared to placebo/no intervention, rifaximin likely has no overall effect on mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.50 to 1.38; P = 48, I2 = 0%; 13 trials, 1007 participants; moderate-certainty evidence), and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.99, 95% CI 0.49 to 1.97; P = 0.97, I2 = 0%; 10 trials, 786 participants; low-certainty evidence). However, there is likely a reduction in the overall risk of mortality when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.69, 95% CI 0.55 to 0.86; number needed to treat for an additional beneficial outcome (NNTB) = 22; P = 0.001, I2 = 0%; 14 trials, 1946 participants; moderate-certainty evidence). There is likely no effect on the overall risk of serious adverse events when comparing rifaximin to placebo/no intervention (RR 1.05, 95% CI 0.83 to 1.32; P = 68, I2 = 0%; 9 trials, 801 participants; moderate-certainty evidence) and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.97, 95% CI 0.66 to 1.40; P = 85, I2 = 0%; 8 trials, 681 participants; low-certainty evidence). However, there was very low-certainty evidence that use of rifaximin plus a non-absorbable disaccharide may be associated with a lower risk of serious adverse events than use of a non-absorbable disaccharide alone (RR 0.66, 95% CI 0.45 to 0.98; P = 0.04, I2 = 60%; 7 trials, 1076 participants). Rifaximin likely results in an overall effect on health-related quality of life when compared to placebo/no intervention (mean difference (MD) -1.43, 95% CI -2.87 to 0.02; P = 0.05, I2 = 81%; 4 trials, 214 participants; moderate-certainty evidence), and may benefit health-related quality of life in people with minimal hepatic encephalopathy (MD -2.07, 95% CI -2.79 to -1.35; P < 0.001, I2 = 0%; 3 trials, 176 participants). The overall effect on health-related quality of life when comparing rifaximin to non-absorbable disaccharides is very uncertain (MD -0.33, 95% CI -1.65 to 0.98; P = 0.62, I2 = 0%; 2 trials, 249 participants; very low-certainty evidence). None of the combined rifaximin/non-absorbable disaccharide trials reported on this outcome. There is likely an overall beneficial effect on hepatic encephalopathy when comparing rifaximin to placebo/no intervention (RR 0.56, 95% CI 0.42 to 0.77; NNTB = 5; P < 0.001, I2 = 68%; 13 trials, 1009 participants; moderate-certainty evidence). This effect may be more marked in people with minimal hepatic encephalopathy (RR 0.40, 95% CI 0.31 to 0.52; NNTB = 3; P < 0.001, I2 = 10%; 6 trials, 364 participants) and in prevention trials (RR 0.71, 95% CI 0.56 to 0.91; NNTB = 10; P = 0.007, I2 = 36%; 4 trials, 474 participants). There may be little overall effect on hepatic encephalopathy when comparing rifaximin to non-absorbable disaccharides (RR 0.85, 95% CI 0.69 to 1.05; P = 0.13, I2 = 0%; 13 trials, 921 participants; low-certainty evidence). However, there may be an overall beneficial effect on hepatic encephalopathy when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.58, 95% CI 0.48 to 0.71; NNTB = 5; P < 0.001, I2 = 62%; 17 trials, 2332 participants; low-certainty evidence).

Authors' conclusions: Compared to placebo/no intervention, rifaximin likely improves health-related quality of life in people with minimal hepatic encephalopathy, and may improve hepatic encephalopathy, particularly in populations with minimal hepatic encephalopathy and when it is used for prevention. Rifaximin likely has no overall effect on mortality, serious adverse events, health-related quality of life, or hepatic encephalopathy compared to non-absorbable disaccharides. However, when used in combination with a non-absorbable disaccharide, it likely reduces overall mortality risk, the risk of serious adverse events, improves hepatic encephalopathy, reduces the length of hospital stay, and prevents the occurrence/recurrence of hepatic encephalopathy. The certainty of evidence for these outcomes is very low to moderate; further high-quality trials are needed.

Trial registration: ClinicalTrials.gov NCT00533910 NCT00298038 NCT02016196 NCT01769040 NCT04787276 NCT04736836 NCT02019784 NCT03077217 NCT02321371 NCT02190357 NCT01904409 NCT01842581 https://clinicaltrials.gov/ct2/show/NCT03515044 NCT02991612 NCT00686920 https://clinicaltrials.gov/ct2/show/NCT01676597 https://clinicaltrials.gov/ct2/show/NCT01846806 https://clinicaltrials.gov/show/nct01897051 https://clinicaltrials.gov/ct2/show/NCT01951209 https://clinicaltrials.gov/ct2/show/NCT02011841 https://clinicaltrials.gov/ct2/show/NCT02485106 https://clinicaltrials.gov/ct2/show/NCT03712280 NCT04159870 NCT03695705 NCT02488993 clinicaltrials.gov/ct2/show/NCT02508623 https://clinicaltrials.gov/ct2/show/NCT03069131 NCT04073290 NCT04775329 NCT05071716.

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Conflict of interest statement

HZ: has declared that they have no conflict of interest.

FK: has declared that they have no conflict of interest.

JT: has declared that they have no conflict of interest.

NK: reports being employed as a postdoctoral fellow in translational medicine by the University of Copenhagen, between 2016 and 2019 supported by the Novo Nordisk Foundation (grant no: NNF18SA0034956); she reports authorship of one of the trials included in this review (Kimer 2017) and of a previous systematic review and meta‐analysis of the effects of rifaximin in hepatic encephalopathy (Kimer 2014).

LG: reports receiving funding for research from Novo Nordisk, Alexion, Gilead, and Sobi International; she reports being a member of an advisory board for Novo Nordisk; she reports authorship of one of the trials included in this review (Kimer 2017) and of a previous systematic review and meta‐analysis of the effects of rifaximin in hepatic encephalopathy (Kimer 2014).

MM: has declared that they have no conflict of interest.

Figures

1
1
PRISMA flow diagram. Date of last search January 2023
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
4
4
Funnel plot for studies assessing the effects of rifaximin versus placebo or no intervention on mortality outcomes
5
5
Funnel plot for studies assessing the effects of rifaximin versus placebo or no intervention on hepatic encephalopathy outcomes
6
6
Funnel plot for studies assessing the effects of rifaximin versus non‐absorbable disaccharide on hepatic encephalopathy outcomes
7
7
Funnel plot for studies assessing the effects of rifaximin plus non‐absorbable disaccharide versus non‐absorbable disaccharide alone on mortality outcomes
8
8
Funnel plot for studies assessing the effects of rifaximin plus non‐absorbable disaccharide versus non‐absorbable disaccharide alone on hepatic encephalopathy outcomes
1.1
1.1. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 1: Mortality
1.2
1.2. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 2: Serious adverse events
1.3
1.3. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 3: Health‐related quality of life
1.4
1.4. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 4: Hepatic encephalopathy
1.5
1.5. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 5: Mortality (worst‐case)
1.6
1.6. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 6: Serious adverse events (worst‐case)
1.7
1.7. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 7: Hepatic encephalopathy (worst‐case)
1.8
1.8. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 8: Mortality (extreme worst‐case)
1.9
1.9. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 9: Serious adverse events (extreme worst‐case)
1.10
1.10. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 10: Hepatic encephalopathy (extreme worst‐case)
1.11
1.11. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 11: Mortality (best‐case)
1.12
1.12. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 12: Serious adverse events (best‐case)
1.13
1.13. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 13: Hepatic encephalopathy (best‐case)
1.14
1.14. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 14: Mortality (extreme best‐case)
1.15
1.15. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 15: Serious adverse events (extreme best‐case)
1.16
1.16. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 16: Hepatic encephalopathy (extreme best‐case)
1.17
1.17. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 17: Non‐serious adverse events
1.18
1.18. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 18: Blood ammonia
1.19
1.19. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 19: Blood ammonia (paired)
1.20
1.20. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 20: Number Connection Test A
1.21
1.21. Analysis
Comparison 1: Rifaximin versus placebo/no intervention, Outcome 21: Number Connection Test A (paired)
2.1
2.1. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 1: Mortality
2.2
2.2. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 2: Serious adverse events
2.3
2.3. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 3: Health‐related quality of life
2.4
2.4. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 4: Hepatic encephalopathy
2.5
2.5. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 5: Mortality (worst‐case)
2.6
2.6. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 6: Mortality (extreme worst‐case)
2.7
2.7. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 7: Mortality (best‐case)
2.8
2.8. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 8: Mortality (extreme best‐case)
2.9
2.9. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 9: Serious adverse events (extreme best‐case)
2.10
2.10. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 10: Serious adverse events (best‐case)
2.11
2.11. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 11: Serious adverse events (worst‐case)
2.12
2.12. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 12: Serious adverse events (extreme worst‐case)
2.13
2.13. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 13: Hepatic encephalopathy (worst‐case)
2.14
2.14. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 14: Hepatic encephalopathy (extreme worst‐case)
2.15
2.15. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 15: Hepatic encephalopathy (best‐case)
2.16
2.16. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 16: Hepatic encephalopathy (extreme best‐case)
2.17
2.17. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 17: Non‐serious adverse events
2.18
2.18. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 18: Blood ammonia
2.19
2.19. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 19: Blood ammonia (paired)
2.20
2.20. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 20: Number Connection Test A
2.21
2.21. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 21: Number Connection Test A (paired)
2.22
2.22. Analysis
Comparison 2: Rifaximin versus non‐absorbable disaccharides, Outcome 22: Length of hospital stay
3.1
3.1. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 1: Mortality
3.2
3.2. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 2: Serious adverse events
3.3
3.3. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 3: Hepatic encephalopathy
3.4
3.4. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 4: Mortality (extreme best‐case)
3.5
3.5. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 5: Mortality (best‐case)
3.6
3.6. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 6: Mortality (worst‐case)
3.7
3.7. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 7: Mortality (extreme worst‐case)
3.8
3.8. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 8: Serious adverse events (worst‐case)
3.9
3.9. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 9: Serious adverse events (extreme worst‐case)
3.10
3.10. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 10: Serious adverse events (best‐case)
3.11
3.11. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 11: Serious adverse events (extreme best‐case)
3.12
3.12. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 12: Hepatic encephalopathy (worst‐case)
3.13
3.13. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 13: Hepatic encephalopathy (extreme worst‐case)
3.14
3.14. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 14: Hepatic encephalopathy (best‐case)
3.15
3.15. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 15: Hepatic encephalopathy (extreme best‐case)
3.16
3.16. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 16: Non‐serious adverse events
3.17
3.17. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 17: Blood ammonia
3.18
3.18. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 18: Blood ammonia (paired)
3.19
3.19. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 19: Number Connection Test A
3.20
3.20. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 20: Number Connection Test A (paired)
3.21
3.21. Analysis
Comparison 3: Rifaximin plus non‐absorbable disaccharides versus non‐absorbable disaccharides alone, Outcome 21: Length of hospital stay
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References

