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

NCT01847651 | Completed Phase 4 DMC

• 4 other identifiers: LOLA-Merz WMDH P399372012-003817-3212/LO/1937CRO2033
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

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.

Conditions

Hepatic Encephalopathy; Minimal Hepatic Encephalopathy; Cirrhosis

Keywords

hepatic encephalopathy; minimal hepatic encephalopathy; cirrhosis; lateral vastus; muscle biopsy; L ornithine L aspartate; functional magnetic resonance imaging; magnetic resonance spectroscopy; cognitive testing; Paper and pencil Hepatic Encephalopathy score (PHES); Cogstate; urine metabonomics; plasma metabonomics; muscle metabonomics

Outcome Measures

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)

  At 0, 4 and 12 weeks

Secondary Outcomes (5)

• Brain Volume

  At 0 , 4 and 12 weeks

• Brain chemical structure

  0, 4, 12 weeks

• Improvement in brain function measured by functional MRI

  0, 4, 12 weeks

• Improvement in Muscle Function and increase in muscle size

  0, 4 and 12 weeks

• Improvement of plasma and urine metabolome

  0, 4 and 12 weeks

Study Arms (2)

LOLA

ACTIVE COMPARATOR

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; 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)

Placebo

PLACEBO COMPARATOR

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)

Interventions

Vastus Muscle Biopsy PROCEDURE

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

LOLA; Placebo

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

LOLA; Placebo

Cognitive assessment (PHES) OTHER

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

LOLA; Placebo

Cognitive Assessement (Cogstate) OTHER

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

LOLA; Placebo

blood and urine sampling OTHER

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

LOLA; Placebo

Nutritional assessment OTHER

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

LOLA; Placebo

MRI brain and spectroscopy OTHER

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

LOLA; Placebo

MRI leg cross section OTHER

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

LOLA; Placebo

Functional MRI (working memory and attention tasks) OTHER

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

LOLA; Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Imperial College London: lead

Study Sites (1)

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

London, London, W2 1NY, United Kingdom

Location

MeSH Terms

Conditions

Hepatic Encephalopathy; Fibrosis

Interventions

Blood Specimen Collection; Nutrition Assessment; Spectrum Analysis

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques; Data Collection; Epidemiologic Methods; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Epidemiologic Measurements; Public Health; Environment and Public Health; Chemistry Techniques, Analytical

Study Officials

• Simon D Taylor-Robinson, MD FRCP

  Imperial College London

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 2, 2013
• First Posted: May 7, 2013
• Study Start: August 1, 2013
• Primary Completion: June 1, 2015
• Study Completion: June 1, 2015
• Last Updated: October 22, 2015

Record last verified: 2013-05

Locations

GB (1)