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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT05700695
Other study ID # IEC/04/2022-2385
Secondary ID
Status Recruiting
Phase Phase 1
First received
Last updated
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
Health authority
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.

Study Design


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 allClick 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
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