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

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ClinicalTrials.gov Identifier: NCT01847651
Recruitment Status : Completed
First Posted : May 7, 2013
Last Update Posted : October 22, 2015
Sponsor:
Information provided by (Responsible Party):

Study Description
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.

Condition or disease Intervention/treatment 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

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

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, 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
Study Start Date : August 2013
Primary Completion Date : June 2015
Study Completion Date : June 2015


Arms and Interventions

Arm Intervention/treatment
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


Outcome Measures

Primary Outcome Measures :
  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 Outcome Measures :
  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.


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01847651


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

Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT01847651     History of Changes
Other Study ID Numbers: LOLA-Merz WMDH P39937
2012-003817-32 ( EudraCT Number )
12/LO/1937 ( Other Identifier: Research Ethics Committee (REC) )
CRO2033 ( Other Identifier: Imperial College London Reference )
First Posted: May 7, 2013    Key Record Dates
Last Update Posted: October 22, 2015
Last Verified: May 2013

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
Fibrosis
Brain Diseases
Pathologic Processes
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
Physiological Effects of Drugs