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Higuera‐de‐la‐Tijera 2018 {published data only (unpublished sought but not used)}
    1. NCT02158182. Lactulose, L-ornithine L-aspartate, or rifaximin versus placebo for preventing hepatic encephalopathy in variceal bleeding. clinicaltrials.gov/show/NCT02158182 (First posted 6 June 2014).
    1. La Tijera FH, Servín-Caamaño AI, Abdo-Francis JM, Salas-Gordillo F, Pérez-Hernández JL, Camacho-Aguilera J, et al. A randomized, double-blind, clinical trial comparing lactulose, l-ornithine l-aspartate, or rifaximin, versus placebo, as primary prophylaxis of hepatic encephalopathy in cirrhotic patients with variceal bleeding. Journal of Hepatology 2017;66(Supplement 1):S49. [DOI: 10.1016/S0168-8278(17)30362-8] - DOI
    1. la Tijera FH, Servín-Caamaño AI, Salas-Gordillo F, Pérez-Hernández JL, Abdo-Francis JM, Camacho-Aguilera J, et al. Primary prophylaxis to prevent the development of hepatic encephalopathy in cirrhotic patients with acute variceal bleeding. Canadian Journal of Gastroenterology and Hepatology 2018;2018:1-10. [DOI: 10.1155/2018/3015891] [PMID: ] - DOI - PMC - PubMed
Kimer 2017 {published and unpublished data}EUCTR2012‐002890‐71‐DK
    1. EudraCT 2012-002890-71. Intestinal decontamination with rifaximin. Effects on the inflammatory and circulatory state in patients with cirrhosis and ascites - a randomised controlled clinical study. www.clinicaltrialsregister.eu/ctr-search/search?query=2012-002890-71 2012.
    1. Kimer N, Gluud LL, Pedersen JS, Tavenier J, Møller S, Bendtsen F. The psychometric hepatic encephalopathy syndrome score does not correlate with blood ammonia, endotoxins or markers of inflammation in patients with cirrhosis. Translational Gastroenterology and Hepatology 2021;6(8):1-9. [DOI: 10.21037/tgh.2020.02.14] [PMCID: PMC7724176] [PMID: ] - DOI - PMC - PubMed
    1. Kimer N, Pedersen JS, Busk TM, Gluud LL, Hobolth L, Krag A, et al. Rifaximin has no effect on hemodynamics in decompensated cirrhosis: a randomized, double-blind, placebo-controlled trial. Hepatology 2017;65(2):592-603. [DOI: 10.1002/hep.28898] [PMID: ] - DOI - PubMed
    1. Kimer N, Pedersen JS, Tavenier J, Christensen JE, Busk TM, Hobolth L, et al. Rifaximin has limited effect on the inflammatory state and bacterial translocation in the patient with stable decompensated cirrhosis. Results from a randomized, placebo controlled trial. Hepatology 2016;64(Suppl 1):1041A. [DOI: 10.1002/hep.28799] - DOI
    1. Kimer N, Pedersen JS, Tavenier J, Christensen JE, Busk TM, Hobolth L, et al. Rifaximin has minor effects on bacterial composition, inflammation and bacterial translocation in cirrhosis; A randomized trial. Journal of Gastroenterology and Hepatology 2018;33(1):307-14. [DOI: 10.1111/jgh.13852] [PMID: ] - DOI - PubMed
Loguercio 2003 {published and unpublished data}
    1. Loguercio C, Federico A, De Girolamo V, Ferrieri A, Del Vecchio Blanco C. Cyclic treatment of chronic hepatic encephalopathy with rifaximin. Results of a double-blind clinical study. Minerva Dietologica e Gastroenterologica 2003;49:53-62. [PMID: ] - PubMed
Maharshi 2015 {published and unpublished data}
    1. Maharshi S, Sharma BC, Srivastava S, Jindal A. Prophylaxis of hepatic encephalopathy in acute variceal bleed in patients with cirrhosis: an open label randomized controlled trial of lactulose versus rifaximin. Journal of Clinical and Experimental Hepatology 2014;4(Suppl 2):S52-3.
    1. Maharshi S, Sharma BC, Srivastava S, Jindal A. Randomised controlled trial of lactulose versus rifaximin for prophylaxis of hepatic encephalopathy in patients with acute variceal bleed. Gut 2015;64:1341-2. [DOI: 10.1136/gutjnl-2014-308521] [PMID: ] - DOI - PubMed
    1. Maharshi S, Sharma BC, Srivastava S, Jindal A. Prophylaxis of hepatic encephalopathy in acute variceal bleed in patients with cirrhosis: An open label controlled trial of lactulose versus rifaximin. Journal of Hepatology 2014;60(Suppl):S59. [DOI: 10.1016/S0168-8278(14)60021-0] - DOI
Majeed 2018 {published data only (unpublished sought but not used)}
    1. Majeed A, Butt MW, Aziz HA. A comparison of rifaximin with placebo for the treatment of hepatic encephalopathy. Journal of Medical and Health Sciences 2018;12(1):362-4.
Manzhalii 2022 {published data only}
    1. Manzhalii E, Moyseyenko V, Jondratiuk V, Molochek N, Falalyeyeva T, Kobyliak N. Effect of a specific Escherichia coli Nissle 1917 strain on minimal/mild hepatic encephalopathy treatment. World Journal of Hepatology 2022;14(3):634-46. [DOI: 10.4254/wjh.v14.i3.634] - DOI - PMC - PubMed
    1. NCT04787276. Efficacy and Safety of E.Coli Nissle 1917 in Patients With Mild (Stage 1-2) or Minimal Hepatic Encephalopathy. https://clinicaltrials.gov/ct2/show/NCT04787276 (First posted 8 March 2021).
Mas 2003 {published and unpublished data}
    1. Mas A, Rodés J, Sunyer L, Rodrigo L, Planas R, Vargas V, et al. Comparison of rifaximin and lactitol in the treatment of hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial. Journal of Hepatology 2003;38:51-8. [DOI: 10.1016/s0168-8278(02)00350-1] [PMID: ] - DOI - PubMed
    1. Mas A. Treatment of hepatic encephalopathy (HE) with rifaximin compared with lactitol. Multicenter randomized, double-blind, double dummy study [Tratamiento de la encefalopatia hepatica (EH) con rifaximina en comparacion con lactitol. Estudio multicentrico aleatorizado, doble ciego, doble simulacion.]. Gastroenterologia y Hepatologia 1999;22(Suppl 1):40.
Massa 1993 {published and unpublished data}
    1. Massa P, Vallerino P, Dodero M. Treatment of hepatic encephalopathy with rifaximin. The European Journal of Clinical Research 1993;4:7-18.
Moneim 2021 {published data only}
    1. Moneim MA, Abdelaziz DH, Nagy YI, Baki AA, Attia AS, Sabry N. Rifaximin microbial resistance and its efficacy and safety as secondary prophylaxis of hepatic encephalopathy in patients with hepatitis C virus-related cirrhosis. International Journal of Clinical Practice 2021;75(11):1-11. [DOI: 10.1111/ijcp.14807] - DOI - PubMed
Muhammad 2016 {published data only}
    1. Muhammad N, Khan MAR, Hussain A. Role of rifaximin in preventing the recurrence of hepatic encephalopathy in patients with chronic liver disease. Pakistan Journal of Medical and Health Sciences 2016;10(4):1417-20.
Nawaz 2015 {published and unpublished data}
    1. Nawaz A, Ghafoor A, Khan A, Ullah H. Rifaximin versus placebo in reducing the risk of clinically overt hepatic encephalopathy recurrence in patients having cirrhosis of liver. Hepatology International 2015;9(Suppl 1):S104-5.
Paik 2005 {published and unpublished data}
    1. Kim MH, Han KH, Lee KS, Paik YH, Song KH, Na HK. Efficacy and safety of short-term administration of rifaximin in the treatment of hepatic encephalopathy. Korean Journal of Hepatology 2001;7(1):55-60. [onlinelibrary.wiley.com/o/cochrane/clcentral/articles/272/CN-01045272/fr...
    1. Paik Y, Lee KS, Han K, Song KH, Kim MH, Moon BS, et al. Comparison of rifaximin and lactulose for the treatment of hepatic encephalopathy: a prospective randomized study. Yonsei Medical Journal 2005;46(3):399-407. [DOI: 10.3349/ymj.2005.46.3.399] [PMCID: PMC2815818] [PMID: ] - DOI - PMC - PubMed
    1. Song KH, Lee KS, Kim MH, Paik YH, Moon BS, Yoon SH, et al. The clinical efficacy of rifaximin in the treatment of hepatic encephalopathy (Comparison with lactulose). Hepatology 2000;32(4):407A.
Patel 2022 {published and unpublished data}2013‐004708‐20
    1. EUCTR2013-004708-20-GB. A trial to determine if rifaximin is more efficient than placebo in treating systemic inflammation and neutrophil (white blood cells) malfunction in patients with cirrhosis and chronic hepatic encephalopathy. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (Registered 3 March 2014).
    1. NCT02019784. RIFSYS: randomised controlled trial of mechanistic effects of rifaximin in cirrhosis and chronic hepatic encephalopathy. clinicaltrials.gov/show/NCT02019784 (First posted 24 December 2013).
    1. Patel V, Lee S, McPhail M, De Silva K, Guilly S, Zamalloa A, et al. Rifaximin reduces gut-derived inflammation and mucin degradation in cirrhosis and encephalopathy: RIFSYS randomised controlled trial. Journal of Hepatology 2022;76(2):332-42. [DOI: 10.1016/j.jhep.2021.09.010] - DOI - PubMed
    1. Patel V, McPhail MJ, Zamalloa A, Støy S, Vijay GM, Huang X, et al. Results of a placebo-controlled double blind randomised trial to investigate the efficacy of rifaximin-alpha versus placebo in improving systemic inflammation in patients with cirrhosis and chronic hepatic encephalopathy (RIFSYS Trial). Journal of Hepatology 2018;68(Suppl 1):S107-8. [DOI: 10.1016/S0168-8278(18)30432-X] - DOI
    1. Patel V, Shawcross D, McPhail M. A placebo controlled single centre double blind randomised trial to investigate the efficacy of RIFaximin versus placebo in improving SYStemic inflammation and neutrophil malfunction in patients with cirrhosis and chronic hepatic encephalopathy. Scientific Report 2018:1-97.
