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

Cirrhosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01847651
• Other study ID #: LOLA-Merz WMDH P39937
• Secondary ID: 2012-003817-3212
• Status: Completed
• Phase: Phase 4
• First received: May 2, 2013
• Last updated: October 21, 2015
• Start date: August 2013
• Est. completion date: June 2015

Study information

• Verified date: May 2013
• Source: Imperial College London
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 42
• Est. completion date: June 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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 Design

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

Related Conditions & MeSH terms

• Brain Diseases
• Cirrhosis
• Hepatic Encephalopathy
• Minimal Hepatic Encephalopathy

Intervention

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
• Cognitive Assessement (Cogstate)
Both Arms, all 3 visits at 0, 4 and 12 weeks
• blood and urine sampling
Both Arms, all 3 visits at 0, 4 and 12 weeks
• Nutritional assessment
Both Arms, all 3 visits at 0, 4 and 12 weeks
• MRI brain and spectroscopy
Both Arms, all 3 visits at 0, 4 and 12 weeks
• MRI leg cross section
Both Arms, all 3 visits at 0, 4 and 12 weeks
• Functional MRI (working memory and attention tasks)
Both Arms, all 3 visits at 0, 4 and 12 weeks

Locations

Country	Name	City	State
United Kingdom	Liver unit St Mary's Hospital, 10th floor QEQM Wing, South Wharf Road	London

Sponsors (1)

Lead Sponsor	Collaborator
Imperial College London

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Brain Volume	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)	At 0 , 4 and 12 weeks	No
Secondary	Brain chemical structure	Improvement in brain chemical structure (by measuring cerebral osmolytes) will be assessed by in-vivo MR spectroscopy	0, 4, 12 weeks	No
Secondary	Improvement in brain function measured by functional MRI	Key brain functions such as attention and working memory (the default mode network) will be assessed through fMRI	0, 4, 12 weeks	No
Secondary	Improvement in Muscle Function and increase in muscle size	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.	0, 4 and 12 weeks	No
Secondary	Improvement of plasma and urine metabolome	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.	0, 4 and 12 weeks	No