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

Phase 4

Completed

• Conditions: Minimal Hepatic Encephalopathy; Cirrhosis; Hepatic Encephalopathy
• Interventions: Procedure: Vastus Muscle Biopsy; Drug: LOLA or placebo; Other: Cognitive assessment (PHES); Other: Cognitive Assessement (Cogstate); Other: blood and urine sampling; Other: Nutritional assessment; Other: MRI brain and spectroscopy; Other: MRI leg cross section; Other: Functional MRI (working memory and attention tasks)

• Registration Number: NCT01847651
• Lead Sponsor: Imperial College London

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

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Status Verified: 2013-05
• Study First Submitted: 2013-05-02
• Study First Submitted QC: 2013-05-06
• Study First Posted: 2013-05-07
• Study Start: 2013-08
• Primary Completion: 2015-06
• Study Completion: 2015-06
• Last Update Submitted: 2015-10-21
• Last Update Posted: 2015-10-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 42

Inclusion Criteria

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	MRI brain and spectroscopy	-
Placebo	Functional MRI (working memory and attention tasks)	-
Placebo	Cognitive assessment (PHES)	-
LOLA	Cognitive assessment (PHES)	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)
LOLA	blood and urine sampling	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)
LOLA	MRI brain and spectroscopy	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)
LOLA	MRI leg cross section	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)
LOLA	Functional MRI (working memory and attention tasks)	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)
Placebo	Vastus Muscle Biopsy	-
Placebo	Cognitive Assessement (Cogstate)	-
LOLA	LOLA or placebo	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)
LOLA	Cognitive Assessement (Cogstate)	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)
Placebo	Nutritional assessment	-
Placebo	MRI leg cross section	-
LOLA	Nutritional assessment	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)
Placebo	LOLA or placebo	-
LOLA	Vastus Muscle Biopsy	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)
Placebo	blood and urine sampling	-

Primary Outcome Measures

Name	Time	Method
Improvement in mental state on paper and pencil Hepatic Encephalopathy score (PHES) testing and Cogstate testing (computer based cognitive assessment research tool)	At 0, 4 and 12 weeks

Secondary Outcome Measures

Name	Time	Method
Brain Volume	At 0 , 4 and 12 weeks	The effect of brain volume reduction due to reduction of brain swelling will be measured by serial brain MRI (at 0, 4 and 12 weeks)
Brain chemical structure	0, 4, 12 weeks	Improvement in brain chemical structure (by measuring cerebral osmolytes) will be assessed by in-vivo MR spectroscopy
Improvement in brain function measured by functional MRI	0, 4, 12 weeks	Key brain functions such as attention and working memory (the default mode network) will be assessed through fMRI
Improvement in Muscle Function and increase in muscle size	0, 4 and 12 weeks	Increase in muscle size(fat free mass) will be measured on by MR imaging of the thigh, in-vitro NMR spectroscopy, mass spectroscopy and histological analysis of muscle biopsy samples.
Improvement of plasma and urine metabolome	0, 4 and 12 weeks	Improvement in blood and urine profiles will be measured with in vitro NMR spectroscopy to assess for biomarkers of treatment response and to determine the amino acids altered by treatment of HE.

Trial Locations

Locations (1)

Liver unit St Mary's Hospital, 10th floor QEQM Wing, South Wharf Road; 🇬🇧 London, United Kingdom