Pawar 2019 {published data only (unpublished sought but not used)}
    1. Pawar V, Sonthalia N, Rathi P, Contractor Q, Surude R, Jain S, et al. Prospective randomized study of effect of lactulose or rifaximin or placebo in minimal hepatic encephalopathy. Indian Journal of Gastroenterology 2016;35(Suppl 1):A44. [DOI: 10.1007/s12664-016-0715-3] - DOI
    1. Pawar VB, Surude RG, Sonthalia N, Zanwar V, Jain S, Contractor Q, et al. Minimal hepatic encephalopathy in Indians: psychometric hepatic encephalopathy score and inhibitory control test for diagnosis and rifaximin or lactulose for its reversal. Journal of Clinical & Translational Hepatology 2019;7(4):304-12. [DOI: 10.14218/JCTH.2017.00037] [PMCID: PMC6943207] [PMID: ] - DOI - PMC - PubMed
Poudyal 2019 {published and unpublished data}
    1. Poudyal N, Chaudhary S, Kc S, Paudel B, Basnet B, Mandal A, et al. Precipitating factors and treatment outcomes of hepatic encephalopathy in liver cirrhosis. Cureus 2019;11(4):e4363. [DOI: 10.7759/cureus.4363] [PMCID: PMC6550494] [PMID: ] - DOI - PMC - PubMed
    1. Silwal NP, Kc S, Chaudhary S, Sharma M. Treatment outcome of hepatic encephalopathy in liver cirrhosis. Journal of Clinical and Experimental Hepatology 2018;8(S1):S51. [DOI: 10.1016/j.jceh.2018.06.363] - DOI
Riggio 2005 {published data only (unpublished sought but not used)}
    1. Masini A, Nicolao F, Efrati C, Merli M, Attili AF, Riggio O. Preliminary results of a randomised controlled trials in the prevention of early post-tips hepatic encephalopathy: a comparison between rifaximin and lactitol. Journal of Hepatology 2002;36(Suppl 1):205. [DOI: 10.1016/S0168-8278(02)80730-9] - DOI
    1. Riggio O, Masini A, Efrati C, Nicolao F, Angeloni S, Salvatori F, et al. Pharmacological prophylaxis of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled study. Journal of Hepatology 2005;42(4):674-9. [DOI: 10.1016/j.jhep.2004.12.028] [PMID: ] - DOI - PubMed
Sharma 2013 {published data only (unpublished sought but not used)}CTRI/2013/07/003845
    1. Lunia M, Sharma P, Sharma B, Sarin S. A double blind randomised controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of hepatic encephalopathy. Journal of Gastroenterology and Hepatology 2012;27(Suppl 5):52. [DOI: 10.1111/jgh.12005] - DOI - PubMed
    1. Lunia MK, Sharma BC, Sharma P, Sarin SK. A randomised double blind controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of hepatic encephalopathy. Journal of Clinical and Experimental Hepatology 2013;3(Suppl 1):S42. [DOI: 10.1016/j.jceh.2013.03.085] - DOI - PubMed
    1. NCT01218568. Rifaximin plus lactulose versus lactulose alone for the treatment of hepatic encephalopathy: a double blind randomized trial. clinicaltrials.gov/ct2/show/record/NCT01218568 (First posted 11 October 2010).
    1. Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R, Sarin SK. A randomised double blind controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Journal of Clinical and Experimental Hepatology 2013;3(1S):S5-7. [DOI: 10.1016/j.jceh.2013.03.011] - DOI - PubMed
    1. Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R, Sarin SK. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. American Journal of Gastroenterology 2013;108(9):1458-63. [DOI: 10.1038/ajg.2013.219] [PMID: ] - DOI - PubMed
Sharma 2014 {published data only (unpublished sought but not used)}
    1. Sharma K, Pant S, Dwivedi M, Misra SP, Misra A, Narang S. Minimal hepatic encephalopathy: effect of rifaximin, probiotics, and L-ornithine L-aspartate. Journal of Gastroenterology and Hepatology 2012;27(Suppl 5):275-6. [DOI: 10.1111/jgh.12006] - DOI - PMC - PubMed
    1. Sharma K, Pant S, Misra S, Dwiwedi M, Misra A, Narang S, et al. Effect of rifaximin, probiotics, and l-ornithine l-aspartate on minimal hepatic encephalopthy: a randomized controlled trial. Saudi Journal of Gastroenterology 2014;20(4):225-32. [DOI: 10.4103/1319-3767.136975] [PMCID: PMC4131305] [PMID: ] - DOI - PMC - PubMed
Sidhu 2011 {published data only}CTRI/2009/091/000979
    1. Sidhu SS, Goyal O, Mishra BP, Sood A, Chhina RS, Soni RK. Rifaximin improves psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (The RIME trial). American Journal of Gastroenterology 2011;106:307-16. [DOI: 10.1038/ajg.2010.455] [PMID: ] - DOI - PubMed
Sidhu 2016 {published and unpublished data}CTRI/2010/091/003045
    1. Goyal O, Sidhu SS, Kishore H. Minimal hepatic encephalopathy in cirrhosis - how long to treat? Annals of Hepatology 2017;16(1):115-22. [DOI: 10.5604/16652681.1226822] - DOI - PubMed
    1. Goyal O, Sidhu SS, Parker RA, Prasad J, Kishore H, Sood A, et al. Rifaximin versus lactulose in the treatment of minimal hepatic encephalopathy in patients with cirrhosis: a prospective, randomised, active-comparator, non-inferiority trial. Journal of Hepatology 2014;60(Suppl 1):S526.
    1. Goyal O, Sidhu S, Kishore H. Relapse of minimal hepatic encephalopathy after treatment in patients with liver cirrhosis. Hepatology International 2017;11(Suppl 1):S188-9. [DOI: 10.1007/s12072-016-9783-9] - DOI
    1. Sidhu SS, Goyal O, Parker RA, Prasad J, Kishore H, Sood A. Rifaximin vs. lactulose in treatment of minimal hepatic encephalopathy. Liver International 2016;36(3):378-85. [DOI: 10.1111/liv.12921] - DOI - PubMed
    1. Wander P, Goyal O, Sidhu SS, Kishore H. Minimal hepatic encephalopathy in cirrhosis: how long to treat? Does minimal hepatic encephalopathy relapse after treatment? American Journal of Gastroenterology 2016;111(Suppl 1):S371.
Suzuki 2018 {published data only (unpublished sought but not used)}JapicCTI‐132086JapicCTI‐132087
    1. Phase II/III clinical trial of L-105 in patients with hepatic encephalopathy. www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-132086 (First posted 19 March 2013).
    1. Phase III clinical trial of L-105 in patients with hepatic encephalopathy. www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-132087 (First posted 19 March 2013).
    1. Suzuki K, Endo R, Takikawa Y, Moriyasu F, Aoyagi Y, Moriwaki H, et al. Efficacy and safety of rifaximin in Japanese patients with hepatic encephalopathy: a phase II/III, multicenter,randomized, evaluator-blinded, active-controlled trial and a phase III, multicenter, open trial. Hepatology Research 2018;48(6):411-23. [DOI: doi: 10.1111/hepr.13045] [PMID: ] - PubMed
Tan 2022 {published data only}
    1. NCT03077217. Low-dose Rifaximin in the Treatment of Covert Hepatic Encephalopathy. https://clinicaltrials.gov/ct2/show/NCT03077217 ( First posted 10 March 2017).
    1. Tan W, Wang J, Shi PM, Feng LM, Shi J, Ning BF, et al. Effects of low-dose and high-dose rifaximin in the treatment of covert hepatic encephalopathy. Journal of Clinical and Translational Hepatology 2022 ;10(6):1099-1106. [DOI: 10.14218/JCTH.2021.00457] [PMCID: PMC9634763] [PMID: ] - DOI - PMC - PubMed
Uthman 2020 {published data only}
    1. Uthman M, Mujtaba SWA, Qaisar AM. Examine the efficacy of rifaximin for hepatic encephalopathy patients with chronic liver disease. Medical Forum Monthly 2020;31(4):19-22.
Vyas 2017 {published data only (unpublished sought but not used)}
    1. NCT02321371. Effect of goal directed ammonia lowering therapy in acute on chronic liver failure patients with hepatic encephalopathy. clinicaltrials.gov/ct2/show/NCT02321371 (First posted 22 December 2014).
    1. Vyas T, Maiwall R, Jinadal A, Sarin S. Goal directed ammonia lowering therapy in acute on chronic liver failure (ACLF) with hepatic encephalopathy (HE): a randomized trial. Journal of Clinical and Experimental Hepatology 2017;7(Suppl 1):S1-21. [DOI: 10.1016/j.jceh.2017.01.026] [NCT: NCT02321371] - DOI
    1. Vyas TS, Jindal A, Maiwall R, Sahney A, Kalal C, Premkumar M, et al. Goal directed ammonia lowering therapy in acute on chronic liver failure (ACLF) with hepatic encephalopathy (HE): a randomized trial. Hepatology 2016;64(Suppl 1):704-5A. [DOI: 10.1002/hep.28799] - DOI
    1. Vyas TS, Sarin SK, Maiwall R. Effect of goal directed ammonia lowering therapy in acute-on-chronic liver failure patients with hepatic encephalopathy. Indian Journal of Gastroenterology 2016;35(Suppl):A67-8. [DOI: 10.1007/s12664-016-0715-3] - DOI
Wahib 2014 {published data only (unpublished sought but not used)}
    1. Wahib AA, El-Deen Salem MN, Ahmed MA, El-Dessouky YM, El-Tiby DM, El-Mola K, et al. Evaluation of rifaximin in management of hepatic encephalopathy. Journal of the Egyptian Society of Parasitology 2014;44(3):677-85. [DOI: 10.12816/0007871] [PMID: ] - DOI - PubMed
Zeng 2021 {published data only (unpublished sought but not used)}
    1. NCT02190357. Rifaximin reduces the complications of decompensated cirrhosis: a randomized controlled trial. www.clinicaltrials.gov/ct2/show/NCT02190357 (First posted 15 July 2014).
    1. Zeng X, Sheng X, Wang PQ, Xin HG, Guo YB, Lin Y, et al. Low-dose rifaximin prevents complications and improves survival in patients with decompensated liver cirrhosis. Hepatology International 2021;15(1):155-65. [DOI: 10.1007/s12072-020-10117-y] [PMID: ] - DOI - PubMed

