Intravenous Branched Chain Amino Acids for Hepatic Encephalopathy in ACLF

NCT04238416 | Completed Phase 1

• 1 other identifier: IEC-08/2019-1336
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

This study analyses the effect of intravenous branched chain amino acids (BCAA) on overt HE in patients with ACLF. The investigators plan to study the efficacy of combining intravenous BCAA with lactulose versus lactulose alone in the medical management of overt HE in patients with ACLF and its impact on overall survival and improvement in grade of HE.

Conditions

Hepatic Encephalopathy; Acute-On-Chronic Liver Failure

Keywords

branched chain amino acids; hepatic encephalopathy; lactulose; acute on chronic liver failure; bispectral index

Outcome Measures

Primary Outcomes (2)

• Improvement of Survival

  All cause Mortality assessment

  At day day 28

• Improvement of encephalopathy by ≥ 1 grade

  Improvement in hepatic encephalopathy

  72 hours

Secondary Outcomes (4)

• Reduction in level of ammonia

  48 and 72 hours

• Reduction of consciousness recovery time among survivors

  30 days

• Prolongation of time to death among non-survivors

  30 days

• Prevention/reduction of cerebral edema based on optic nerve sheath diameter

  72 hours

Study Arms (2)

IV BCAA + Lactulose

EXPERIMENTAL

IV Branched Chain Amino Acids - 500mL once daily for 3 days plus Lactulose

Drug: Branched chain amino acid; Drug: Lactulose

Lactulose alone

ACTIVE COMPARATOR

Oral Lactulose alone

Drug: Lactulose

Interventions

Branched chain amino acid DRUG

Intravenous branched chain amino acids will be given for 3 days to patients in experimental arm

IV BCAA + Lactulose

Lactulose DRUG

Oral lactulose will be given to patients in both arms

IV BCAA + Lactulose; Lactulose alone

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-75 years
• Either gender
• Patients with ACLF (CANONIC definition) of any aetiology with HE ≥grade 2 as per West-Haven Criteria or Hepatic encephalopathy scoring algorithm (HESA)

You may not qualify if:

• Those who do not consent to participate in the study
• Patients with structural brain lesions or stroke
• Inability to obtain informed consent from patient or relatives
• Severe preexisting cardiopulmonary disease
• Renal dysfunction (S. Creatinine ≥ 2mg/dL)
• Pregnancy/Lactation
• Post liver transplant patients
• HIV infection
• Patients who are on psychoactive drugs, like sedatives or antidepressants
• Patients who are too sick to carry out the protocol
• As the study was carried out during the peak of the COVID-19, patients who developed COVID-19 after randomization were excluded from the analysis as they were shifted to dedicated COVID-19 ICU's.

Sponsors & Collaborators

• Post Graduate Institute of Medical Education and Research, Chandigarh: lead

Study Sites (1)

PGIMER

Chandigarh, 160012, India

Location

Related Publications (12)

• 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.

  PMID: 21163546 BACKGROUND

• 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.

  PMID: 9504517 BACKGROUND

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

  PMID: 17006913 BACKGROUND

• 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.

  PMID: 31966 BACKGROUND

• Albrecht J, Dolinska M, Hilgier W, Lipkowski AW, Nowacki J. Modulation of glutamine uptake and phosphate-activated glutaminase activity in rat brain mitochondria by amino acids and their synthetic analogues. Neurochem Int. 2000 Apr;36(4-5):341-7. doi: 10.1016/s0197-0186(99)00142-4.

  PMID: 10733001 BACKGROUND

• 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.

  PMID: 10336125 BACKGROUND

• 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.

  PMID: 24128414 BACKGROUND

• 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.

  PMID: 818729 RESULT

• 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.

  PMID: 30568347 RESULT

• 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.

  PMID: 6749458 RESULT

• 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.

  PMID: 25715177 RESULT

• Mehtani R, Premkumar M, Garg S, Kajal K, Kulkarni AV, Duseja AK, Dhiman RK, De A, Verma N, Taneja S, Rathi S, Singh V, Chakma J, Soni SL, Kakkar A, Kapila AT, Ahuja CK, Divyaveer S, Praharaj D. Intravenous BCAA Infusion Does Not Lead to a Sustained Recovery From Overt HE in ACLF - An Open Label Randomized Clinical Trial. J Clin Exp Hepatol. 2023 Nov-Dec;13(6):977-988. doi: 10.1016/j.jceh.2023.05.015. Epub 2023 Jun 1.

  PMID: 37975059 DERIVED

MeSH Terms

Conditions

Hepatic Encephalopathy; Acute-On-Chronic Liver Failure

Interventions

Amino Acids, Branched-Chain; Lactulose

Condition Hierarchy (Ancestors)

Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Liver Failure, Acute

Intervention Hierarchy (Ancestors)

Amino Acids; Amino Acids, Peptides, and Proteins; Disaccharides; Oligosaccharides; Polysaccharides; Carbohydrates; Sugars

Study Officials

• Madhumita Premkumar, MD, DM

  Post Graduate Institute of Medical Education and Research, Chandigarh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Model Details: Prospective interventional cohort study

Study Record Dates

• First Submitted: September 28, 2019
• First Posted: January 23, 2020
• Study Start: November 1, 2019
• Primary Completion: December 30, 2021
• Study Completion: December 30, 2021
• Last Updated: August 16, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

IN (1)