Therapeutic Efficacy of L-Ornithine L-Aspartate Infusion in Patients With Acute Liver Failure

January 4, 2008 updated by: All India Institute of Medical Sciences, New Delhi

Therapeutic Efficacy of L-Ornithine L-Aspartate Infusion in Patients With Acute Liver Failure: A Double- Blind, Randomized, Placebo- Controlled Study

The purpose of the study is to determine whether L-Ornithine L-Aspartate infusion improves the survival of patients with acute liver failure.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Acute liver failure (ALF) has a high mortality. However, those who survive recover completely without any sequel. Liver transplantation is logistically and financially difficult in most countries with the highest disease burden. It also entails a lifelong commitment to immunosuppression. We therefore need new treatment options to improve the survival of medically managed patients with ALF.

Ammonia is believed to be the major neurotoxin in ALF. There is experimental evidence of direct and indirect ammonia neurotoxicity in ALF. The brain does not have a urea cycle, and relies on glutamine synthesis in the astrocytes for removal of excess ammonia. Increased intracellular glutamine in the astrocytes leads to cellular swelling. Increased brain ammonia concentrations also result in altered expression of key astrocyte proteins including glial fibrillary acidic protein, glutamate and glycine transporters and "peripheral-type" (mitochondrial) BZD receptors. Accumulation of ammonia in brain results in a redistribution of cerebral blood flow from cortical to sub-cortical structures, and also has direct effects on neurotransmission. Increased ammonia concentration upregulates the peripheral-type benzodiazepine (PTBR) receptors in the outer membrane of astroglial mitochondria, and enhance the synthesis and release of neurosteroids, some of which are known GABA (A) receptor agonists.

There is now evidence of high blood ammonia levels in ALF , with a substantial blood-to-brain ammonia transfer.Brain-blood ammonia concentration ratios (normally of the order of 2) are increased up to 4 fold in liver failure. Higher ammonia levels have been co-related with higher mortality and complications in human clinical trials. Clemmesen et al found that ALF patients who died of cerebral herniation had higher ammonia levels as compared to the survivors. We have also previously shown that higher ammonia levels at admission predicts a poorer survival rate, and arterial ammonia levels are an independent predictor of mortality by logistic regression analysis. An arterial ammonia level of > 124 μmol/l was found to predict mortality with 78.6% sensitivity and 76.3% specificity.There is thus a strong rationale for using ammonia lowering therapies in ALF.

LOLA is a compound salt of Ornithine and Aspartate. The mechanism of its ammonia lowering action has been defined. LOLA provides critical substrates for both urea and glutamine synthesis- the key pathways of ammonia detoxification in the liver. Urea synthesis is carried out in a low affinity, high capacity system that exists largely in the periportal hepatocytes. In these cells, Ornithine serves as an activator of ornithine-carbamoyltransferase and carbamylphosphate-synthetase. In addition, Ornithine itself acts as a substrate for urea genesis. Hence LOLA can activate the periportal urea cycle. Glutamine synthesis is a high affinity, relatively low capacity system located in the perivenous hepatocytes. Ornithine is converted to α -ketoglutarate, and taken up by these perivenous hepatocytes and serves as a carbon source for glutamine synthesis. LOLA also upregulates glutamine synthesis in the skeletal muscle via glutamine synthetase (GS). Recently, in animal models an increased transport of ornithine across the blood brain barrier and an increase in the brain glutamine synthesis after LOLA treatment has been described, and suggests that LOLA may have both centrally (CNS) and peripherally mediated effects. , LOLA has been shown to reduce raised ammonia levels in experimental models of hyper-ammonemia, and in human cirrhotic patients. In patients with cirrhosis,LOLA improves psychometric performance and improves the mental status.

LOLA is therefore a promising agent for use in ALF patients. It has scientific rationale and has been found to be effective in cirrhosis. There is however only a single experimental study of LOLA in a rat model of acute liver injury. LOLA infusion could normalize the plasma ammonia and lead to a significant reduction in brain water content. We would like to study whether LOLA infusion in patients with ALF can reduce ammonia levels and improve survival.

Study Type

Interventional

Enrollment (Actual)

150

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • India
      • Delhi, India
        • All India Institute of Medical Sciences

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients with acute liver failure, as defined by the development of encephalopathy within 4 weeks of onset of symptoms in the absence of preexisting liver disease.

Exclusion Criteria:

  • Presence of > 3 adverse prognostic factors (Age > 40 years, clinical evidence of cerebral edema, bilirubin >15mg/dL, and prothrombin time prolonged by > 25 seconds) at the initial patient evaluation.
  • Suspicion of underlying cirrhosis.
  • Previous treatment with LOLA or other ammonia lowering treatments before admission.
  • Malarial hepatopathy, enteric hepatitis, alcoholic hepatitis, or ischemic hepatitis.
  • Active alcohol use of >40 gm/week at the onset of illness.
  • Renal insufficiency at admission, as defined by a urine output of <500 mL/d and /or creatinine level of > 3mg/dL.
  • Inability to randomize within 24 hours of admission.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Improvement in survival.
Time Frame: Within 30 days of disease onset
Within 30 days of disease onset

Secondary Outcome Measures

Outcome Measure
Time Frame
Reduction in ammonia levels during and at the end of 72 hour LOLA infusion.
Time Frame: 72 hours
72 hours
Improvement of encephalopathy by one or more grades.
Time Frame: 72 hours
72 hours
Reduction of consciousness recovery time (CRT) among survivors.
Time Frame: Within 30 days of disease onset
Within 30 days of disease onset
Prolongation of time to death among non-survivors.
Time Frame: Within 30 days of disease onset
Within 30 days of disease onset
Prevention / reduction of cerebral edema.
Time Frame: 72 hours
72 hours
Reduction of seizures frequency.
Time Frame: Within 30 days of disease onset
Within 30 days of disease onset

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

All India Institute of Medical Sciences, New Delhi

Investigators

  • Principal Investigator: Vikram Bhatia, M.D., D.M., All India Institute of Medical Sciences, New Delhi
  • Study Director: Subrat Kr Acharya, M.D., D.M., All India Institute of Medical Sciences, New Delhi
  • Principal Investigator: Amit Singhal, M.D., All India Institute of Medical Sciences, New Delhi

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2005

Study Completion (Anticipated)

May 1, 2007

Study Registration Dates

First Submitted

May 4, 2007

First Submitted That Met QC Criteria

May 4, 2007

First Posted (Estimate)

May 7, 2007

Study Record Updates

Last Update Posted (Estimate)

January 7, 2008

Last Update Submitted That Met QC Criteria

January 4, 2008

Last Verified

April 1, 2007

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GE-LOLA/2005

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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