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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Acute-On-Chronic Liver Failure; Hepatic Encephalopathy
• Intervention / Treatment: Drug: Lactulose; Drug: Branch Chain Amino Acid

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 Type: Interventional
• Enrollment (Estimated): 226
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Dr Madhumita Premkumar, DM; Phone Number: 7087003409; Email: drmadhumitap@gmail.com
• Study Contact Backup: Name: Dr Ashish Kakkar, DM; Phone Number: +91 172 2755266

Study Locations

• India
  • Chandigarh, India, 160012
    • Recruiting
    • Dr. Madhumita Premkumar
    • Contact: Dr. Madhumita Premkumar, MD; Phone Number: +919540951061; Email: drmadhumitap@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	Survival assessment will be made by recording all deaths	Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement of encephalopathy by one or more grade	Improvement in scoring of hepatic Encephalopathy	Day 7
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.	Systemic inflammation will be accessed by Cytometric Bead Array	Day 0
Assessment of metabolomics following BCAA + Lactulose and Lactulose alone	Metabolomics will be performed by LC/GC-MS	Day 7
Reduction of arterial ammonia Level	Level of ammonia will be measured by Point of care device	Day 3
Reduction of arterial ammonia Level	Level of ammonia will be measured by Point of care device	Day 7
Assessment of cerebral edema	Cerebral edema will be assessed by Magnetic Resonance Imaging+ Magnetic Resonance Spectroscopy	Discharge form Hospital and 3 month of episode of HE
Prevention/reduction of cerebral edema based on optic nerve sheath diameter (ONSD)	ONSD measurement will be done by Ultrasound	72 Hours
Reduction of consciousness recovery time among survivors	Consciousness will be assessed by cognitive battery tests	Day 28
Survival	Survival assessment will be done with recording all cause mortality	Day 28
Survival	Survival assessment will be done with recording all cause mortality	Day 90

Collaborators and Investigators

• Sponsor: Post Graduate Institute of Medical Education and Research, Chandigarh
• Collaborators: All India Institute of Medical Sciences, Bhubaneswar; Asian Institute of Gastroenterology, India; Amrita Institute of Medical Sciences & Research Center; Kalinga Institute of Medical Sciences, Bhubaneswar

Publications and helpful links

General Publications

• 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.
• 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.
• Albrecht J, Norenberg MD. Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology. 2006 Oct;44(4):788-94. doi: 10.1002/hep.21357.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2023
• Primary Completion (Estimated): April 25, 2025
• Study Completion (Estimated): April 25, 2025

Study Registration Dates

• First Submitted: December 6, 2022
• First Submitted That Met QC Criteria: January 17, 2023
• First Posted (Actual): January 26, 2023

Study Record Updates

• Last Update Posted (Actual): April 24, 2024
• Last Update Submitted That Met QC Criteria: April 23, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Acute-On-Chronic Liver Failure; Metabolomics; bispectral index; Hepatic Encephalopathy; Cerebral edema; Lactulose; Neurological Dysfunction; Systemic Inflammations; Branch Chain Amino Acid
• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Liver Diseases; Liver Failure, Acute; Brain Diseases, Metabolic; End Stage Liver Disease; Liver Failure; Hepatic Insufficiency; Acute-On-Chronic Liver Failure; Hepatic Encephalopathy; Brain Diseases; Gastrointestinal Agents; Lactulose
• Other Study ID Numbers: IEC/04/2022-2385

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