References to studies excluded from this review

Abd‐Elsalam 2016 {published data only}
    1. Abd-Elsalam S, Ali LA, Soliman S, Ibrahim S, Elfert A. Randomized controlled trial of rifaximin versus norfloxacin for secondary prophylaxis of spontaneous bacterial peritonitis. Journal of Hepatology 2016;64(S2):S211. [CLINICALTRIALS.GOV: NCT02120196] [DOI: 10.1016/S0168-8278(16)00176-8] - DOI - PubMed
    1. Elfert A, Abo Ali L, Soliman S, Ibrahim S, Abd-Elsalam S. Randomized-controlled trial of rifaximin versus norfloxacin for secondary prophylaxis of spontaneous bacterial peritonitis. European Journal of Gastroenterology & Hepatology 2016;28(12):1450-4. [DOI: 10.1097/MEG.0000000000000724] - DOI - PubMed
    1. NCT02120196. Comparative study of rifaximin versus norfloxacin in the secondary prophylaxis of spontaneous bacterial peritonitis (SBP). clinicaltrials.gov/ct2/show/NCT02120196 (First posted 22 April 2014).
Ahire 2017 {published data only}
    1. Ahire K, Sonawale A. Comparison of rifaximin plus lactulose with the lactulose alone for the treatment of hepatic encephalopathy. Journal of the Association of Physicians of India 2017;65:42-6. - PubMed
Ahluwalia 2014 {published data only}
    1. Ahluwalia V, Wade JB, Heuman DM, Hammeke TA, Sanyal AJ, Sterling RK, et al. Enhancement of functional connectivity, working memory and inhibitory control on multi-modal brain MR imaging with rifaximin in cirrhosis: implications for the gut-liver-brain axis. Metabolic Brain Disease 2014;29(4):1017-25. [DOI: 10.1007/s11011-014-9507-6] [PMCID: PMC4155029] [PMID: ] - DOI - PMC - PubMed
Anon 2014a {published data only}
    1. Hepatic encephalopathy. Rifaximin opens new perspectives. MMW Fortschritte der Medizin 2014;156(13):78-9. - PubMed
Anon 2014b {published data only}
    1. Intestine specific broad spectrum antibiotic. Rifaximin: therapy option in hepatic encephalopathy. MMW Fortschritte der Medizin 2014;156(3):64-5. - PubMed
Bajaj 2013 {published data only}
    1. Bajaj JS, Heuman DM, Sanyal AJ, Hylemon PB, Sterling RK, Stravitz RT, et al. Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy. PLOS One 2013;8(4):e60042. [CLINICALTRIALS.GOV: NCT01069133] [DOI: 10.1371/journal.pone.0060042] - DOI - PMC - PubMed
Bajaj 2016b {published data only (unpublished sought but not used)}
    1. Bajaj J, Flamm SL, Chalassani NP, Diaz E, Kayali Z, Kang R, et al. Oral rifaximin soluble solid dispersion immediate release 40 mg prevents development of cirrhosis related complications: A phase 2, randomized, multicenter, double-blind, placebo-controlled trial. Hepatology 2016;64(Suppl 1):1027A.
    1. Kakiyama G, Pandak W, Heimanson Z, Zhou H, Thacker L, Zhao D, et al. Rifaximin solube solid dispersion tablets modify gut microbial function, as shown by increased faecal secondary bile acid levels compared with placebo, in patients with early decompensated cirrhosis. United European Gastroenterology Journal 2020;8(Suppl 8):611. [DOI: 10.1177/2050640620927345] - DOI
    1. Kakiyama G, Pandak W, Heimanson Z, Zhou H, Thacker L, Zhao D, et al. Rifaximin soluble solid dispersion tablets modify gut microbial function, as shown by increased fecal secondary bile acid levels compared with placebo, in patients with early decompensated cirrhosis. Gastroenterology 2020;158(6 Suppl 1):S1456. [DOI: 10.1016/S0016-5085(20)34307-9] - DOI
    1. NCT01904409. A randomized, double-blind, placebo-controlled, dose-ranging, multicenter study to assess the efficacy and safety of rifaximin soluble solid dispersion (SSD) tablets for the prevention of complications in subjects with early decompensated liver cirrhosis. clinicaltrials.gov/ct2/show/record/NCT01904409 (First 22 July 2013).
    1. Sanyal AJ, Chalassani N, Bajaj J, Diaz E, Kayali Z, Harmon M, et al. Impact of baseline chronic liver disease characteristics on the efficacy of oral rifaximin soluble solid dispersion tablets for the prevention of further decompensation or all-cause mortality in patients with cirrhosis and ascites. Hepatology 2016;64(Suppl 1):47A.
Bajaj 2020a {published data only}
    1. Bajaj J, Sundaram V, Frenette C, Heimanson Z, Israel R, Sanyal A. Lactulose withdrawal can potentiate breakthrough overt hepatic encephalopathy in patients controlled with rifaximin plus lactulose therapy: a post hoc analysis of a randomized controlled trial. Journal of Hepatology 2020;73(S1):S721. [CLINICALTRIALS.GOV: NCT01842581] [DOI: 10.1016/S0168-8278(20)31898-5] - DOI
    1. Flamm S, Mullen K, Heimanson Z, Zeev P, Sanyal A. Assessment of potential impact of demographic and baseline disease characteristics on rifaximin monotherapy versus lactulose combination therapy for the prevention of overt hepatic encephalopathy (OHE) recurrence. American Journal of Gastroenterology 2017;112(S1):S494. [DOI: 10.1038/ajg.2017.305] - DOI
    1. NCT01842581. The safety/efficacy of rifaximin with/without lactulose in participants with a history of recurrent hepatic encephalopathy. clinicaltrials.gov/ct2/show/NCT01842581 (First posted 29 April 2013).
    1. Sanyal A, Heimanson Z, Flamm S. SAT-110-Impact of rifaximin monotherapy or rifamixin plus lactulose on markers of inflammation in patients with cirrhosis and a history of hepatic encephalopathy. Journal of Hepatology 2019;70(Suppl 1):e677-8. [DOI: 10.1016/S0618-8278(19)31349-0] - DOI
    1. Sanyal A, Heimanson Z, Israel R, Mullen K, Flamm S. Prevention of overt hepatic encephalopathy recurrence with rifaximin alone versus rifaximin plus lactulose therapy: impact on quality of life and caregiver burden in patients with cirrhosis. Journal of Hospital Medicine 2018;13(4):1.
Bajaj 2020b {published data only}
    1. Bajaj JS, Rahimi RS, Hassanein T, Pyrsopoulos NT, Heimanson Z, Israel RJ, et al. Investigational water-soluble rifaximin formulation significantly shortens time to recovery in hospitalized patients with overt hepatic encephalopathy (OHE): a phase 2, randomized, double-blind, placebo-controlled trial. Hepatology 2020;72(Suppl 1):57-8A. [DOI: 10.1002/hep.31578] - DOI
    1. NCT03515044. Rifaximin Soluble Solid Dispersion (SSD) tablets plus lactulose for the treatment of overt hepatic encephalopathy (OHE). clinicaltrials.gov/ct2/show/study/NCT03515044 (First posted 2 May 2018).
Block 2010 {published data only}
    1. Block JP. Rifaximin improves the treatment of hepatic encephalopathy. Journal of Clinical Outcomes Management 2010;17(5):16-9.
Bohra 2020 {published data only}
    1. Bohra A, Worland T, Hui S, Terbah R, Farrell A, Robertson M. Prognostic significance of hepatic encephalopathy in patients with cirrhosis treated with current standards of care. World Journal of Gastroenterology 2020;26(18):2221-31. [DOI: 10.3748/wjg.v26.i18.2221] - DOI - PMC - PubMed
Chang 2021 {published data only}
    1. Chang C, Huang CH, Tseng HJ, Yang FC, Chien RN. Real-world experience of the one-year efficacy of rifaximin add-on to lactulose is superior to lactulose alone in patients with cirrhosis complicated with recurrent hepatic encephalopathy in Taiwan. Journal of Personalized Medicine 2021;11(6):478. [PMID: 10.3390/jpm11060478] - DOI - PMC - PubMed
Cobbold 2018 {published and unpublished data}
    1. Cobbold JFL, Atkinson S, Marchesi JR, Smith A, Wai SN, Stove J, et al. Rifaximin in non-alcoholic steatohepatitis: An open-label pilot study. Hepatology Research 2018;48(1):69-77. [DOI: 10.1111/hepr.12904] [PMID: ] - DOI - PubMed
    1. NCT01355575. Rifaximin in fatty liver disease (RiFL). clinicaltrials.gov/ct2/show/NCT01355575 First posted 18 May 2011.
Crisafulli 2016 {published data only}
    1. Crisafulli A, Demma S, Rigano G, Bertino G. Treatment with rifaximin high dose plus lactulose vs rifaximin standard dose plus lactulose for acute hepatic encephalopathy. Journal of Hepatology 2016;64(2):S258. [DOI: 10.1016/S0168-8278(16)00286-5] - DOI
CTRI/2019/05/018966 {published data only}
    1. CTRI/2019/05/018966. A double blind randomised controlled trial comparing lactulose plus rifaximin with lactulose plus rifaximin plus L-ornithin L-aspartate in the treatment of overt hepatic encephalopathy (grade III-grade IV) in patients with cirrhosis. www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=32692&EncHid... (Registered 7 May 2019).
Danulescu 2013 {published data only}
