Intravenous BCAA for HE in ACLF (BCAA-HE-ACLF)

• Sponsor: Postgraduate Institute of Medical Education and Research (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT05700695
• Collaborator: Amrita Institute of Medical Sciences & Research Center (Other), Asian Institute of Gastroenterology, India (Other), All India Institute of Medical Sciences, Bhubaneswar (Other), Kalinga Institute of Medical Sciences, Bhubaneswar (Other)
• Enrollment: 246
• Location: 1
• Arms: 2
• Anticipated Duration (Months): 27.2
• Patients Per Site Per Month: 9

Study Details

Study Description

Brief Summary

This multi-centric study analyses the effect of intravenous branched-chain amino acids (BCAA) on overt HE in patients with ACLF. The investigators aim to study the efficacy of combining intravenous BCAA with lactulose versus lactulose alone, ammonia measures, endotoxin, metabolomics, and cerebral edema in the medical management of overt HE in patients with ACLF. The study will also access the impact on overall survival and improvement in the grade of HE.

Condition or Disease	Intervention/Treatment	Phase
Hepatic Encephalopathy; Acute-On-Chronic Liver Failure	Drug: Branch Chain Amino Acid; Drug: Lactulose	Phase 1

Detailed Description

Treatment of HE in ACLF is based on extrapolation of data available from cirrhotic patients with HE. The mainstay of treatment remains Lactulose. Rifaximin is added on to therapy who have a breakthrough episode of HE on lactulose. BCAA is used as an add-on therapy if patients have minimal/covert encephalopathy, are protein intolerant or have recurrent HE. No studies are available assessing the adjuvant effect of intravenous BCAA on ammonia reduction in HE in patients with ACLF. So, this study has been designed to analyze the effect of intravenous BCAA on hepatic encephalopathy in patients with ACLF. This study will also analyze the systemic and neuronal inflammation, metabolomics, and cerebral edema under the effect of intravenous BCAA in HE patients with ACLF.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 246 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Prospective interventional cohort studyProspective interventional cohort study
• Masking: Single (Investigator)
• Masking Description: Double-blind
• Primary Purpose: Treatment
• Official Title: Intravenous Branched-chain Amino Acids for Overt Hepatic Encephalopathy in Patients With Acute on Chronic Liver Failure - A Multi-centric Double-blind Randomized Controlled Trial
• Actual Study Start Date: Jan 17, 2023
• Anticipated Primary Completion Date: Apr 25, 2025
• Anticipated Study Completion Date: Apr 25, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experiential Arm Drug: iv Branch Chain Amino Acid + Lactulose Intravenous Branched Chain Amino Acids - 500mL once daily for 3 days plus Lactulose	Drug: Branch Chain Amino Acid; Intravenous branched chain amino acids will be given for 3 days to patients in experimental arm; Drug: Lactulose; Oral lactulose will be given to patients in both arms
Active Comparator: Comparator Arm Drug: Lactulose + Placebo	Drug: Lactulose; Oral lactulose will be given to patients in both arms

Outcome Measures

Primary Outcome Measures

1. Improvement in survival [Day 7]

   Survival assessment will be made by accessing all cause Mortality

2. Improvement in survival [Day 28]

   Survival assessment will be made by accessing all cause Mortality

3. Improvement of encephalopathy by one or more grade [Day 3]

   Improvement in scoring of hepatic Encephalopathy

4. Improvement of encephalopathy by one or more grade [Day 7]

   Improvement in scoring of hepatic Encephalopathy

5. Dynamic Assessment of systemic inflammation (Cytokines: IL-1b, IL-6, INF-g, TNF-a, IL-15, IL-17, IL-18) at presentation and after Specific management. [Day 0]

   Systemic inflammation will be accessed by Cytometric Bead Array

6. Assessment of metabolomics following BCAA + Lactulose and Lactulose alone [Day 7]

   Metabolomics will be performed by LC/GC-MS

Secondary Outcome Measures

1. Reduction of arterial ammonia Level [Day 3]

   Level of ammonia will be measured by Point of care device

2. Reduction of arterial ammonia Level [Day 7]

   Level of ammonia will be measured by Point of care device

3. Assessment of cerebral edema [Discharge form Hospital and 3 month of episode of HE]

   Cerebral edema will be assessed by Magnetic Resonance Imaging+ Magnetic Resonance Spectroscopy

4. Prevention/reduction of cerebral edema based on optic nerve sheath diameter (ONSD) [72 Hours]

   ONSD measurement will be done by Ultrasound

5. Reduction of consciousness recovery time among survivors [30 Days]

   Consciousness will be assessed by cognitive battery tests

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age 18-75 years

2. Either gender

3. Patients with ACLF (CANONIC definition) of any etiology with HE ≥grade 2 as per West-Haven Criteria

Exclusion Criteria:

