Brain Muscle Axis During Treatment of Hepatic Encephalopathy With L-ornithine L-aspartate
Condition: Hepatic Encephalopathy; Minimal Hepatic Encephalopathy; Cirrhosis
MeSH terms: Hepatic Encephalopathy; Brain Diseases; Fibrosis
Study type: Interventional
Phase: Phase 4

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.
    

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
    

Intervention name(s): Vastus Muscle Biopsy; LOLA or placebo; Cognitive assessment (PHES); Cognitive Assessement (Cogstate); blood and urine sampling; Nutritional assessment; MRI brain and spectroscopy; MRI leg cross section; Functional MRI (working memory and attention tasks)
Intervention type(s): Procedure; Drug; Other; Other; Other; Other; Other; Other; Other
Intervention description(s): Both Arms, all 3 visits at 0, 4 and 12 weeks; 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; Both Arms, all 3 visits at 0, 4 and 12 weeks; Both Arms, all 3 visits at 0, 4 and 12 weeks; Both Arms, all 3 visits at 0, 4 and 12 weeks; Both Arms, all 3 visits at 0, 4 and 12 weeks; Both Arms, all 3 visits at 0, 4 and 12 weeks; Both Arms, all 3 visits at 0, 4 and 12 weeks; Both Arms, all 3 visits at 0, 4 and 12 weeks
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
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