L-ornithine L-aspartate in Overt Hepatic Encephalopathy

NCT01722578 | Completed Phase 4 DMC

• 1 other identifier: HEAL-123
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 2

Brief Summary

Hepatic encephalopathy (HE) is a potentially reversible functional disorder of the brain with neurological and psychiatric symptoms. HE occurs in up to 70% of patients with cirrhosis at some time during the course of disease. The chief neurotoxin implicated in the development of HE is ammonia. An important aim of treatment of HE is the reduction of the ammonia in the body by lowering the amount of ammonia produced and increasing its detoxification. Enteric production of ammonia can be decreased by non-absorbable disaccharides such as lactulose and antibiotics such as rifaximin. L-ornithine- L-aspartate (LOLA), the salt of the natural amino acids ornithine and aspartate acts through the mechanism of substrate activation to detoxify ammonia. In clinical trials, LOLA has shown a statistically significant effect with respect to reduction in HE grade, reduction of blood ammonia concentration and positive effects on psychomotor function in patients of cirrhosis with minimal HE and overt chronic Grade I HE, as compared to placebo. However, there is lack of data on the efficacy of LOLA in patients with overt acute hepatic encephalopathy which is one of the major causes of hospital admissions and resource utilization in decompensated cirrhotics. Each admission for HE causes a major financial loss to the family and financial burden on the society. Any drug which decreases the hospital stay by rapidly improving HE, will clearly lead to decreased hospital costs to the individual and the society as a whole. Hence, such a trial is a national priority. The investigators hypothesize that LOLA, if added to the standard treatment of overt acute HE (i.e lactulose), may lead to a faster recovery and decrease in hospital stay of these patients. In this prospective, randomized, placebo controlled trial, the investigators aim to evaluate the efficacy of intravenous L-ornithine, L-aspartate in reversal of overt acute hepatic encephalopathy in patients with liver cirrhosis.

Conditions

Cirrhosis of Liver; Hepatic Encephalopathy

Keywords

Cirrhosis; Encephalopathy; L-ornithine L-aspartate

Outcome Measures

Primary Outcomes (1)

• Mental state grade

  Mental state grade according to West Haven criteria for Hepatic encephalopathy

  5 days

Secondary Outcomes (4)

• Blood Ammonia levels

  5 days

• Mortality

  4 weeks

• Length of Hospital stay

  4 weeks

• Serum Cytokine levels

  5 days

Study Arms (2)

L-ornithine L-aspartate

EXPERIMENTAL

L-ornithine L-aspartate (6 ampules, each ampule containing 5 grams of the drug in 10 ml solution) to be diluted in 440 ml of Dextrose 5% (to make a total of 500 ml of solution), as intravenous infusion at the rate of 21 ml/hour, over 24 hours, for 5 days

Drug: L-ornithine L-aspartate

Placebo (sterile water)

PLACEBO COMPARATOR

Placebo (sterile water, 6 ampuoles of 10 ml each) diluted in 440 ml of Dextrose 5%, as intravenous infusion at the rate of 21 ml/hour, over 24 hours, for 5 days

Drug: Placebo

Interventions

L-ornithine L-aspartate DRUG

L-ornithine L-aspartate (6 ampules, each ampule containing 5 grams of the drug in 10 ml solution) to be diluted in 440 ml of Dextrose 5% (to make a total of 500 ml of solution), as intravenous infusion at the rate of 21 ml/hour, over 24 hours, for 5 days

Also known as: Hepamerz

L-ornithine L-aspartate

Placebo DRUG

Placebo (sterile water, 60 ml) diluted in 440 ml of Dextrose 5%, as intravenous infusion at the rate of 21 ml/hour, over 24 hours, for 5 days

Placebo (sterile water)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Hepatic cirrhosis based on clinical, biochemical, radiological and/or histological data
• Patients with overt acute grade 2, 3 and 4 HE, according to the West Haven criteria, with or without precipitating factors.
• Age of patient 18-70 years

You may not qualify if:

• Patients who are terminally ill
• Acute on chronic liver failure
• Hepatocellular carcinoma
• Wilson's disease as the etiological factor of liver disease
• Advanced cardiac or pulmonary disease
• Presence of underlying chronic renal failure
• Neuro-degenerative disease or major psychiatric illness
• Patients on sedatives or antidepressants
• Pregnancy or breastfeeding

Sponsors & Collaborators

• Dayanand Medical College and Hospital: lead

Study Sites (2)

G.B. Pant Hospital

New Delhi, New Delhi, 110002, India

Location

Department of Gastroenterology, D.M.C. and Hospital

Ludhiana, Punjab, 141001, India

Location

Related Publications (28)

• Mas A. Hepatic encephalopathy: from pathophysiology to treatment. Digestion. 2006;73 Suppl 1:86-93. doi: 10.1159/000089783. Epub 2006 Feb 8.

