What is the evidence to support rifaximin 400 mg TID for hepatic encephalopathy?

Comment by InpharmD Researcher

Available literature identifies rifaximin 400 mg TID (1,200 mg/day) as a common dosing regimen for patients with various severity of hepatic encephalopathy (HE). Despite discrepancies in the definition of treatment responses among clinical studies, rifaximin 400 mg TID, with or without lactulose, has been reported to induce favorable response rates and a well-tolerated safety profile. Results from the meta-analysis also find rifaximin to be comparably effective as nonabsorbable disaccharides, with fewer adverse events. Individual primary literature reports conflicting findings with respect to the effects of rifaximin in the recovery of HE, mortality, and neurological status compared to lactulose alone. As such, non-US societal guidelines do not provide strong recommendations for rifaximin as first-line treatment in the setting of HE.

Background

The European Association for the Study of the Liver (EASL) 2022 guidelines for the management of hepatic encephalopathy recommends rifaximin as an adjunct to lactulose if secondary prophylaxis is indicated to prevent recurrent episodes. A dose recommendation is not provided. The Japanese Society of Gastroenterology (JSGE) 2020 third guideline update for liver cirrhosis also recommends rifaximin as a standard treatment for hepatic encephalopathy, although it fails to provide dose recommendations. In both guidelines, the lack of quality evidence for rifaximin as first-line treatment is notable, but has a small or no effect on their recommendations. [1, 2]

A 2008 systematic review investigated the use of rifaximin for the treatment of hepatic encephalopathy. Included trials compared rifaximin with placebo, other antimicrobials, and nonabsorbable disaccharides. Many of the trials were randomized, double-blind, and enrolled patients with grade 1-3 hepatic encephalopathy according to the West Haven grading scale for mental state. The treatment regimen commonly consisted of rifaximin 400 mg three times daily (1,200 mg/day) with or without lactulose to cause 2 to 3 bowel movements/day. Overall, the clinical trials suggest rifaximin is effective in treating patients with cirrhosis and mild-to-moderate severity hepatic encephalopathy, with response rates ranging from 80 to 90%. Rifaximin was also associated with less tolerance issues and lower rates of hospitalization. However, primary outcome measures varied greatly between studies and sometimes failed to clearly define the efficacy criteria of treatment. See Table 1 for the authors’ summary of clinical trials. [3]

A 2013 meta-analysis (N= 8 randomized controlled trials; 407 patients) evaluated the efficacy and safety of rifaximin compared with nonabsorbable disaccharides for the treatment of hepatic encephalopathy. The dose of rifaximin was noted to typically be 1,200 mg/day in the included studies. The efficacy of rifaximin was found to be similar to that of nonabsorbable disaccharides (risk ratio [RR] 1.06; 95% confidence interval [CI] 0.94 to 1.19; p= 0.34). Rifaximin treatment was associated with improved serum ammonia levels, mental status, asterixis, and electroencephalogram response; however, these differences were not statistically significant. A significant difference was seen for grades of portosystemic encephalopathy (weighted mean difference [WMD] -2.3; 95% CI -2.78 to -1.82; p<0.00001). In terms of safety, pooled analysis for the incidence of severe diarrhea and abdominal pain indicated that rifaximin had lower rates of these adverse events (RR 0.19; 95% CI 0.1 to 0.37; p<0.00001). Overall, rifaximin was shown to be at least as effective as nonabsorbable disaccharides, with an improved safety profile. [4]

References:

[1] European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of hepatic encephalopathy [published correction appears in J Hepatol. 2023 Sep 26;:]. J Hepatol. 2022;77(3):807-824. doi:10.1016/j.jhep.2022.06.001
[2] Yoshiji H, Nagoshi S, Akahane T, et al. Evidence-based clinical practice guidelines for Liver Cirrhosis 2020. J Gastroenterol. 2021;56(7):593-619. doi:10.1007/s00535-021-01788-x
[3] Lawrence KR, Klee JA. Rifaximin for the treatment of hepatic encephalopathy. Pharmacotherapy. 2008;28(8):1019-1032. doi:10.1592/phco.28.8.1019
[4] Wu D, Wu SM, Lu J, Zhou YQ, Xu L, Guo CY. Rifaximin versus Nonabsorbable Disaccharides for the Treatment of Hepatic Encephalopathy: A Meta-Analysis. Gastroenterol Res Pract. 2013;2013:236963. doi:10.1155/2013/236963
Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What is the evidence to support rifaximin 400 mg TID for hepatic encephalopathy?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-5 for your response.

