Brain Muscle Axis During Treatment of Hepatic Encephalopathy With L-ornithine L-aspartate

NCT ID: NCT01847651

Last Updated: 2015-10-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-08-31
• Study Completion Date: 2015-06-30

Brief Summary

Patients with cirrhosis of the liver may suffer from a condition called hepatic encephalopathy which in its mildest form as mental slowing and impaired reaction times in driving and machinery operation. Left untreated it may lead to deep coma. The cause is not fully understood but is though to be related to the inability of a damaged liver to filter out toxins such as ammonia in the blood, which then accumulate within the brain and result in altered function and swelling within certain brain cells,astrocytes. These patients also suffer from muscle loss, which is associated with a poor outcome. L-ornithine L-aspartate(LOLA) is a licensed drug in Germany and has been shown to promote ammonia elimination from the body in the form of urea. Some experimental studies have suggested that LOLA also potentially attenuates muscle loss by incorporating ammonia into muscle in the form of glutamine. The aim of this study is to determine cognitive and nutritional effects of 12 weeks of LOLA administration and its effect on brain muscle structure and function in patients with cirrhosis.

Detailed Description

This is a Phase IV randomised double blind, placebo controlled study. Thirty four patients with cirrhosis will be studied with psychometric tests, clinical brain magnetic resonance imaging(MRI),including functional MRI) and magnetic resonance spectroscopy (MRS) and muscle MRI of leg muscle before (time 0)during (4weeks)and after LOLA or placebo treatment at 12 weeks. Samples will also be taken for ex vivo MRS of blood and urine to identify potential biomarkers. Histological analysis and MRS would also be performed on the muscle tissue at the same time points.

Hypotheses Primary objective

1) Improvement in mental state by paper and pencil based Psychometric Hepatic Encephalopathy Score (PHES) and Cogstate Research test (computer based cognitive research assessment tool)

Secondary objectives

1. Brain volume reduction due to reduction in brain swelling measured by MRI and improvement in the chemical structure of the brain due to (cerebral osmolytes)measured by in vivo MR Spectroscopy (MRS)scanning of the brain.

2. Improvement in brain function

3. Improvement in muscle function (muscle metabolome normalisation) and increased muscle size (fat free mass), measured in vivo by MRI scanning and by in vitro mass spectroscopy and NMR spectroscopy and histological analysis of muscle samples.

4. Improvement in the chemical profile of key chemicals in the blood and urine, measured with in vitro NMR spectroscopy

Conditions

Hepatic Encephalopathy; Minimal Hepatic Encephalopathy; Cirrhosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

LOLA

Other Names:

Hepa-Merz Granulat 3000 Hepa-Merz granules 3g (Each 5g sachet contains 3g of L-ornithine L-aspartate) L-ornithine L-aspartate LOLA

Randomised to a daily dose 18g per day, two sachets of Hepa-Merz granules three times a day (or placebo)

Group Type: ACTIVE_COMPARATOR

Vastus Muscle Biopsy

Intervention Type: PROCEDURE

Both Arms, all 3 visits at 0, 4 and 12 weeks

LOLA or placebo

Intervention Type: DRUG

Hepa-Merz Granulat 3000 Hepa-Merz granules 3g (Each 5g sachet contains 3g of L-ornithine L-aspartate) L-ornithine L-aspartate LOLA Randomised to a daily dose 18g per day, two sachets of Hepa-Merz granules three times a day (or placebo)for 12 weeks

Cognitive assessment (PHES)

Intervention Type: OTHER

Both Arms, all 3 visits at 0, 4 and 12 weeks

Cognitive Assessement (Cogstate)

Intervention Type: OTHER

Both Arms, all 3 visits at 0, 4 and 12 weeks

blood and urine sampling

Intervention Type: OTHER

Both Arms, all 3 visits at 0, 4 and 12 weeks

Nutritional assessment

Intervention Type: OTHER

Both Arms, all 3 visits at 0, 4 and 12 weeks

MRI brain and spectroscopy

Intervention Type: OTHER

Both Arms, all 3 visits at 0, 4 and 12 weeks

MRI leg cross section

Intervention Type: OTHER

Both Arms, all 3 visits at 0, 4 and 12 weeks

Functional MRI (working memory and attention tasks)