    1. Danulescu RM, Ciobica A, Stanciu C, Trifan A. The role of rifaximine in the prevention of the spontaneous peritonitis. Revista Medico-Chirurgicala Societatii de Medici si Naturalisti din Iasi 2013;117(2):315-20. [PMID: ] - PubMed
De Marco 1984 {published data only}
    1. De Marco F, Santamaria Amato P, D'Arienzo A. Rifaximin in collateral treatment of portal systemic encephalopathy: a preliminary report. Current Therapeutic Research 1984;36(4):668-74.
Deshmukh 2016 {published data only (unpublished sought but not used)}
    1. Deshmukh PG, Konar A. An open label randomized study to evaluate the efficacy and safety of lactulose versus rifaximin in cirrhotics with covert hepatic encephalopathy. Indian Journal of Gastroenterology 2016;35(Suppl 1):LO-66.
Diana‐Maria 2019 {published data only}
    1. Diana-Maria S, Leahu A, Asaftei M, Garleanu I, Petrea O, Stanciu C, et al. Therapeutic approaches in patients with overt hepatic encephalopathy and liver cirrhosis. Journal of Gastrointestinal and Liver Diseases 2019;28(Suppl 1):68-9.
Di Piazza 1991 {published data only}
    1. Di Piazza S, Gabriella Filippazzo M, Valenze LM, Morello S. Rifaximin versus neomycine in the treatment of portosystemic encephalopathy. Italian Journal of Gastroenterology 1991;23(7):403-7. - PubMed
Dupont 2016 {published data only}
    1. DuPont HL, Flamm SL, Wolf RA, Sanyal AJ. Changes in antimicrobial susceptibility of fecal bacteria during rifaximin treatment for the prevention of overt hepatic encephalopathy (HE) recurrence. Hepatology 2016;64(Suppl 1):1047A.
    1. DuPont HL, Hassanein TI, Sanyal AJ, Wolf RA, Mullen KD. Genomic characterization of stool microbiota with rifaximin monotherapy versus lactulose in combination therapy for prevention of overt hepatic encephalopathy (HE) recurrence. Hepatology 2016;64(Suppl 1):720A.
EUCTR2014‐001856‐51‐DK {published data only}
    1. Anti-fibrotic and molecular aspects of rifaximin in alcoholic liver disease: A randomized placebo controlled clinical trial. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (Date of registration 10 June 2014).
Frenette 2020a {published data only}
    1. Frenette C, Sundaram V, Heimanson Z, Israel R, Sanyal A. Lack of colonic microbial cross-resistance to other antibiotics in patients treated with rifaximin alone vs rifaximin plus lactulose for reducing the risk of overt hepatic encephalopathy (OHE) recurrence. American Journal of Gastroenterology 2020;115(Supplement):S517. [DOI: 10.14309/01.ajg.0000706100.58826.f6] - DOI
Frenette 2020b {published data only}
    1. Frenette C, Vinay S, Heimanson Z, Israel R, Sanyal A. Lactulose on intestinal microbial diversity and composition in patients with cirrhosis. American Journal of Gastroenterology 2020;115(Supplement):S517-8. [DOI: 10.14309/01.ajg.0000706104.30097.6e] - DOI
Gangarapu 2015 {published data only}
    1. Gangarapu V, Ince AT, Baysal B, Kayar Y, Kılıç U, Gök Ö, et al. Efficacy of rifaximin on circulating endotoxins and cytokines in patients with nonalcoholic fatty liver disease. European Journal of Gastroenterology and Hepatology 2015;27(7):840-5. [DOI: 10.1097/MEG.0000000000000348] [PMID: ] - DOI - PubMed
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Giacomo 1993 {published data only}
    1. Giacomo F, Francesco A, Michele N, Oronzo S, Antonella F. Rifaximin in the treatment of hepatic encephalopathy. European Journal of Clinical Research 1993;4(Suppl 1):57-66.
Gupta 2021 {published data only}
    1. CTRI/2021/09/036321. Comparative study of Rifaximin alone versus combination therapy with Norfloxacin for secondary prophylaxis of spontaneous bacterial peritonitis with hepatic encephalopathy. https://trialsearch.who.int/Trial2.aspx?TrialID=CTRI/2021/09/036321 2021.
    1. Gupta T, Gaur V. Rifaximin alone versus combination with norfloxacin for secondary prophylaxis of spontaneous bacterial peritonitis with hepatic encephalopathy: a randomized-controlled trial. Hepatology (Baltimore, Md.) 2021;74(Suppl.1):1232A: 2073. [DOI: 10.1002/hep.32188] - DOI
Habib 2020 {published data only}
    1. Habib N, Amjad M, Afzal M, Iqbal MZ, Shehzad MA. Compare the efficacy of low versus high dose of rifaximin for primary prophylaxis of protosystemic encephalopathy. Pakistan Journal of Medical & Health Sciences 2020;14(3):843-5.
Hammond 2017 {published data only}
    1. Hammond DA, Dayama N, Martin BC. Impact of rifaximin and lactulose versus lactulose alone on hospitalization for acute recurrent hepatic encephalopathy. Value in Health 2017;20(5):A181.
Hotten 2003 {published data only}
    1. Hotten P, Marotta F, Naito Y, Minelli E, Helmy A, Lighthouse J, et al. Effects of probiotics, lactitol and rifaximin on intestinal flora and fecal excretion of organic acids in cirrhotic patients. Chinese Journal of Digestive Diseases 2003;4(1):13-8. [DOI: 10.1046/j.1443-9611.2003.00110.x] - DOI
Huang 2018 {published data only}
    1. Huang X, Chen S. Effect of rifaximin on gut microbiome in cirrhotic patients with variceal bleeding. Journal of Gastroenterology and Hepatology 2018;33(S4):53: OE-0898 (PD-0020). [DOI: 10.1111/jgh.14481] - DOI
    1. NCT02964195. Efficacy of rifaximin in treatment of cirrhotic gastroesophageal variceal hemorrhage: A multi-center randomized controlled clinical trial .. clinicaltrials.gov/ct2/show/NCT02964195 First posted 10 November 2016.
    1. NCT02991612. Efficacy of rafiximin in patients with cirrhotic gastroesophageal variceal hemorrhage: A single-center pilot study. clinicaltrials.gov/ct2/show/NCT02991612 First posted December 13, 2016: Sudy completed February 28, 2018.
Jain 2022 {published data only}
    1. Jain A, Sharma BC, Mahajan B, Srivastava S, Kumar A, Sachdeva S, et al. L- ornithine L-aspartate in acute treatment of severe hepatic encephalopathy: A double-blind randomized controlled trial. Hepatology (Baltimore, Md) 2022;75(5):1194-1203. [DOI: 10.1002/hep.32255.] [PMID: ] - DOI - PubMed
Jiménez 2022 {published data only}
    1. Jiménez C, Ventura-Cots M, Sala M, Calafat M, Garcia-Retortillo M, Cirera I, et al. Effect of rifaximin on infections, acute-on-chronic liver failure and mortality in alcoholic hepatitis: A pilot study (RIFA-AH). Liver International 2022;42(5):1109-20. [DOI: 10.1111/liv.15207] [PMID: ] - DOI - PMC - PubMed
John 2018 {published data only}
    1. John N, Aloysius M, Zaman M. Bovine immunoglobulin orally with modified doses of rifaximin for advanced cirrhotics in overt hepatic encephalopathy: a randomized placebo control prospective clinical pilot trial (BRAIN trial). Hepatology International 2018;12(2):S298. [DOI: 10.1007/s12072-018-9852-3] - DOI
Jones 2020 {published data only}
    1. Jones B, Berni E, Poole C, Jenkins-Jones S, Orr J, Amlani B, et al. Increased survival in patients with hepatic encephalopathy treated with rifaximin-alpha in combination with lactulose: an observational study from UK clinical practice. Journal of Hepatology 2020;73(Suppl 1):S37. [DOI: 10.1016/S0168-8278(20)30626-7] - DOI
Kaji 2017 {published data only}UMIN000029127
    1. Kaji K, Takaya H, Saikawa S, Furukawa M, Sato S, Kawaratani H, et al. Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity. World Journal of Gastroenterology 2017;23(47):8355-66. [DOI: 10.3748/wjg.v23.i47.8355] - DOI - PMC - PubMed
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Kalambokis 2012a {published data only}
    1. Kalambokis GN, Mouzaki A, Rodi M, Pappas K, Fotopoulos A, Xourgia X, et al. Rifaximin improves systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites. Clinical Gastroenterology and Hepatology 2012;10(7):815-8. [DOI: 10.1016/j.cgh.2012.02.025] [PMID: ] - DOI - PubMed
Kalambokis 2012b {published data only}
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    1. Kalambokis, Mouzaki A, Rodi M, Tsianos EV. Rifaximin improves thrombocytopenia in patients with alcoholic cirrhosis in association with reduction of endotoxiemia. Liver International 2012;32(3):467-75. - PubMed
Kalambokis 2012c {published data only}
    1. Kalambokis GN, Mouzaki A, Rodi M, Tsianos EV. Rifaximin for the prevention of spontaneous bacterial peritonitis. World Journal of Gastroenterology 2012;18(14):1700-2. [DOI: 10.3748/wjg.v18.i14.1700] [PMCID: PMC3325539] [PMID: ] - DOI - PMC - PubMed
Kalambokis 2012d {published data only}
    1. Kalambokis GN, Tsianos EV. Rifaximin reduces endotoxemia and improves liver function and disease severity in patients with decompensated cirrhosis. Hepatology 2012;55(2):655-6. - PubMed
