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

Hepatic Encephalopathy Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05700695
• Other study ID #: IEC/04/2022-2385
• Status: Recruiting
• Phase: Phase 1
• Start date: January 17, 2023
• Est. completion date: April 25, 2025

Study information

• Verified date: April 2024
• Source: Post Graduate Institute of Medical Education and Research, Chandigarh
• Contact: Dr Madhumita Premkumar, DM
• Phone: 7087003409
• Email: drmadhumitap[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 226
• Est. completion date: April 25, 2025
• Est. primary completion date: April 25, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute-On-Chronic Liver Failure
• Brain Diseases
• End Stage Liver Disease
• Hepatic Encephalopathy
• Hepatic Insufficiency
• Liver Failure

Intervention

Drug:
• Branch Chain Amino Acid
Intravenous branched chain amino acids will be given for 3 days to patients in experimental arm
• Lactulose
Oral lactulose will be given to patients in both arms

Locations

Country	Name	City	State
India	Dr. Madhumita Premkumar	Chandigarh

Sponsors (5)

Lead Sponsor	Collaborator
Post Graduate Institute of Medical Education and Research, Chandigarh	All India Institute of Medical Sciences, Bhubaneswar, Amrita Institute of Medical Sciences & Research Center, Asian Institute of Gastroenterology, India, Kalinga Institute of Medical Sciences, Bhubaneswar

Country where clinical trial is conducted

India, 

References & Publications (11)

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival	Survival assessment will be made by recording all deaths	Day 28
Secondary	Reduction of arterial ammonia Level	Level of ammonia will be measured by Point of care device	Day 3
Secondary	Reduction of arterial ammonia Level	Level of ammonia will be measured by Point of care device	Day 7
Secondary	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
Secondary	Prevention/reduction of cerebral edema based on optic nerve sheath diameter (ONSD)	ONSD measurement will be done by Ultrasound	72 Hours
Secondary	Reduction of consciousness recovery time among survivors	Consciousness will be assessed by cognitive battery tests	Day 28
Secondary	Survival	Survival assessment will be done with recording all cause mortality	Day 28
Secondary	Survival	Survival assessment will be done with recording all cause mortality	Day 90
Secondary	Improvement of encephalopathy by one or more grade	Improvement in scoring of hepatic Encephalopathy	Day 7
Secondary	Assessment of metabolomics following BCAA + Lactulose and Lactulose alone	Metabolomics will be performed by LC/GC-MS	Day 7
Secondary	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