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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00470314
Recruitment Status : Unknown
Verified April 2007 by All India Institute of Medical Sciences, New Delhi.
Recruitment status was:  Active, not recruiting
First Posted : May 7, 2007
Last Update Posted : January 7, 2008
Information provided by:
All India Institute of Medical Sciences, New Delhi

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

Condition or disease Intervention/treatment Phase
Acute Liver Failure Drug: L-Ornithine L-Aspartate Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double
Primary Purpose: Treatment
Official Title: Therapeutic Efficacy of L-Ornithine L-Aspartate Infusion in Patients With Acute Liver Failure: A Double- Blind, Randomized, Placebo- Controlled Study
Study Start Date : January 2005
Estimated Study Completion Date : May 2007

Resource links provided by the National Library of Medicine

Primary Outcome Measures :
  1. Improvement in survival. [ Time Frame: Within 30 days of disease onset ]

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

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00470314

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All India Institute of Medical Sciences
Delhi, India
Sponsors and Collaborators
All India Institute of Medical Sciences, New Delhi
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Study Director: Subrat Kr Acharya, M.D., D.M. All India Institute of Medical Sciences, New Delhi
Principal Investigator: Vikram Bhatia, 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
Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
Layout table for additonal information Identifier: NCT00470314    
Other Study ID Numbers: GE-LOLA/2005
First Posted: May 7, 2007    Key Record Dates
Last Update Posted: January 7, 2008
Last Verified: April 2007
Keywords provided by All India Institute of Medical Sciences, New Delhi:
Acute liver failure
Ornithine Aspartate
Additional relevant MeSH terms:
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Liver Failure
Hepatic Insufficiency
Liver Failure, Acute
Liver Diseases
Digestive System Diseases
Excitatory Amino Acid Agonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs