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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified May 2013 by Imperial College London
Sponsor:
Information provided by (Responsible Party):
Imperial College London
ClinicalTrials.gov Identifier:
NCT01847651
First received: May 2, 2013
Last updated: May 6, 2013
Last verified: May 2013
  Purpose

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.


Condition Intervention Phase
Hepatic Encephalopathy
Minimal Hepatic Encephalopathy
Cirrhosis
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)
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official 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

Resource links provided by NLM:


Further study details as provided by Imperial College London:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Brain Volume [ Time Frame: At 0 , 4 and 12 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0, 4, 12 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0, 4, 12 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0, 4 and 12 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: 0, 4 and 12 weeks ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 34
Study Start Date: May 2013
Estimated Study Completion Date: October 2015
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
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

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
  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01847651

Contacts
Contact: Simon D Taylor-Robinson, MD FRCP (44)02078866454 s.taylor-robinson@imperial.ac.uk

Locations
United Kingdom
Liver unit St Mary's Hospital, 10th floor QEQM Wing, South Wharf Road Enrolling by invitation
London, United Kingdom, W2 1NY
Sponsors and Collaborators
Imperial College London
Investigators
Principal Investigator: Simon D Taylor-Robinson, MD FRCP Imperial College London
  More Information

No publications provided

Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT01847651     History of Changes
Other Study ID Numbers: LOLA-Merz WMDH P39937, 2012-003817-32, 12/LO/1937, CRO2033
Study First Received: May 2, 2013
Last Updated: May 6, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Imperial College London:
hepatic encephalopathy
minimal hepatic encephalopathy
Paper and pencil Hepatic Encephalopathy score (PHES)
cirrhosis
lateral vastus
muscle biopsy
L ornithine L aspartate
functional magnetic resonance imaging
magnetic resonance spectroscopy
cognitive testing
Cogstate
urine metabonomics
plasma metabonomics
muscle metabonomics

Additional relevant MeSH terms:
Hepatic Encephalopathy
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Liver Failure
Hepatic Insufficiency
Liver Diseases
Digestive System Diseases
Brain Diseases, Metabolic
Metabolic Diseases
N-Methylaspartate
Excitatory Amino Acid Agonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 01, 2014