Kang 2017 {published data only}
    1. Kang SH, Lee YB, Lee JH, Nam JY, Chang Y, Cho H, et al. Rifaximin treatment is associated with reduced risk of cirrhotic complications and prolonged overall survival in patients experiencing hepatic encephalopathy. Alimentary Pharmacology & Therapeutics 2017;46(9):845-5. [DOI: 10.1111/apt.14275] [PMID: ] - DOI - PubMed
    1. Kang SH, Yoo JJ, Lee JH, Nam JY, Chang Y, Cho H, et al. Rifaximin reduces cirrhotic complications and prolongs overall survival in patients experiencing hepatic encephalopathy. Journal of Hepatology 2017;66(Suppl 1):S572-3. [DOI: 10.1016/S0168-8278(17)31566-0] - DOI - PubMed
Kawaratani 2022 {published data only}
    1. Kawaratani H, Kondo Y, Tatsumi R, Kawabe N, Tanabe N, Sakamaki A, et al. Long-term efficacy and safety of rifaximin in japanese patients with hepatic encephalopathy: a multicenter retrospective study. Journal of Clinical Medicine 2022;157110.3390/jcm11061571.(6):1571. [DOI: 10.3390/jcm11061571.] [PMCID: PMC8948903] [PMID: ] - DOI - PMC - PubMed
Khokhar 2015 {published data only}
    1. Khokhar N, Qureshi MO, Ahmad S, Ahmad A, Khan HH, Shafqat F, et al. Comparison of once a day rifaximin to twice a day dosage in the prevention of recurrence of hepatic encephalopathy in patients with chronic liver disease. Journal of Gastroenterology and Hepatology 2015;30:1420-2. [DOI: 10.111/jgh.12970] - DOI - PubMed
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Kimer 2018 {published data only}
    1. Kimer N, Gudmann NS, Pedersen J, Møller S, Nielsen MJ, Leeming DJ, et al. No effect of rifaximin on soluble CD163, mannose receptor or type III and IV neoepitope collagen markers in decompensated cirrhosis: Results from a randomized, placebo controlled trial. PLOS One 2018;13(9):1-12. [DOI: 10.1371/journal.pone.0203200] [EUDRACT: 2012-002890-71] - DOI - PMC - PubMed
Kimer 2022 {published data only}
    1. EUCTR2014-002264-33-DK. Rifaximin (an antibiotic) treatment of acute alcoholic liver injury. https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2014-002264-33-DK 2014.
    1. Kimer N, Meldgaard M, Hamberg O, Kronborg TM, Lund AM, Møller HJ, et al. The impact of rifaximin on inflammation and metabolism in alcoholic hepatitis: a randomized clinical trial. PLoS One 2022;17(3):e0264278. [DOI: 10.1371/journal.pone.0264278] [PMID: ] - DOI - PMC - PubMed
Kubota 2022 {published data only}
    1. Kubota K, Uojima H, Shao X, Iwasaki S, Hidaka H, Wada N, et al. Additional L-carnitine reduced the risk of hospitalization in patients with overt hepatic encephalopathy on rifaximin. Digestive Diseases 2022;40(3):313-21. [DOI: 10.1159/000518067] [PMID: ] - DOI - PubMed
    1. UMIN000027511. Combination therapy with levocarnitine and rifaximin for hepatic encephalopathy in patients with cirrhosis: a randomized study. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000031535 Registered 7 June 2017.
Lauridsen 2018 {published data only}
    1. Lauridsen MM, Gram J, Vilstrup H, Schaffalitzky de Muckadell OB. The continuous reaction times test for minimal hepatic encephalopathy validated by a randomized controlled multi-modal intervention. Journal of Clinical and Experimental Hepatology 2017;7(Suppl 1):S12-3. [DOI: 10.1016/j.jceh.2017.01.017] - DOI - PMC - PubMed
    1. Lauridsen MM, Gram J, Muckadell OB, Vilstrup H. The continuous reaction time test for minimal hepatic encephalopathy validated by a randomized controlled multimodal intervention. Journal of Hepatology 2018;68(Suppl 1):S740-1. [DOI: 10.1016/S0168-8278(18)31744-6] - DOI
    1. Lauridsen MM, Mikkelsen S, Svensson T, Holm J, Klüver C, Gram J, et al. The continuous reaction time test for minimal hepatic encephalopathy validated by a randomized controlled multi-modal intervention - a pilot study. PLOS One 2017;12(10):e0185412. [DOI: 10.1371/journal.pone.0185412] - DOI - PMC - PubMed
    1. NCT01773538. Diagnosis of covert/minimal hepatic encephalopathy by means of continuous reaction time measurement. clinicaltrials.gov/ct2/show/NCT01773538 (First posted 23 January 2013).
Lighthouse 2004 {published data only}
    1. Lighthouse J, Naito Y, Helmy A, Hotten P, Fuji H, Min CH, et al. Endotoxinemia and benzodiazepine-like substances in compensated cirrhotic patients: a randomized study comparing the effect of rifaximine alone and in association with a symbiotic preparation. Hepatology Research 2004;28(3):155-60. [DOI: 10.1016/j.hepres.2003.11.005] [PMID: ] - DOI - PubMed
Miglio 1997 {published data only}
    1. Miglio F, Valpiani D, Rossellini SR, Ferrieri A. Rifaximin, a non-absorbable rifamycin, for the treatment of hepatic encephalopathy. A double-blind, randomized trial. Current Medical Research and Opinion 1997;13(10):593-601. [DOI: 10.1185/03007999709113333] [PMID: ] - DOI - PubMed
Mohamed 2018 {published data only}
    1. Mohamed AM, Ahmad RR, Marwa AG, Mohamed OAM, Yosef MS. Rifaximin versus metronidazole in management of acute episode of hepatic encephalopathy: An open labeled randomized clinical trial. Arab Journal of Gastroenterology 2018;19(2):76-9. [DOI: 10.1016/j.ajg.2018.06.001] - DOI - PubMed
Mostafa 2015 {published data only}
    1. Mostafa T, Badra G, Abdallah M. The efficacy and the immunomodulatory effect of rifaximin in prophylaxis of spontaneous bacterial peritonitis in cirrhotic Egyptian patients. Turkish Journal of Gastroenterology 2015;26(2):163-9. [DOI: 10.5152/tjg.2015.7782] [PMID: ] - DOI - PubMed
Mullen 2014 {published data only}
    1. Mullen K, Sanyal A, Bass N, Poordad F, Huang S, Merchant K. The long term efficacy and safety of rifaximin in the maintenance of remission from overt hepatic encephalopathy in cirrhotic patients. Gastroenterology 2012;142(5 Suppl 1):S41-2. [DOI: 10.1016/S0016-5085(12)60157-7] - DOI
    1. Mullen K, Sanyal A, Bass N, Poordad F, Sheikh M, Frederick RT, et al. Rifaximin is safe and well tolerated for long-term maintenance of remission from over hepatic encephalopathy. Clincial Gastroenterology and Hepatology 2014;12(8):1390-7. [DOI: 10.1016/j.cgh.2013.12.021] - DOI - PubMed
    1. Neff GW, Flamm SL, Mullen KD, Barrett AC, Bortey E. Improved outcomes in hepatic encephalopathy using rifaximin monotherapy compared to rifaximin and lactulose combination therapy. Gastroenterology 2013;144(Suppl 5):S-451. [DOI: 10.1016/S0016-5085(13)61665-0] - DOI
    1. Poordad F, Bass N, Sanyal AJ, Sheikh MY, Mullen KD, Sigal S, et al. The protective effect of rifaximin (1100 mg daily) from hepatic encephalopathy observed in a double-blind placebo controlled study is substantiated and durable over the long term. Hepatology 2009;50(Suppl 4):448-9A. [DOI: 10.1002/hep.23301] - DOI
    1. Sanyal A, Mullen KD, Bass NM, Frederick T, Poordad F, Hee J, et al. Rates of commonly occuring infections in cirrhosis patients remain stable during long-term rifaximin treatment. Journal of Hepatology 2012;56(Suppl 2):S255-6. [DOI: 10.1016/S0168-8278(12)60658-8] - DOI
NCT00364689 {published data only}
    1. RICE Trial: Rifaximin In Chronic Hepatic Encephalopathy - A Randomized, Controlled Trial. https://clinicaltrials.gov/show/NCT00364689.
NCT00748904 {published data only}
    1. NCT00748904. A Randomized Comparison of Rifaximin Versus Lactulose in Hospitalized Cirrhotic Patients With Progressive Renal Failure. ClinicalTrials.gov: https://www.clinicaltrials.gov/ct2/show/NCT00748904 First posted 9 September 2008.
NCT01676597 {published data only}
    1. NCT01676597. Efficacy of pentoxifylline and rifaximin combination in pentoxifylline refractory clinical and subclinical hepatopulmonary syndrome. clinicaltrials.gov/ct2/show/NCT01676597 (First posted 31 August 2012).
NCT01846806 {published data only}
    1. NCT01846806. The role of bacterial overgrowth and delayed intestinal transit in hepatic encephalopathy. clinicaltrials.gov/ct2/show/NCT01846806 (First posted 3 May 2013).
NCT01897051 {unpublished data only}
    1. NCT01897051. Rifaximin and propranolol combination therapy versus propranolol monotherapy in cirrhotic patients (RECOVER) [Hemodynamic response of rifaximin and non-selective β-blocker combination therapy versus non-selective β-blocker monotherapy in cirrhotic patients with esophageal varices]. clinicaltrials.gov/show/nct01897051 (First posted 11 July 2013).
