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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Hepatic Encephalopathy, Acute-On-Chronic Liver Failure

Intervention / Treatment
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* Drug: Branch Chain Amino Acid
* Drug: Lactulose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-75 years Either gender Patients with ACLF (CANONIC definition) of any etiology with HE ≥grade 2 as per West-Haven Criteria Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective interventional cohort study
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experiential Arm<br>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<br>* Intravenous branched chain amino acids will be given for 3 days to patients in experimental arm<br>Drug: Lactulose<br>* Oral lactulose will be given to patients in both arms<br>|
| Active Comparator: Comparator Arm<br>Drug: Lactulose + Placebo | Drug: Lactulose<br>* Oral lactulose will be given to patients in both arms<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in survival | Survival assessment will be made by accessing all cause Mortality | Day 7 | 
| Improvement in survival | Survival assessment will be made by accessing all cause Mortality | Day 28 | 
| Improvement of encephalopathy by one or more grade | Improvement in scoring of hepatic Encephalopathy | Day 3 | 
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 30 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatic Encephalopathy, Acute-On-Chronic Liver Failure, Neurological Dysfunction, Metabolomics, Systemic Inflammations, Branch Chain Amino Acid, bispectral index, Cerebral edema, Lactulose