  PMID: 16498256 BACKGROUND

• Lizardi-Cervera J, Almeda P, Guevara L, Uribe M. Hepatic encephalopathy: a review. Ann Hepatol. 2003 Jul-Sep;2(3):122-30.

  PMID: 15115963 BACKGROUND

• Groeneweg M, Moerland W, Quero JC, Hop WC, Krabbe PF, Schalm SW. Screening of subclinical hepatic encephalopathy. J Hepatol. 2000 May;32(5):748-53. doi: 10.1016/s0168-8278(00)80243-3.

  PMID: 10845661 BACKGROUND

• Shawcross DL, Olde Damink SW, Butterworth RF, Jalan R. Ammonia and hepatic encephalopathy: the more things change, the more they remain the same. Metab Brain Dis. 2005 Sep;20(3):169-79. doi: 10.1007/s11011-005-7205-0.

  PMID: 16167195 BACKGROUND

• Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002 Mar;35(3):716-21. doi: 10.1053/jhep.2002.31250.

  PMID: 11870389 BACKGROUND

• Atluri DK, Prakash R, Mullen KD. Pathogenesis, diagnosis, and treatment of hepatic encephalopathy. J Clin Exp Hepatol. 2011 Sep;1(2):77-86. doi: 10.1016/S0973-6883(11)60126-6. Epub 2011 Nov 9.

  PMID: 25755319 BACKGROUND

• Bajaj JS, Cordoba J, Mullen KD, Amodio P, Shawcross DL, Butterworth RF, Morgan MY; International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN). Review article: the design of clinical trials in hepatic encephalopathy--an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement. Aliment Pharmacol Ther. 2011 Apr;33(7):739-47. doi: 10.1111/j.1365-2036.2011.04590.x. Epub 2011 Feb 9.

  PMID: 21306407 BACKGROUND

• Shawcross D, Jalan R. Dispelling myths in the treatment of hepatic encephalopathy. Lancet. 2005 Jan 29-Feb 4;365(9457):431-3. doi: 10.1016/S0140-6736(05)17832-5.

  PMID: 15680459 BACKGROUND

• Ferenci P, Herneth A, Steindl P. Newer approaches to therapy of hepatic encephalopathy. Semin Liver Dis. 1996 Aug;16(3):329-38. doi: 10.1055/s-2007-1007245. No abstract available.

  PMID: 8989818 BACKGROUND

• Uribe M, Moran S, Poo JL, Mendez-Sanchez N, Guevara L, Garcia-Ramos G. Beneficial effect of carbohydrate maldigestion induced by a disaccharidase inhibitor (AO-128) in the treatment of chronic portal-systemic encephalopathy. A double-blind, randomized, controlled trial. Scand J Gastroenterol. 1998 Oct;33(10):1099-106. doi: 10.1080/003655298750026822.

  PMID: 9829367 BACKGROUND

• Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ. 2004 May 1;328(7447):1046. doi: 10.1136/bmj.38048.506134.EE. Epub 2004 Mar 30.

  PMID: 15054035 BACKGROUND

• Bongaerts G, Severijnen R, Timmerman H. Effect of antibiotics, prebiotics and probiotics in treatment for hepatic encephalopathy. Med Hypotheses. 2005;64(1):64-8. doi: 10.1016/j.mehy.2004.07.029.

  PMID: 15533613 BACKGROUND

• Paik YH, Lee KS, Han KH, Song KH, Kim MH, Moon BS, Ahn SH, Lee SJ, Park HJ, Lee DK, Chon CY, Lee SI, Moon YM. Comparison of rifaximin and lactulose for the treatment of hepatic encephalopathy: a prospective randomized study. Yonsei Med J. 2005 Jun 30;46(3):399-407. doi: 10.3349/ymj.2005.46.3.399.

  PMID: 15988813 BACKGROUND

• Mas A, Rodes J, Sunyer L, Rodrigo L, Planas R, Vargas V, Castells L, Rodriguez-Martinez D, Fernandez-Rodriguez C, Coll I, Pardo A; Spanish Association for the Study of the Liver Hepatic Encephalopathy Cooperative Group. Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol. 2003 Jan;38(1):51-8. doi: 10.1016/s0168-8278(02)00350-1.

  PMID: 12480560 BACKGROUND

• Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med. 1997 Aug 14;337(7):473-9. doi: 10.1056/NEJM199708143370707. No abstract available.

  PMID: 9250851 BACKGROUND

• Rose C, Michalak A, Pannunzio P, Therrien G, Quack G, Kircheis G, Butterworth RF. L-ornithine-L-aspartate in experimental portal-systemic encephalopathy: therapeutic efficacy and mechanism of action. Metab Brain Dis. 1998 Jun;13(2):147-57. doi: 10.1023/a:1020613314572.

  PMID: 9699922 BACKGROUND

• Staedt U, Leweling H, Gladisch R, Kortsik C, Hagmuller 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. doi: 10.1016/s0168-8278(05)80553-7.