Intervention Type: OTHER

Both Arms, all 3 visits at 0, 4 and 12 weeks

Placebo

Group Type: PLACEBO_COMPARATOR

Vastus Muscle Biopsy

Intervention Type: PROCEDURE

Both Arms, all 3 visits at 0, 4 and 12 weeks

LOLA or placebo

Intervention Type: DRUG

Hepa-Merz Granulat 3000 Hepa-Merz granules 3g (Each 5g sachet contains 3g of L-ornithine L-aspartate) L-ornithine L-aspartate LOLA Randomised to a daily dose 18g per day, two sachets of Hepa-Merz granules three times a day (or placebo)for 12 weeks

Cognitive assessment (PHES)

Intervention Type: OTHER

Both Arms, all 3 visits at 0, 4 and 12 weeks

Cognitive Assessement (Cogstate)

Intervention Type: OTHER

Both Arms, all 3 visits at 0, 4 and 12 weeks

blood and urine sampling

Intervention Type: OTHER

Both Arms, all 3 visits at 0, 4 and 12 weeks

Nutritional assessment

Intervention Type: OTHER

Both Arms, all 3 visits at 0, 4 and 12 weeks

MRI brain and spectroscopy

Intervention Type: OTHER

Both Arms, all 3 visits at 0, 4 and 12 weeks

MRI leg cross section

Intervention Type: OTHER

Both Arms, all 3 visits at 0, 4 and 12 weeks

Functional MRI (working memory and attention tasks)

Intervention Type: OTHER

Both Arms, all 3 visits at 0, 4 and 12 weeks

Interventions

Vastus Muscle Biopsy

Both Arms, all 3 visits at 0, 4 and 12 weeks

Intervention Type: PROCEDURE

LOLA or placebo

Hepa-Merz Granulat 3000 Hepa-Merz granules 3g (Each 5g sachet contains 3g of L-ornithine L-aspartate) L-ornithine L-aspartate LOLA Randomised to a daily dose 18g per day, two sachets of Hepa-Merz granules three times a day (or placebo)for 12 weeks

Intervention Type: DRUG

Cognitive assessment (PHES)

Both Arms, all 3 visits at 0, 4 and 12 weeks

Intervention Type: OTHER

Cognitive Assessement (Cogstate)

Both Arms, all 3 visits at 0, 4 and 12 weeks

Intervention Type: OTHER

blood and urine sampling

Both Arms, all 3 visits at 0, 4 and 12 weeks

Intervention Type: OTHER

Nutritional assessment

Both Arms, all 3 visits at 0, 4 and 12 weeks

Intervention Type: OTHER

MRI brain and spectroscopy

Both Arms, all 3 visits at 0, 4 and 12 weeks

Intervention Type: OTHER

MRI leg cross section

Both Arms, all 3 visits at 0, 4 and 12 weeks

Intervention Type: OTHER

Functional MRI (working memory and attention tasks)

Both Arms, all 3 visits at 0, 4 and 12 weeks

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Ambulant patients of any Child-Pugh stage cirrhosi and PHEs defined MHe or grade 1 encephalopathy

Exclusion Criteria

• Previous episodes of overt HE without a clear precipitant
• Recurrent excessive alcohol consumption (abstinence for those with alcoholic liver disease otherwise less than 28 units per week)
• Severe coagulopathy (INR>2, platelets <60 000/uL, Fibrinogen <1mg/dl)
• known myopathy or myositis, taruma to lower extremities within 3 months)
• Renal dysfunction with a serum creatinine>3mg/dl (265micromol/L)
• Ferromagnetic implants
• Recent intestinal haemorrhage within 1 month
• Claustrophobia
• Weight >120kg
• Major psychoactive medication such as antipsychotic agents
• Known cerebrovascular disease or pre-existing neurological conditions
• Age less than 18 or greater than 65.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Imperial College London

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Simon D Taylor-Robinson, MD FRCP

Role: PRINCIPAL_INVESTIGATOR

Imperial College London

Locations

Liver unit St Mary's Hospital, 10th floor QEQM Wing, South Wharf Road

London, London, United Kingdom

Countries

United Kingdom

Other Identifiers

2012-003817-32

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

12/LO/1937

Identifier Type: OTHER

Identifier Source: secondary_id

CRO2033

Identifier Type: OTHER

Identifier Source: secondary_id

LOLA-Merz WMDH P39937

Identifier Type: -

Identifier Source: org_study_id