 

Clinical Trials of Rifaximin in Patients with Hepatic Encephalopathy
Study Design Treatment Regimen Primary Outcome Measures

Results
Open-label (n= 55)

Rifaximin 400 mg TID for 7 days

Plus

Lactulose

 Not specified. Assessed speech, gait, memory, asterixis, alterations in handwriting, behavioral changes, intellectual performance, blood ammonia levels, and EEG abnormalities

All patients improved within 2-3 days of starting therapy. Asterixis decreased by 50% on day 3 and only 2 patients remained with symptoms (p= 0.002). EEG abnormalities were no longer present by day 8. Blood ammonia levels significantly decreased by day 3 and continued to decrease towards normal by day 15 (p< 0.05).

Randomized, multicenter, open-label

(n= 54)

 Rifaximin 200, 400, or 800 mg TID for 7 days PSE index

PSE scores decreased by 25%, 28.8%, and 39.3% for the 200, 400, and 800 mg TID groups, respectively.

Changes for the 400 mg and 800 mg TID groups were significant.

Open-label

(n= 26)

Rifaximin 400 mg TID for 10 days

 PSE index

PSE scores decreased from 0.32 to 0.22 in the lactulose-intolerant patients (p< 0.01) and from 0.38 to 0.2 in the lactulose nonresponders (p< 0.05).

Randomized, open-label

(n= 20)

Rifaximin 400 mg TID for 5 days

Vs.

Paromomycin 500 mg TID for 5 days

 Daily plasma ammonia levels and number correction test Plasma ammonia levels decreased by > 30% from baseline in both treatment groups (p< 0.05). The time to decrease in completing the number correction test favored rifaximin (p< 0.001).

Randomized open-label

(n= 20)

Rifaximin 400 mg TID for 5 days

Vs.

Paromomycin 500 mg TID for 5 days

 Blood ammonia levels and daily psychometric tests Both groups reported identical clinical improvements in psychometric tests and normalization of ammonia levels.
Randomized, open-label (n= 32)

Rifaximin 400 mg TID for 6-12 days

Vs.

Paromomycin 500 mg TID for 6-15 days

 Remission of encephalopathy Both groups improved signs/symptoms and blood ammonia levels by day 3 (p< 0.05). Difference between groups were not significant.

Double-blind, randomized

(n= 30)

Rifaximin 400 mg TID for 21 days

Vs.

Neomycin 1000 mg TID for 21 days

 PSE sum and PSE index

Significant improvement in PSE sum and PSE index were observed for both groups on days 14 and 21 (p< 0.001). Decrease in blood ammonia levels on days 14 and 21 were greater for rifaximin-treated patients (p< 0.005).

Randomized

(n= 30)

Rifaximin 400 mg TID for 10 days

Vs.

Paromomycin 500 mg TID for 10 days

 Consciousness, intellectual function, behavior, and neurological signs assessed daily. Serum ammonia concentration assessed at baseline and on days 5 and 10

Improvements in all signs of hepatic encephalopathy were observed in both groups within 5 days (p< 0.05) and further decreased at end of therapy (p< 0.005). Blood ammonia decreased in both rifaximin and paromomycin groups by day 5 (p< 0.001).

Double-blind, multicenter, randomized

(n= 60)

Rifaximin 400 mg TID for 14 consecutive days/month for 6 months

Vs.

Neomycin 1000 mg TID for 14 consecutive days/month for 6 months

 Improvements in hepatic encephalopathy Both groups reported a decrease in hepatic encephalopathy grade after 30 days (p< 0.001). Blood ammonia levels decreased in both groups (p< 0.001).

Double-blind, randomized

(n= 58)

Rifaximin 400 mg and placebo lactulose TID for 15 days

Vs.

Lactulose 10 g and placebo rifaximin TID for 15 days

 PSE score measured with arbitrary scales Significant decrease in PSE scores occurred in both groups by day 12 of treatment (p< 0.05). Rifaximin-treated patients reported more robust improvements vs lactulose-treated patients at both day 12 and end of treatment.