NCT01951209 {published data only}
    1. NCT01951209. Pilot study of the effect of rifaximin on B-cell dysregulation in cirrhosis. clinicaltrials.gov/ct2/show/NCT01951209 (First posted 26 September 2013).
NCT02011841 {published data only}
    1. NCT02011841. Rifaximin for the secondary prevention of spontaneous bacterial peritonitis recurrence in cirrhotic patients. clinicaltrials.gov/ct2/show/NCT02011841 (First posted 13 December 2013).
NCT02485106 {published data only}
    1. NCT02485106. Rifaximin use in severe alcoholic hepatitis. clinicaltrials.gov/ct2/show/NCT02485106 (First posted 30 June 2015).
NCT03712280 {published data only}
    1. NCT03712280. MNK6106 for liver disease (hepatic cirrhosis) that in the past has affected the brain (hepatic encephalopathy). clinicaltrials.gov/ct2/show/NCT03712280 (First posted 19 October 2018).
NCT04159870 {published data only}
    1. NCT04159870. Rifaximin versus norfloxacin in the primary prophylaxis of spontaneous bacterial peritonitis. clinicaltrials.gov/ct2/show/NCT04159870 (First posted 12 November 2019).
Oey 2019 {published data only}
    1. Oey RC, Buck LE, Erler NS, Burren HR, Man RA. The efficacy and safety of rifaximin-α: a 2-year observational study of overt hepatic encephalopathy. Therapeutic Advances in Gastroenterology 2019;12(1):1-10. - PMC - PubMed
Orr 2016 {published data only}
    1. Orr J, Currie CJ, Berni E, Anurag B, Goel KJ, Moriarty A. The impact on hospital resource utilisation of treatment of hepatic encephalopathy with rifaximin-α. Liver International 2016;36(9):1295-303. [DOI: 10.1111/liv.13111] - DOI - PubMed
Parini 1992 {published data only}
    1. Parini P, Cipolla A, Ronchi M, Salzetta A, Mazella G, Roda E. Effect of rifaximin and paromomycin in the treatment of portal-systemic encephalopathy. Current Therapeutic Research 1992;52(1):34-9.
Pedretti 1991 {published data only}
    1. Pedretti G, Calzetti C, Missale G, Fiaccadori F. Rifaximin versus neomycin on hyper-ammoniemia in chronic portal systemic encephalopathy of cirrhotics. A double-blind, randomized trial. Italian Journal of Gastroenterology 1991;23:175-8. - PubMed
Ponziani 2016 {published data only}
    1. Ponzani FR, Scaldaferri F, Pecere S, Sterbini F, Petito V, Lopetuso LR, et al. Increased abundance of beneficial bacteria is associated with clinical improvement after rifaximin treatment. Digestive and Liver Disease 2016;48(Suppl 2):E176-7. [DOI: 10.1016/S1590-8658(16)30264-X] - DOI
    1. Ponziani FR, Scaldaferri F, Sterbini FP, Petito V, Pecere S, Lopetuso LR, et al. Increased abundance of beneficial bacteria is associated with clinical improvement in patients receiving rifaximin treatment. United European Gastroenterology Journal 2016;4(Suppl 5):A649-50. [DOI: 10.1177/2050640616663689] - DOI
Pose 2020 {published data only}
    1. EUCTR2018-001698-25-GB. Efficacy of the combination of simvastatin plus rifaximin in patients with decompensated cirrhosis to prevent ACLF development: a multicenter, double-blind, placebo controlled randomized clinical trial. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (Date of registration 01 October 2018).
    1. NCT03780673. Efficacy of the combination of simvastatin plus rifaximin in patients with decompensated cirrhosis to prevent ACLF development. clinicaltrials.gov/ct2/show/NCT03780673 (First posted 19 December 2018).
    1. Pose E, Napoleone L, Amin A, Campion D, Jimenez C, Piano S, et al. Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. Gastroenterology and Hepatology 2020;5(1):31-41. [DOI: 10.1016/S2468-1253(19)30320-6] [PMID: ] - DOI - PubMed
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Praharaj 2022 {published data only}
    1. NCT03695705. Rifaximin and norfloxacin for prevention of SBP in adults with decompensated cirrhosis. clinicaltrials.gov/ct2/show/NCT03695705 (First posted 4 October 2018).
    1. Praharaj D, Taneja S, Duseja A, Chawla YK, Dhiman RK. Randomized control trial of rifaximin and norfloxacin in primary and secondary prophylaxis of spontaneous bacterial peritonitis in cirrhotic patients. Indian Journal of Gastroenterology 2017;36(1):A57-8. [DOI: 10.1007/s12664-017-0798-5] - DOI
    1. Praharaj D, Taneja S, Duseja A, Chawla YK, Dhiman RK. Randomized control trial of rifaximin and norfloxacin in primary and secondary prophylaxis of spontaneous bacterial peritonitis (SBP) in cirrhotic patients. Journal of Clinical and Experimental Hepatology 2017;7(S2):S71. [DOI: 10.1016/j.jceh.2017.05.133] - DOI
    1. Praharaj D. Randomized control trial of rifaximin and norfloxacin in primary and secondary prophylaxis of spontaneous bacterial peritonitis (SBP) in cirrhotic patients. Hepatology International 2018;12(2):S553-4. [DOI: 10.1007/s12072-018-9852-3] - DOI
    1. Praharaj DL, Premkumar M, Roy A, Verma N, Taneja S, Duseja A, Dhiman RK. Rifaximin vs. norfloxacin for spontaneous bacterial peritonitis prophylaxis: A randomized controlled trial. Journal of Clinical and Experimental Hepatology 2022;12(2):336-342. [DOI: 10.1016/j.jceh.2021.08.010] [PMCID: PMC9077172] [PMID: ] - DOI - PMC - PubMed
Saboo 2021 {published data only}
    1. Saboo K, Shamsaddini A, Iyer M, Hu C, Fagan A, Gavis E. Sex is associated with differences in gut microbial composition and function in hepatic encephalopathy. Journal of Hepatology 2021;74(1):80-8. [DOI: 10.1016/j.jhep.2020.06.046] [PMCID: PMC7749850] [PMID: ] - DOI - PMC - PubMed
Salehi 2019 {published data only}
    1. Salehi S, Lim S, Heneghan M, Aluvihare V, Heaton N, Patel V, et al. Rifaximin reduced the incidence of sepsis and all cause admissions whilst on the liver transplant waiting list. Journal of Hepatology 2018;68(Suppl 1):S119-20. [DOI: 10.1016/S0168-8278(18)30454-9] - DOI
    1. Salehi S, Tranah T, Lim S, Heaton N, Heneghan M, Aluvihare V, et al. Rifaximin reduces the incidence of spontaneous bacterial peritonitis, variceal bleeding and all-cause admissions in patients on the liver transplant waiting list. Alimentary Pharmacology & Therapeutics 2019;50(4):435-41. [DOI: 10.1111/apt.15326] - DOI - PMC - PubMed
Sama 2004 {published data only}
    1. Sama C, Morselli-Labate AM, Pianta P, Lambertini L, Berardi S, Martini G. Clinical effects of rifaximin in patients with hepatic encephalopathy intolerant or nonresponsive to previous lactulose treatment: an open-label, pilot study. Current Therapeutic Research 2004;65(5):413-22. [DOI: 10.1016/j.curtheres.2004.10.002] - DOI - PMC - PubMed
Sarwar 2019 {published data only}
    1. Sarwar S, Muhyuddin B, Aleem A, Nadeem MA. Primary prophylaxis of hepatic encephalopathy in decompensated cirrhosis: low dose vs. full dose rifaximin. Pakistan Journal of Medical Sciences 2019;35(5):1446-50. [DOI: 10.12669/pjms.35.5.549] - DOI - PMC - PubMed
Schulz 2019 {published data only}
    1. Schulz C, Schütte K, Vilchez-Vargas R, Vasapolli R, Malfertheiner P. Long-term effect of rifaximin with and without lactulose on the active bacterial assemblages in the proximal small bowel and faeces in patients with minimal hepatic encephalopathy. Digestive Diseases 2019;37(2):161-9. [DOI: 10.1159/000494216] - DOI - PubMed
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Seifert 2021 {published data only}
    1. Seifert LL, Schindler P, Schoster M, Weller JF, Wilms C, Schmidt HH. Recurrence of hepatic encephalopathy after TIPS: effective prophylaxis with combination of lactulose and rifaximin. Journal of Clinical Medicine 2021;10(20):1-12. [DOI: 10.3390/jcm10204763] [PMCID: PMC8537523] [PMID: ] - DOI - PMC - PubMed
Song 2021 {published data only}
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Suzuki 2019 {published data only}
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    1. Randomized controlled trial comparing zinc-rifaximin combination therapy with zinc monotherapy in liver cirrhosis patients with minimal hepatic encephalopathy. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000042151 (Registered 10 June 2019). 2019. [UMIN: 000036998]
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    1. UMIN000038487. Use of rifaximin therapy in primary prevention of hepatorenal syndrome in cirrhotic patients with ascites. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000043845 (Registered 3 November 2019).
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References to ongoing studies

