BCAA vs. Rifaximin in Patients With Cirrhosis for Secondary Prophylaxis of HE (HERB)

Branch Chain Amino Acids vs. Rifaximin in Patients With Cirrhosis for Secondary Prophylaxis of Hepatic Encephalopathy: Double-blind Placebo-controlled Multicentric Randomized Controlled Trial

Rationale

• Patients who recover from an episode of overt HE(OHE) are at risk of recurrent episodes of HE and persistent minimal hepatic encephalopathy, impacting their daily functioning and mental health.
• A multicentric pan-India team will evaluate the role of oral branched-chain amino acids (BCAA) vs Rifaximin as secondary prophylaxis following overt HE as compared with improvement in cognitive function.

Novelty:

• This study is intended to investigate the role of BCAA vs rifaximin as the ideal second-line therapy for HE management, recurrence, and overall health, including cognitive function, depression and anxiety.
• The head-to-head comparison of BCAA+lactulose+ pill-placebo vs rifaximin+ lactulose+ powder-placebo ensures minimization of bias and has adequate power to determine rates of recurrence,

Objectives:

• To assess the 1st breakthrough episode of HE during 6months in BCAA vs rifaximin groups as ideal secondary prophylaxis in HE. Methodology
• Double-blind placebo-controlled double-dummy randomized trial of BCAA supplementation vs rifaximin as the ideal second-line therapy in patients with cirrhosis who have recovered from an episode of OHE. Expected Outcome
• Ideal second line agent HE prophylaxis (rifaximin or BCAA) following 1st line lactulose is unclear in an Indian context where dysbiosis and sarcopenia are prevalent, and cost of therapy needs to be optimized.
• Optimal HE management prevents recurrence episodes of HE, and improves prognosis, neurocognitive function, and overall health-related quality of life(HRQOL).
• Creation of a management algorithm based deductive models incorporating etiology and severity of liver disease, cognitive performance, sarcopenia, and ammonia, and neuropsychiatric impact of using BCAA vs Rifaximin will be created.

Study Overview

• Status: Recruiting
• Conditions: Decompensated Cirrhosis; Hepatic Encephalopathy; Minimal Hepatic Encephalopathy
• Intervention / Treatment: Drug: Lactulose; Drug: Placebo for Rifaximin 550mg; Drug: Placebo for BCAA; Drug: Oral Branched chain Amino acid; Drug: Rifaximin 550 MG

Detailed Description

Hepatic encephalopathy (HE), a complex neuropsychiatric syndrome arising from liver dysfunction and the establishment of portosystemic shunts (PSS), presents a significant clinical challenge, marked by a spectrum of cognitive, emotional, and motor disturbances. These conditions necessitate precise diagnostic and therapeutic approaches to mitigate its impact on patient well-being and quality of life.

• The prevalence of OHE at the time of diagnosis of cirrhosis is 10%-14% in general, 16%-21% in those with decompensated cirrhosis. The cumulated numbers indicate that OHE will occur in 30%-40% of those with cirrhosis at some time during their clinical course and in the survivors in most cases repeatedly. Minimal HE (MHE) or covert HE (CHE) occurs in 20%-80% of patients with cirrhosis. This high incidence rate calls for effective, accessible, and cost-efficient treatment modalities to improve patient outcomes and quality of life.
• Indian patients have sarcopenia and reduced muscle strength impairing peripheral ammonia metabolism, and also have gut dysbiosis which can predispose to another episode of HE. A critical initial step in addressing HE involves the identification of precipitating factors, with evidence suggesting that reversible elements contribute to over 80% of HE cases.
• Current therapeutic interventions primarily target the reduction of blood ammonia levels, yet the effectiveness of these treatments varies, underscoring the necessity for ongoing research and innovation in HE management.
• Patients recovering from OHE are at risk of recurrent episodes and may suffer from persistent MHE, a condition often undiagnosed due to its subtle cognitive manifestations. Such individuals may have cognitive impairment that affect patients' daily functioning and mental health, necessitating the development of standardized diagnostic psychometric tests protocols tailored to diverse populations.
• Mainstay for treatment of HE has been lactulose or lactitol. How lactulose acts in HE has been a matter of debate and various hypotheses have been postulated. Inglefenger et al., suggested it to be due to proliferation of Lactobacillus with inhibition of Bacteroides and other organisms (28). Lactulose has pleiotropic effects, and reduction of ammonia is only one of the ways in which it acts on HE.
• Rifaximin is an oral antibiotic having <0.4% of systemic absorption. It acts against coliforms like Escherichia coli and plays a role in the reduction of ammonia levels and prevention of recurrence of HE . Several trials have compared Rifaximin as a therapy of HE with placebo, neomycin and non-absorbable disaccharides . Rifaximin emerged as a promising alternative, showing comparable efficacy in managing OHE and preventing its recurrence..
• This is a double-blind, randomized placebo-controlled trial of branched-chain amino acid supplementation vs rifaximin as the ideal second-line therapy in patients with cirrhosis who have recovered from an episode of overt hepatic encephalopathy, with either drug given over 12 weeks with endpoints being prevention of recurrence of another episode of HE, efficacy, safety, and improvement in neurocognitive function