Multicenter, open-label

(n= 80)

 Rifaximin 400 mg TID for 21 days Neurologic signs or symptoms and blood ammonia levels

Reduced frequency of neurologic signs including asterixis and EEG abnormalities by day 5 and 7 of treatment, respectively (p< 0.05). Blood ammonia levels normalized from baseline by day 7 of treatment.

Randomized

(n= 35)

Rifaximin 1200 mg/day for 21 days

Vs.

Neomycin 3000 mg/day for 21 days

 Neurologic signs or symptoms and blood ammonia levels

Rifaximin was associated with significant improvements in asterixis (p< 0.001) and EEG abnormalities (p< 0.001) by day 3 of treatment. Similar improvements in lactulose-treated patients occurred on day 5. Blood ammonia levels normalized in both groups by day 7.

Randomized

(n= 21)

Rifaximin 1200 mg/day for 21 days

Vs.

Lactulose 40 g/day for 21 days

 Neurologic signs and symptoms and blood ammonia levels

Both agents effectively improved neurologic signs. Rifaximin had more pronounced effects on asterixis (p= not significant) vs. lactulose. Blood ammonia levels normalized in both groups by day 7 of treatment (p< 0.01)

Randomized, double-blind

(n= 40)

Rifaximin 400 mg TID and placebo lactulose for 15 days

Vs.

Lactulose 20 g/day and placebo rifaximin TID for 15 days

 Improvements defined as decrease in hepatic encephalopathy grade by at least one grade at the end of treatment

Improvements were observed in all patients of both groups. Complete regression was achieved in 14 (70%) of rifaximin patients and 11 (55%) of lactulose patients (p> 0.05)

Randomized, multicenter, double-blind

(n= 103)

Rifaximin 400 mg TID and placebo lactitol for 5-10 days

Vs.

Lactitol 20 g and placebo rifaximin TID for 5-10 days

 Changes in PSE index

At the end of treatment, PSE index decreased from 0.61 to 0.14 in the rifaximin group and from 0.55 to 0.21 in the lactitol group. The difference between groups was significant, favoring rifaximin (p< 0.01)

Randomized

(n= 54)

Rifaximin 400 mg TID for 7 days

Vs.

Lactulose 90 mL/day for 7 days

Efficacy was graded as improved, unchaged, or worsened based on changes in the hepatic encephalopathy index at the end of treatment

 Improvement in index occurred in 84% of rifaximin patients and 95% of lactulose patients

Randomized, double-blind

(n= 93)

Rifaximin 400 mg TID for 14 days

Vs.

Placebo

 None specified, but PSE index was measured at baseline and at the end of treatment At the end of treatment, both groups reported improvements in PSE index (p< 0.05). Astrixis improvements was only observed in teh rifaximin group (p= 0.006)

EEG, electroencephalogram; PSE, portal-systemic encephalopathy

 

References:

Adapted from:
Lawrence KR, Klee JA. Rifaximin for the treatment of hepatic encephalopathy. Pharmacotherapy. 2008;28(8):1019-1032. doi:10.1592/phco.28.8.1019

 

Effect of Rifaximin, Probiotics, and l-Ornithine l-Aspartate on Minimal Hepatic Encephalopathy: A Randomized Controlled Trial

Design

Two-phase, randomized, non-blinded trial

N= 124

Objective

To determine the prevalence of mild hepatic encephalopathy (MHE) in patients with liver cirrhosis and to find out the effect of rifaximin, probiotics, and l-ornithine l-aspartate (LOLA) individually in reversal of MHE by comparing it with placebo group

Study Groups

LOLA (n= 31)

Rifaximin (n= 31)

Probiotics (n= 32)

Placebo (n= 30)

Inclusion Criteria

Phase I: Apparently healthy patients

Phase II: Patients with cirrhosis and evaluated for MHE

Exclusion Criteria

Overt HE or history of overt HE in the past 6 months; alcohol use in the past 6 weeks; antibiotic, lactulose, or probiotic use in the past 3 weeks; gastrointestinal bleeding; recent drug use that affects psychometric performance; spontaneous bacterial peritonitis or other infection; renal insufficiency with creatinine > 1.5 mg/L; electrolyte imbalance; hepatocellular carcinoma; significant comorbid illness; pregnancy

Methods

In phase 1, healthy patients were recruited to establish a baseline for the three neuropsychometric tests (NPTs [number connection test-A (NCT-A), Figure connection test-A (FCT-A), and Digit Symbol Test (DST)]) and critical flicker frequency (CFF) test used in the outcomes.