ChiCTR1800018070 {published data only}
    1. ChiCTR1800018070. Clinical study of rehoci combined with long-acting octreotide in reducing the risk of rebleeding in patients with cirrhosis and portal hypertension. www.chictr.org.cn/showprojen.aspx?proj=30575 (Registered 29 August 2018).
EUCTR2014‐000102‐35‐IT {published data only}
    1. EUCTR2014-000102-35-IT. Effect of administration "add on" of Rifaximin on portal hypertension of patients with liver cirrhosis and esophageal varices in standard therapy with propranolol. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (Date of registration 24 October 2014).
EUCTR2017‐000488‐34‐IT {published data only}EUCTR2017‐000488‐34‐IT
    1. EUCTR2017-000488-34-IT. Rifaximin blunted higher levels of endotoxin in cirrhosis patients: a randomized, double blind, short term interventional trial - rifaximin in cirrhotic patient. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (Date of registration 8 June 2021).
EUDRACT2016‐002628‐96 {published data only}
    1. EUDRACT2016-002628-96. A multi-centre, double-blind, randomised, controlled clinical trial of Rifaximin to reduce infection in patients admitted to hospital with decompensated cirrhosis. www.clinicaltrialsregister.eu/ctr-search/search?query=2016-002628-96 (Date of registration September 2016).
    1. ISRCTN10994757. A multi-centre, double-blind, randomised, controlled clinical trial of Rifaximin to reduce infection in patients admitted to hospital with decompensated cirrhosis. www.isrctn.com/ISRCTN10994757 (Trial start date 15 April 2016).
NCT01846663 {published data only}
    1. NCT01846663. The efficacy, safety, and pharmacokinetics of rifaximin In subjects with severe hepatic impairment and hepatic encephalopathy. clinicaltrials.gov/ct2/show/NCT01846663 (First posted 3 May 2013).
NCT02439307 {published data only}
    1. NCT02439307. Effect of rifaximin on minimal hepatic encephalopathy and small intestinal bacterial overgrowth. clinicaltrials.gov/show/NCT02439307 (First posted 8 May 2015).
NCT02508623 {published data only}NCT02508623
    1. NCT02508623. Effect of administration of rifaximin on the portal pressure of patients with liver cirrhosis and esophageal varices (ERASE). clinicaltrials.gov/show/NCT02508623 (First posted 27 July 2015).
NCT02931123 (Riggio 2016) {published data only}
    1. NCT02931123. A RCT comparing lactulose and rifaximin associated with a vegetable diet in the preventions of post-TIPS overt hepatic encephalopathy. clinicaltrials.gov/show/NCT02931123 (First posted 12 October 2016).
NCT03069131 {published data only}
    1. NCT03069131. Two strategies of primary prophylaxis of spontaneous bacterial peritonitis in severe cirrhotic patients with ascites (ProPILARifax). clinicaltrials.gov/ct2/show/NCT03069131 (First posted 3 March 2017).
NCT04073290 (PEARL Study) {published data only}EUCTR2018‐004323‐37
    1. EUCTR2018-004323-37-NL. Prevention of hepatic encephalopathy by administration of rifaximin and lactulose in patients with liver cirrhosis undergoing placement of a transjugular intrahepatic portosystemic shunt: a multi-centre randomized, double blind, placebo controlled trial. The PEARL trial. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (Date of registration 07 January 2019). - PMC - PubMed
    1. NCT04073290. Prevention of post-TIPS hepatic encephalopathy by administration of rifaximin and lactulose (PEARL). clinicaltrials.gov/ct2/show/NCT04073290 (First posted 29 August 2019).
    1. Wit K, Schaapman JJ, Nevens F, Verbeek J, Coenen S, Cuperus FJ, et al. Prevention of hepatic encephalopathy by administration of rifaximin and lactulose in patients with liver cirrhosis undergoing placement of a transjugular intrahepatic portosystemic shunt (TIPS): a multicentre randomised, double blind, placebo controlled trial (PEARL trial). BMJ Open Gastroenterology 2020;7(1):e000531. [DOI: 10.1136/bmjgast-2020-000531] [PMID: ] - DOI - PMC - PubMed
NCT04775329 {published data only}
    1. NCT04775329. Primary prophylaxis for spontaneous bacterial peritonitis (SIBOC). clinicaltrials.gov/ct2/show/NCT04775329 (First posted 1 March 2021).
NCT05071716 (RNLC3131) {published data only}
    1. NCT05071716. A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of rifaximin soluble solid dispersion (SSD) for the delay of encephalopathy decompensation in cirrhosis. clinicaltrials.gov/ct2/show/NCT05071716 (First posted 8 October 2021).
TCTR20180509001 {published data only}
    1. TCTR20180509001. Comparison between rifaximin vs lactulose for treatment of hepatic encephalopathy. www.thaiclinicaltrials.org/show/TCTR20180509001 (Date of registration 09 May 2018).

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