• Study Type: Interventional
• Enrollment (Estimated): 336
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Madhumita Premkumar; Phone Number: +9101722754777; Email: drmadhumitap@gmail.com

Study Locations

• India
  • Chandigarh, India
    • Recruiting
    • PGIMER
    • Contact: Anchal Sandhu; Phone Number: +9101722754777; Email: anchalsandhu04@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Cirrhosis defined by standard clinical, ultrasonographic findings and/or histological criteria. Cirrhosis of any etiology may be included. However, patients with cirrhosis due to autoimmune hepatitis must be on stable corticosteroid doses for ≥3-month period before study inclusion; those with viral hepatitis, must similarly be on anti-viral therapy with controlled viremia or with SVR.
2. Any gender
3. Discharged from the hospital following an episode of overt hepatic encephalopathy.
4. Participants able to give informed consent

Exclusion Criteria:

1. Subjects with active bacterial or fungal infection
2. Subjects with active or very recent gastrointestinal bleeding in the last 2 weeks.
3. Current overt hepatic encephalopathy, defined as grade II-IV hepatic encephalopathy according to the West-Haven classification.

4. Conditions that can impact interpretation of cognitive function:

   i) Untreated viremic hepatitis C virus infection ii) Established neurological/degenerative disorders iii) Patient undergoing active alcohol withdrawal treatment Iv) Patient is intoxicated or under the influence of illicit drugs as per clinician assessment V) Treatment with antipsychotics or other psychotropic drugs with sedative effects

