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NCT Number: NCT01847651

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

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.

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Key information

Conditions

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

Age range

18 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

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

London, W2 1NY, United Kingdom

About this study

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

  • 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

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Vastus Muscle Biopsy

Procedure

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

LOLA or placebo

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)

Other

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

Cognitive Assessement (Cogstate)

Other

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

Blood and urine sampling

Other

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

Nutritional Assessment

Other

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

MRI brain and spectroscopy

Other

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

MRI leg cross section

Other

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

Functional MRI (working memory and attention tasks)

Other

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

Primary outcomes

  1. Improvement in mental state on paper and pencil Hepatic Encephalopathy score (PHES) testing and Cogstate testing (computer based cognitive assessment research tool)

    Time frame: At 0, 4 and 12 weeks

Secondary outcomes

  1. Brain Volume

    Time frame: 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)

  2. Brain chemical structure

    Time frame: 0, 4, 12 weeks

    Improvement in brain chemical structure (by measuring cerebral osmolytes) will be assessed by in-vivo MR spectroscopy

  3. Improvement in brain function measured by functional MRI

    Time frame: 0, 4, 12 weeks

    Key brain functions such as attention and working memory (the default mode network) will be assessed through fMRI

  4. Improvement in Muscle Function and increase in muscle size

    Time frame: 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.

  5. Improvement of plasma and urine metabolome

    Time frame: 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.

Sponsors and collaborators

Lead sponsor

Imperial College London

Other

Registry information

Official study title

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

Important dates

Study start
2013
Primary completion
2015
Study completion
2015
First posted
May 7, 2013
Registry last updated
Oct 22, 2015

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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