In phase 2, patients with cirrhosis were examined using the three NPTs and CFF to establish MHE. A CFF of < 39 Hz or if any two of the three NPTs were abnormal, then MHE was diagnosed.

Duration

Enrollment period: August 2009 to August 2010

Treatment period: 2 months ± 3 days

Outcome Measures

One-way analysis of variance (ANOVA) to compare the three drug groups for CFF improvements

Post hoc multiple comparisons analysis after ANOVA to compare the four groups for CFF and NPTs improvements

Baseline Characteristics

  

LOLA (n= 31)

Rifaximin (n= 31)

 Probiotics (n= 32) Placebo (n= 30)

Age, years

 42.0 43.9 33.87 38.0

Female

11 11 15 10

Education, years

 10 8 10 10

AST/ALT, IU/L

 68/45 54/38 65/65 65/43

Albumin, gm/dL

 2.9 3.0 3.1 2.9

Serum creatinine, mg/dL

 0.99 0.96 1.04 0.99

Results

Endpoint

LOLA (n= 31)

Rifaximin (n= 31)

Probiotics (n= 32)

Placebo (n= 30)

ANOVA for CFF, mean difference ^

LOLA

Rifaximin

Probiotics

 

--

1.80

1.13

 

-1.80

--

-0.67

 

-1.13

0.67

--

--

Multiple comparisons analysis for CFF, mean difference

LOLA

Rifaximin

Probiotics

Placebo

 

--

0.47

0.30

0.89*

 

-0.47

--

-0.17

0.42

 

-0.30

0.17

--

0.59*

 

-0.89*

-0.42

-0.59*

--

Multiple comparisons analysis for NPTs, mean difference

LOLA

Rifaximin

Probiotics

Placebo

 

--

0.13

-0.29

-1.02*

 

-0.13

--

-0.42

-1.15*

 

0.29

0.42

--

-0.72*

 

1.02*

1.15*

0.73*

--

^ Differences between groups were not statistically significant.

* p< 0.05

Adverse Events

 N/A

Study Author Conclusions

Prevalence of MHE is high in patients with cirrhosis of liver. Rifaximin, LOLA, and probiotics are better than giving a placebo in patients with MHE.

InpharmD Researcher Critique

 The study was unblinded and consisted of a small sample size, which limits the strength of the findings. A duration of 2 months of treatment may not provide adequate data on the sustained effects of the intervention.



References:

Sharma K, Pant S, Misra S, et al. Effect of rifaximin, probiotics, and l-ornithine l-aspartate on minimal hepatic encephalopathy: a randomized controlled trial. Saudi J Gastroenterol. 2014;20(4):225-232. doi:10.4103/1319-3767.136975

 

A Randomized Controlled Trial Comparing the Efficacy of a Combination of Rifaximin and Lactulose with Lactulose only in the Treatment of Overt Hepatic Encephalopathy

Design

Non-inferiority type of randomized controlled

N= 91

Objective

To compare a combination therapy against monotherapy with the hypothesis that the response of treatment with lactulose and rifaximin is non-inferior when compared to standard therapy with lactulose only

Study Groups

Rifaximin group (n = 45)

Placebo group (n = 46)

Inclusion Criteria

Adult patients with diagnosed chronic liver disease having encephalopathy (grade I to IV), after exclusion of metabolic/infective causes

Exclusion Criteria

Age <18 yrs, presence of any diagnosed neuropsychiatric illness and/or current use of antipsychotic/antidepressant medications, presence of any intestinal obstruction or inflammatory bowel disease, diagnosed hypersensitivity to rifamycin or disaccharides, serum creatinine >1.5 mg/dL, electrolyte abnormality (sodium <125 or >150 mEq/L), minimal hepatic encephalopathy, hypoglycemia

Methods

After enrollment, the patients were randomly assigned into two groups. One group received lactulose at a dose of 15 mL three to four times daily, adjusted to achieve 3 to 4 loose stools per day, in addition to rifaximin 400 mg TID. The other group was administered a placebo in conjunction with lactulose. Both groups received appropriate supportive treatments, such as intravenous antibiotics, enemas, inotropic support, and blood/blood products when necessary. The patients were monitored until they recovered from hepatic encephalopathy (HE) or for a maximum of ten days.

Duration

Follow-up: maximum of 10 days

Outcome Measures

 Any reduction in grade of encephalopathy according to Conn scale

Baseline Characteristics

  

Rifaximin group (n= 45)

Placebo group (n= 46)

  

Age, years

 44.73 ± 10.59 44.98 ± 10.12   

Female

20.0%  17.4%   

Alcohol addiction

 93.3%  84.8%  

Presenting signs and symptoms

Constipation

Haematemesis

Melaena

Jaundice

Ascites

 

48.9%

20.0%

26.7%

75.6%

95.6%

 

60.9%

10.9%

23.9%

78.3%

91.3% 

  

Initial Sensorium level

1

2

3

4

 

0.0%

28.9%

37.8%

33.3%

 

4.3%

21.7%

41.3%

32.6%

  

Blood Pressure

Systolic

Diastolic

 

117.38 ± 22.02

71.96 ± 13.54

 

115.87 ± 18.06

72.02 ± 12.47

  

Results

Endpoint

Rifaximin group (n= 45)

Placebo group (n= 46)

Effect size

Neurological status

Unchanged/worsened

Improved

 

12 (27.9%) 

31 (72.1%)

 

8 (20.0%)

32 (80.0%) 

 0.646 (0.232 to 1.794)

Mortality

Absent

Present

 

32 (74.4%)

11 (25.6%)

 

32 (80.0%)

8 (20.0%)

 0.727 (0.259 to 2.046) 

Mean survival time, days (95% CI)

8.562 (7.829 to 9.295)

8.873 (8.165 to 9.582) 

 --
Abbreviations: CI, confidence interval

100% of the cases having an initial sensorium level of Grade 1 improved, 89.5% presenting with Grade 2, 65.5% with initial Grade 3, and 58.3% with Grade 4 improved post-admission. Survival analysis by Kaplan Meier method revealed no difference in the overall survival distributions between the groups. The mean survival in the placebo group was higher. 

Adverse Events

Not disclosed

Study Author Conclusions

The present study reveals that improvement in neurological status of the group treated with lactulose only was that of a higher percentage than that of the group being treated with lactulose and rifaximin, which reiterates the recommendation that lactulose be used as a first-line therapy in overt HE. Also, the outcome was better in patients who had a lower grade of encephalopathy on admission.

InpharmD Researcher Critique

The close monitoring of all patients within an intensive care facility could have influenced certain outcomes, potentially leading to results that may not be directly applicable to less-controlled clinical settings. Moreover, an etiological investigation to explore the underlying causes of HE would be an additional avenue to pursue a more comprehensive understanding of relative prognosis and expected treatment responses. 



References:

Hasan S, Datta S, Bhattacherjee S, Banik S, Saha S, Bandyopadhyay D. A Randomized Controlled Trial Comparing the Efficacy of a Combination of Rifaximin and Lactulose with Lactulose only in the Treatment of Overt Hepatic Encephalopathy. J Assoc Physicians India. 2018;66(1):32-36.

 

A Randomized , Double-Blind, Controlled Trial Comparing Rifaximin Plus Lactulose With Lactulose Alone in Treatment of Overt Hepatic Encephalopathy

Design

Prospective double-blind randomized controlled trial

N= 120

Objective

 To evaluate the efficacy and safety of rifaximin plus lactulose vs. lactulose alone for the treatment of overt hepatic encephalopathy (HE)

Study Groups

Rifaximin + lactulose (n= 63) 

Lactulose + placebo (n= 57)

Inclusion Criteria

Aged 18 to 80 years with liver cirrhosis and overt HE; cirrhosis diagnosed on a clinical basis involving laboratory tests, endoscopic evidence, sonographic findings, and liver histology, if available

Exclusion Criteria

Serum creatinine >1.5 mg/dL on admission, active alcohol intake <4 weeks before the present episode, other metabolic encephalopathies, hepatocellular carcinoma, degenerative central nervous system disease or major psychiatric illness, and significant comorbidity

Methods

Eligible patients were randomized to receive either rifaximin (one 400 mg capsule TID) plus lactulose 30-60 mL TID or one placebo capsule (sugar) TID plus the same lactulose regimen. In both groups, the therapeutic target was to have 2-3 semisoft stools in a day. Patients received assigned treatment through a nasogastric tube under strict intensive care monitoring and continued till
complete recovery of HE or a maximum of 10 days for HE. For those who failed the treatment, patients in the lactulose + placebo group were given rifaximin, and those in the rifaximin + lactulose group were given L-ornithine and L-aspartate. 