5. Patients with active hepatocellular carcinoma or history of hepatocellular carcinoma that is in remission for less than six months.
6. Patients with a history of significant extrahepatic disease with impaired short-term prognosis, including: i) Congestive heart failure New York Heart Association Grade III/IV or ejection fraction<30% ii) COPD: GOLD >2, ii) Chronic kidney disease with serum creatinine >2mg/dL or under renal replacement therapy.
7. Patients with current extra hepatic malignancies, including solid tumours and hematologic disorders.
8. Patients with MELD>20
9. Patients with mental incapacity, or those unlikely to survive 12 weeks or any other reason considered by the investigator precluding adequate understanding, cooperation, or compliance in the study activities.
10. Patients with TIPS shunt in situ
11. Pregnancy (urine pregnancy test at inclusion)
12. Refusal or inability to give informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A1=Experimental: Drug: Oral BCAA + Rifaximin placebo + Lactulose ( Oral BCAA 15 gm in once daily dose With Lactulose for 12 weeks)	Drug: Lactulose; Both groups will be treated with will be treated with 30-60 ml lactulose three times a day to ensure passage of 2-3 semisoft stools per day; Drug: Placebo for Rifaximin 550mg; Identical placebo sugar pills will be used as a placebo.; Drug: Oral Branched chain Amino acid; The active drug BCAA supplement will be dispensed in a dose of 15 gm once daily x 12 weeks
Experimental: A2= Experimental: Drug: Rifaximin+ BCAA Placebo + Lactulose ( Oral Rifaximin 550 mg twice daily daily + Lactulose therapy for 12 weeks)	Drug: Lactulose; Both groups will be treated with will be treated with 30-60 ml lactulose three times a day to ensure passage of 2-3 semisoft stools per day; Drug: Placebo for BCAA; A placebo comparator of 15 gm of skimmed milk powder will be used.; Drug: Rifaximin 550 MG; Active drug rifaximin will be dispensed in a dose of 550mg twice daily x 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of breakthrough event of overt hepatic encephalopathy in BCAA vs rifaximin arm	Time to a breakthrough overt HE episode will be the duration (number of days) from time of first dose of study drug to the first breakthrough overt HE episode. The number of events of a first breakthrough overt HE episode during the treatment period will be assessed	24 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Computerized Cognitive Test battery for Cognitive performance	A curated Computer based Cognitive test battery has been created for this protocol with a fixed set of tasks comprising Animal Naming Test, reaction times, digit span and number connection tests. This has been designed using the PEBL opensource language. Psychology Experiment Building Language. [2019-03] PEBL Version 2.1. The battery has been validated by us previously in patients with chronic hepatitis C infection.	At Enrolment
Computerized Cognitive Test battery for Cognitive performance	Computerized Cognitive Test battery: A curated Computer based Cognitive test battery has been created for this protocol with a fixed set of tasks comprising Animal Naming Test, reaction times, digit span and number connection tests. This has been designed using the PEBL opensource language. Psychology Experiment Building Language. [2019-03] PEBL Version 2.1. The battery has been validated by us previously in patients with chronic hepatitis C infection.	30 days
Computerized Cognitive Test battery for Cognitive performance	Computerized Cognitive Test battery A curated Computer based Cognitive test battery has been created for this protocol with a fixed set of tasks comprising Animal Naming Test, reaction times, digit span and number connection tests. This has been designed using the PEBL opensource language. Psychology Experiment Building Language. [2019-03] PEBL Version 2.1. The battery has been validated by us previously in patients with chronic hepatitis C infection.	90 days
Psychiatric Assessment	Beck's Depression Inventory (BDI) test will be performed. The scoring is as follows 1-10: These ups and downs are considered normal 11-16: Mild mood disturbance 17-20: Borderline clinical depression 21-30: Moderate depression31-40: Severe depression 40: Extreme depression	0 days
Psychiatric Assessment	Generalized anxiety disorder (GAD 7 score) will be performed. It has 7 questions. Using the threshold score of 10, the GAD-7 has a sensitivity of 89% and a specificity of 82% for GAD	0 days
Psychiatric Assessment	Generalized anxiety disorder (GAD 7 score) test will be performed	30 days
Psychiatric Assessment	Beck's Depression Inventory (BDI) test will be performed. The scoring is as follows 1-10: These ups and downs are considered normal 11-16: Mild mood disturbance 17-20: Borderline clinical depression 21-30: Moderate depression31-40: Severe depression 40: Extreme depression	30 days
Psychiatric Assessment	Beck's Depression Inventory (BDI)test will be performed The scoring is as follows 1-10: These ups and downs are considered normal 11-16: Mild mood disturbance 17-20: Borderline clinical depression 21-30: Moderate depression31-40: Severe depression 40: Extreme depression	90 days
Psychiatric Assessment	Generalized anxiety disorder (GAD 7 score) tests will be performed	90 days
HRQOL will be performed by SF-36	Health related query of life will be performed.	0 days
HRQOL will be performed by SF-36	Health related query of life will be performed.	30 days
HRQOL will be performed by SF-36	Health related query of life will be performed.	90 days
Assessment of changes in ammonia	Estimation of ammonia by arterial fasting test/ capillary test will be performed	At enrolment
Assessment of changes in ammonia	Estimation of ammonia by arterial fasting test/ capillary test will be performed	24 week
Assessment of changes in muscle health	Estimation of sarcopenia will be performed by muscle ultrasound by SARCUS.	Baseline
Assessment of changes in muscle health	Estimation of sarcopenia by muscle ultrasound by SARCUS.	30 days
Assessment of changes in muscle health	Estimation of sarcopenia by muscle ultrasound by SARCUS.	90 days

Collaborators and Investigators

• Sponsor: Post Graduate Institute of Medical Education and Research, Chandigarh
• Collaborators: Indian Council of Medical Research

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2025
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): August 1, 2027

Study Registration Dates

• First Submitted: April 23, 2024
• First Submitted That Met QC Criteria: July 31, 2024
• First Posted (Actual): August 5, 2024

Study Record Updates

• Last Update Posted (Actual): June 10, 2025
• Last Update Submitted That Met QC Criteria: June 5, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: rifaximin; Hepatic encephalopathy; Branched-chain amino acids; Computerized neurocognitive test battery; Double blind placebo controlled multicentric randomized controlled trial
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Metabolic Diseases; Digestive System Diseases; Liver Diseases; Brain Diseases, Metabolic; Liver Failure; Hepatic Insufficiency; Fibrosis; Liver Cirrhosis; Brain Diseases; Hepatic Encephalopathy; Anti-Bacterial Agents; Anti-Infective Agents; Gastrointestinal Agents; Rifaximin; Lactulose
• Other Study ID Numbers: PGI/HEP/567

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No