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

Acute Liver Failure Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00470314
• Other study ID #: GE-LOLA/2005
• Status: Active, not recruiting
• Phase: Phase 2
• First received: May 4, 2007
• Last updated: January 4, 2008
• Start date: January 2005
• Est. completion date: May 2007

Study information

• Verified date: April 2007
• Source: All India Institute of Medical Sciences, New Delhi
• Contact: n/a
• Is FDA regulated: No
• Health authority: India: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 150
• Est. completion date: May 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Liver Failure
• Liver Failure
• Liver Failure, Acute

Intervention

Drug:
• L-Ornithine L-Aspartate

Locations

Country	Name	City	State
India	All India Institute of Medical Sciences	Delhi

Sponsors (1)

Lead Sponsor	Collaborator
All India Institute of Medical Sciences, New Delhi

Country where clinical trial is conducted

India, 

References & Publications (5)

Bhatia V, Singh R, Acharya SK. Predictive value of arterial ammonia for complications and outcome in acute liver failure. Gut. 2006 Jan;55(1):98-104. Epub 2005 Jul 15. — View Citation

Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology. 1999 Mar;29(3):648-53. — View Citation

Kircheis G, Nilius R, Held C, Berndt H, Buchner M, Görtelmeyer R, Hendricks R, Krüger B, Kuklinski B, Meister H, Otto HJ, Rink C, Rösch W, Stauch S. Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study. Hepatology. 1997 Jun;25(6):1351-60. — View Citation

Rose C, Michalak A, Rao KV, Quack G, Kircheis G, Butterworth RF. L-ornithine-L-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure. Hepatology. 1999 Sep;30(3):636-40. — View Citation

Staedt U, Leweling H, Gladisch R, Kortsik C, Hagmüller E, Holm E. Effects of ornithine aspartate on plasma ammonia and plasma amino acids in patients with cirrhosis. A double-blind, randomized study using a four-fold crossover design. J Hepatol. 1993 Nov;19(3):424-30. — View Citation

Outcome

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

External Links

•   An easy to navigate site providing overview of liver failure, and treatment options
•   Comprehensive details of liver failure in the pediatric population