  PMID: 8151104 BACKGROUND

• Kircheis G, Nilius R, Held C, Berndt H, Buchner M, Gortelmeyer R, Hendricks R, Kruger B, Kuklinski B, Meister H, Otto HJ, Rink C, Rosch 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. doi: 10.1002/hep.510250609.

  PMID: 9185752 BACKGROUND

• Stauch S, Kircheis G, Adler G, Beckh K, Ditschuneit H, Gortelmeyer R, Hendricks R, Heuser A, Karoff C, Malfertheiner P, Mayer D, Rosch W, Steffens J. Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study. J Hepatol. 1998 May;28(5):856-64. doi: 10.1016/s0168-8278(98)80237-7.

  PMID: 9625322 BACKGROUND

• Rees CJ, Oppong K, Al Mardini H, Hudson M, Record CO. Effect of L-ornithine-L-aspartate on patients with and without TIPS undergoing glutamine challenge: a double blind, placebo controlled trial. Gut. 2000 Oct;47(4):571-4. doi: 10.1136/gut.47.4.571.

  PMID: 10986219 BACKGROUND

• Chen MF, Li RC, Chen CH, Gao XC. [Therapeutic effect of L-ornithine-L-aspartate on liver cirrhosis complicated by hepatic encephalopathy]. Di Yi Jun Yi Da Xue Xue Bao. 2005 Jun;25(6):718-9, 722. Chinese.

  PMID: 15958319 BACKGROUND

• Poo JL, Gongora J, Sanchez-Avila F, Aguilar-Castillo S, Garcia-Ramos G, Fernandez-Zertuche M, Rodriguez-Fragoso L, Uribe M. Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study. Ann Hepatol. 2006 Oct-Dec;5(4):281-8.

  PMID: 17151582 BACKGROUND

• Abdo-Francis JM, Perez-Hernandez JL, Hinojosa-Ruiz A, Hernandez-Vasquez JR. [Reduction of hospital stay with the use of L-ornithine L-aspartate (LOLA) in patients with hepatic encephalopathy]. Rev Gastroenterol Mex. 2010;75(2):135-41. Spanish.

  PMID: 20615780 BACKGROUND

• Ahmad I, Khan AA, Alam A, Dilshad A, Butt AK, Shafqat F, Malik K, Sarwar S. L-ornithine-L-aspartate infusion efficacy in hepatic encephalopathy. J Coll Physicians Surg Pak. 2008 Nov;18(11):684-7.

  PMID: 18983791 BACKGROUND

• Kircheis G, Wettstein M, Dahl Sv, Haussinger D. Clinical efficacy of L-ornithine-L-aspartate in the management of hepatic encephalopathy. Metab Brain Dis. 2002 Dec;17(4):453-62. doi: 10.1023/a:1021934607762.

  PMID: 12602521 BACKGROUND

• Jiang Q, Jiang XH, Zheng MH, Chen YP. L-Ornithine-l-aspartate in the management of hepatic encephalopathy: a meta-analysis. J Gastroenterol Hepatol. 2009 Jan;24(1):9-14. doi: 10.1111/j.1440-1746.2008.05582.x. Epub 2008 Sep 24.

  PMID: 18823442 BACKGROUND

• Acharya SK, Bhatia V, Sreenivas V, Khanal S, Panda SK. Efficacy of L-ornithine L-aspartate in acute liver failure: a double-blind, randomized, placebo-controlled study. Gastroenterology. 2009 Jun;136(7):2159-68. doi: 10.1053/j.gastro.2009.02.050.

  PMID: 19505424 BACKGROUND

• Goggs R, Serrano S, Szladovits B, Keir I, Ong R, Hughes D. Clinical investigation of a point-of-care blood ammonia analyzer. Vet Clin Pathol. 2008 Jun;37(2):198-206. doi: 10.1111/j.1939-165X.2008.00024.x.

  PMID: 18533920 BACKGROUND

MeSH Terms

Conditions

Fibrosis; Hepatic Encephalopathy; Brain Diseases

Interventions

ornithylaspartate

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases; Brain Diseases, Metabolic; Central Nervous System Diseases; Nervous System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Sandeep S Sidhu, MD,DM

  Professor, Dept of Gastroenterology, DMC and Hospital, Ludhiana, India

  PRINCIPAL INVESTIGATOR

• Omesh Goyal, MD, DM

  Assistant Professor, Dept of Gastroenterology, DMC and Hospital, Ludhiana, India

  PRINCIPAL INVESTIGATOR

• B C Sharma, D.M.

  Professor, Dept of Gastroenterology, G.B. Pant Hospital, New Delhi

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: October 30, 2012
• First Posted: November 7, 2012
• Study Start: December 1, 2013
• Primary Completion: January 1, 2017
• Study Completion: January 1, 2017
• Last Updated: February 8, 2017

Record last verified: 2017-02

Locations

IN (2)