Duration

Follow-up: until discharge or deceased during hospital stay 

Outcome Measures

Primary: complete reversal of HE as per West Haven criteria

Secondary: mortality and hospital stay

Baseline Characteristics

  

Rifaximin + lactulose (n= 63) 

Lactulose + placebo (n= 57)

  

Age, years

 40.4 ± 8.5 37.5 ± 10.5  

Female

16 15  

Etiology

Alcohol 

Hepatitis B virus

Hepatitis C virus

 

63.4%

15.9%

4.8 %

 

56.1%

21.1%

7%

  

Child-Turcotte-Pugh

B

C

Score

 

24.1%

75.9 %

9.9 ± 2.8

 

29.8%

70.2%

9.4 ± 2.5

  

Model for end-stage liver disease

 24.9 ± 6.6 23.8 ± 5.18  

Baseline HE grade (1/2/3/4)

 0/10/20/33 0/12/20/25  

History of previous HE

Median episodes of HE 

47.6%

1 (0 to 2)

43.9%

1 (0 to 2)

  

Laboratory values 

Bilirubin, m%

Albumin, g%

AST, IU/L

ALT, IU/L

ALP, U/L

Urea, g%

Art ammonia, μmol/L

 

4.9 ± 2.1

2.5 ± 0.9

62.9 ± 15.2

68.1 ± 17.9

101.2 ± 36.4

27.8 ± 9.5

132.6 ± 29.8

 

5.7 ± 2.6

2.7 ± 0.8

51.1 ± 11.2

59.4 ± 13.2

118.4 ± 39.2

31.4 ± 6.3

115.7 ± 22.7

  

ALP, akaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase

No significant differences were noted in baseline characteristics. 

Results

Endpoint

Rifaximin + lactulose (n= 63) 

Lactulose + placebo (n= 57)

p-value

Recovery of HE 

 48 (76%) 25 (44%) 0.004

Hospital stay, days 

 5.8 ± 3.4 8.2 ± 4.6 0.001

Mortality 

Due to sepsis

Due to gastrointestinal bleed 

Due to hepatorenal syndrome

15 (24%)

7

4

4

28 (49.1%)

17

4

7

< 0.05

0.01

NS

NS

NS, not significant. 

Univariate and multivariate analyses found that baseline total leukocyte count (p= 0.024) and treatment with lactulose + placebo (p= 0.0001) were the only two independent predictors of nonresponse in patients with HE. 

Adverse Events

Common Adverse Events: diarrhea needing modification of lactulose therapy (8 vs. 6; NS), abdominal pain (4 vs. 4; NS)

Serious Adverse Events: None

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Combination of lactulose plus rifaximin is more effective than lactulose alone in the treatment of overt HE.

InpharmD Researcher Critique

Results confirmed the additional therapeutic benefits of rifaximin TID in patients with over HE. Additional stool cultures could have provided more insights into the effect of rifaximin on colonic bacteria. 



References:

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. Am J Gastroenterol. 2013;108(9):1458-1463. doi:10.1038/ajg.2013.219

 

Rifaximin Improves Psychometric Performance and Health-Related Quality of Life in Patients With Minimal Hepatic Encephalopathy (The RIME Trial)

Design

Double-blinded randomized pilot study

N= 94

Objective

 To assess the efficacy of rifaximin in improving neuropsychometric (NP) test performance and health-related quality of life (HRQOL) in patients with minimal hepatic encephalopathy (MHE)

Study Groups

Placebo (n= 45)

Rifaximin (n= 49)

Inclusion Criteria

Aged 18-65 years; MHE diagnosed by abnormalities in NP tests; liver cirrhosis without overt HE (OHE); women of childbearing potential required to use at least two effective contraceptive methods