1. Those who do not consent to participate in the study

2. Patients with structural brain lesions or stroke

3. Inability to obtain informed consent from patient or relatives

4. Severe preexisting cardiopulmonary disease

5. Renal dysfunction (S. Creatinine ≥ 2mg/dL)

6. Pregnancy/Lactation

7. Post liver transplant patients

8. HIV infection

9. Patients who are on psychoactive drugs, like sedatives or antidepressants

10. Patients who are too sick to carry out the protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dr. Madhumita Premkumar	Chandigarh		India	160012

Sponsors and Collaborators

• Postgraduate Institute of Medical Education and Research
• Amrita Institute of Medical Sciences & Research Center
• Asian Institute of Gastroenterology, India
• All India Institute of Medical Sciences, Bhubaneswar
• Kalinga Institute of Medical Sciences, Bhubaneswar

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Albrecht J, Norenberg MD. Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology. 2006 Oct;44(4):788-94. doi: 10.1002/hep.21357.
• Bajaj JS, Wade JB, Sanyal AJ. Spectrum of neurocognitive impairment in cirrhosis: Implications for the assessment of hepatic encephalopathy. Hepatology. 2009 Dec;50(6):2014-21. doi: 10.1002/hep.23216. No abstract available.
• Cordoba J, Ventura-Cots M, Simon-Talero M, Amoros A, Pavesi M, Vilstrup H, Angeli P, Domenicali M, Gines P, Bernardi M, Arroyo V; CANONIC Study Investigators of EASL-CLIF Consortium. Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF). J Hepatol. 2014 Feb;60(2):275-81. doi: 10.1016/j.jhep.2013.10.004. Epub 2013 Oct 12.
• Dam G, Aamann L, Vistrup H, Gluud LL. The role of Branched Chain Amino Acids in the treatment of hepatic Encephalopathy. J Clin Exp Hepatol. 2018 Dec;8(4):448-451. doi: 10.1016/j.jceh.2018.06.004. Epub 2018 Jun 27.
• Donovan JP, Schafer DF, Shaw BW Jr, Sorrell MF. Cerebral oedema and increased intracranial pressure in chronic liver disease. Lancet. 1998 Mar 7;351(9104):719-21. doi: 10.1016/S0140-6736(97)07373-X.
• Fischer JE, Rosen HM, Ebeid AM, James JH, Keane JM, Soeters PB. The effect of normalization of plasma amino acids on hepatic encephalopathy in man. Surgery. 1976 Jul;80(1):77-91.
• Gluud LL, Dam G, Les I, Cordoba J, Marchesini G, Borre M, Aagaard NK, Vilstrup H. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst Rev. 2015 Feb 25;(2):CD001939. doi: 10.1002/14651858.CD001939.pub2.
• Laake JH, Takumi Y, Eidet J, Torgner IA, Roberg B, Kvamme E, Ottersen OP. Postembedding immunogold labelling reveals subcellular localization and pathway-specific enrichment of phosphate activated glutaminase in rat cerebellum. Neuroscience. 1999;88(4):1137-51. doi: 10.1016/s0306-4522(98)00298-x.
• Norenberg MD, Martinez-Hernandez A. Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res. 1979 Feb 2;161(2):303-10. doi: 10.1016/0006-8993(79)90071-4.
• Rossi-Fanelli F, Riggio O, Cangiano C, Cascino A, De Conciliis D, Merli M, Stortoni M, Giunchi G. Branched-chain amino acids vs lactulose in the treatment of hepatic coma: a controlled study. Dig Dis Sci. 1982 Oct;27(10):929-35. doi: 10.1007/BF01316578.
• Shawcross DL, Sharifi Y, Canavan JB, Yeoman AD, Abeles RD, Taylor NJ, Auzinger G, Bernal W, Wendon JA. Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. J Hepatol. 2011 Apr;54(4):640-9. doi: 10.1016/j.jhep.2010.07.045. Epub 2010 Dec 1.

• Responsible Party: Madhumita Premkumar, ASSOCIATE PROFESSOR, Postgraduate Institute of Medical Education and Research
• ClinicalTrials.gov Identifier: NCT05700695
• Other Study ID Numbers: IEC/04/2022-2385
• First Posted: Jan 26, 2023
• Last Update Posted: Jan 26, 2023
• Last Verified: Jan 1, 2023

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Madhumita Premkumar, ASSOCIATE PROFESSOR, Postgraduate Institute of Medical Education and Research: Hepatic Encephalopathy; Acute-On-Chronic Liver Failure; Neurological Dysfunction; Metabolomics; Systemic Inflammations; Branch Chain Amino Acid; bispectral index; Cerebral edema; Lactulose
• Additional relevant MeSH terms: Liver Failure; Hepatic Insufficiency; Hepatic Encephalopathy; End Stage Liver Disease; Acute-On-Chronic Liver Failure; Brain Diseases; Lactulose

Study Results

No Results Posted as of Jan 26, 2023