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

October 21, 2015 updated by: Imperial College London

LOLA in Hepatic Encephalopathy Brain Muscle Axis During Treatment of Hepatic Encephalopathy With L-ornithine L-aspartate A Phase iv Randomised Double Blind Placebo- Controlled Trial

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

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

Study Type

Interventional

Enrollment (Actual)

Phase

Phase 4

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

United Kingdom
- - London, United Kingdom, W2 1NY
    - Liver unit St Mary's Hospital, 10th floor QEQM Wing, South Wharf Road

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

16 years to 63 years (Adult, Older Adult)

Accepts Healthy Volunteers

Genders Eligible for Study

All

Description

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.

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: Quadruple

Number of Arms

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Procedure: Vastus Muscle Biopsy Both Arms, all 3 visits at 0, 4 and 12 weeks Drug: 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 Other: Cognitive assessment (PHES) Both Arms, all 3 visits at 0, 4 and 12 weeks Other: Cognitive Assessement (Cogstate) Both Arms, all 3 visits at 0, 4 and 12 weeks Other: blood and urine sampling Both Arms, all 3 visits at 0, 4 and 12 weeks Other: Nutritional assessment Both Arms, all 3 visits at 0, 4 and 12 weeks Other: MRI brain and spectroscopy Both Arms, all 3 visits at 0, 4 and 12 weeks Other: MRI leg cross section Both Arms, all 3 visits at 0, 4 and 12 weeks Other: Functional MRI (working memory and attention tasks) Both Arms, all 3 visits at 0, 4 and 12 weeks
Active Comparator: 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)	Procedure: Vastus Muscle Biopsy Both Arms, all 3 visits at 0, 4 and 12 weeks Drug: 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 Other: Cognitive assessment (PHES) Both Arms, all 3 visits at 0, 4 and 12 weeks Other: Cognitive Assessement (Cogstate) Both Arms, all 3 visits at 0, 4 and 12 weeks Other: blood and urine sampling Both Arms, all 3 visits at 0, 4 and 12 weeks Other: Nutritional assessment Both Arms, all 3 visits at 0, 4 and 12 weeks Other: MRI brain and spectroscopy Both Arms, all 3 visits at 0, 4 and 12 weeks Other: MRI leg cross section Both Arms, all 3 visits at 0, 4 and 12 weeks Other: Functional MRI (working memory and attention tasks) Both Arms, all 3 visits at 0, 4 and 12 weeks