Exclusion Criteria

Known allergy to rifaximin/rifabutin/rifampin/rifapentine; current or recent (<6 weeks) use of alcohol; use of antibiotics within last 6 weeks; use of lactulose/lactitol, probiotics, L-ornithine-L-aspartate, zinc, metronidazole, neomycin, or rifaximin within last 6 weeks; use of interferon or psychoactive drugs such as benzodiazepines, psychotropic drugs, anti-epileptics within last 6 weeks; infection or gastrointestinal hemorrhage within last 6 weeks; acute superimposed liver injury; advanced medical problems such as congestive cardiac failure, advanced pulmonary disease, or renal insufficiency or electrolyte imbalance; presence of hepatocellular carcinoma; history of portosystemic shunt surgery or transjugular intrahepatic portosystemic shunt; pregnancy and breastfeeding; neurological or psychiatric problems that may influence quality of life measurement; poor vision or motor defects that interfere with the performance of psychometric tests; and current or past history of OHE

Methods

Eligible patients were randomized to receive either placebo or rifaximin 1,200 mg/day (frequency not defined). Diagnosis of MHE was based on the following NP tests performed: number Connection Test A (NCT-A), Figure Connection Test-A (FCT-A), and three performance subtests of the Wechsler Adult Intelligence Scale-Digit Symbol Test, Picture Completion Test (PCT), and Block Design Test (BDT). If any two of the NP tests were impaired beyond 2 standard deviations of known control values, MHE was then confirmed. HRQOL assessment was carried out using the ‘sickness impact profile (SIP)’ Questionnaire (John Hopkins University), which consisted of 136 items categorized into 12 scales. 

Duration

Follow-up: 8 weeks 

Outcome Measures

Primary: reversal of MHE at 8 weeks 

Secondary: reversal of MHE at 2 weeks; change in overall HRQOL after 8 weeks of treatment (measured as change in the total SIP score); development of OHE or treatment-related side effects 

Baseline Characteristics

  

Placebo (n= 45)

Rifaximin (n= 49)

  

Age, years

 54.3 51.7  

Female

13 9  

Child-Turcotte-Pugh

A

B

C

 

16

23

5

 

14

31

4

  

Duration of cirrhosis, years

 3.1 2.4  

Etiology

Alcohol 

Hepatitis B

Hepatitis C

 

21

1

20

 

27

0

19

  

Presence of varices 

 13 14  

Presence of ascites  

 23  23   

Total SIP score (95% confidence interval [CI])

 9.86 (8.66 to 11.06) 11.67 (10.31 to 13.03)  

No significant differences in baseline characteristics were noted between placebo and rifaximin groups. 

Results

Endpoint

Placebo (n= 45)

Rifaximin (n= 49)

p-value

Reversal of MHE

At 2 weeks

At 8 weeks 

 

8/45 (17.8%)

9/45 (20%)

 

28/49 (57.1%)

37/49 (75.5%) 

 

< 0.0001

< 0.0001 

Mean number of abnormal NP tests (95% CI)

Baseline 

At 2 weeks 

p-value vs baseline

At 8 weeks 

p-value vs baseline

 

2.31 (2.03 to 2.59)

2.03 (1.74 to 2.31)

>0.05

1.97 (1.69 to 2.25)

>0.05

 

2.35 (2.17 to 2.53)

1.29 (1.02 to 1.56)

0.002

0.81 (0.61 to 1.02)

0.000

 -

Mean total SIP score

Baseline 

At 8 weeks

p-value vs baseline 

 

9.86 (8.66 to 11.06)

8.51 (7.35 to 9.67)

0.82

 

11.67 (10.31 to 13.03)

6.45 (5.59 to 7.30)

0.000 

 -

Development of OHE

 2

1

 0.605

Adverse Events

Common Adverse Events: Two patients in rifaximin group reported epigastric discomfort and vomiting aft er 7 and 15 days of randomization. In the former, treatment was temporarily stopped for 3 days because of persistent symptoms, whereas symptoms of other patient improved after taking antacids. Both these patients were subsequently lost to follow-up. None of the patients in placebo group reported any side effects (p= 0.495). 

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Rifaximin significantly improves both cognitive functions and HRQOL in patients with MHE.

InpharmD Researcher Critique

As the study primarily focused on patients with MHE, results may not be readily applicable to patients with more severe HE. Clinical or laboratory parameters used to define reversal of MHE are not explicitly stated. 



References:

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). Am J Gastroenterol. 2011;106(2):307-316. doi:10.1038/ajg.2010.455