Hepatic EncephalopathyPhase 4NCT01847651
Brain Muscle Axis During Treatment of Hepatic Encephalopathy With L-ornithine L-aspartate
A Phase 4 study testing Vastus Muscle Biopsy, Cognitive assessment (PHES) and Cognitive Assessement (Cogstate) in people with Hepatic Encephalopathy and Minimal Hepatic Encephalopathy, run by Imperial College London at 1 site in United Kingdom.
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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Hepatic Encephalopathy, Minimal Hepatic Encephalopathy, Cirrhosis
- What is being tested?
- Vastus Muscle Biopsy, Cognitive assessment (PHES) and Cognitive Assessement (Cogstate)
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 42 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Aug 2013to Jun 2015
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Ambulant patients of any Child-Pugh stage cirrhosi and PHEs defined MHe or grade 1 encephalopathy
Who cannot join
- 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
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- 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.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Liver unit St Mary's Hospital, 10th floor QEQM Wing, South Wharf Road
London, London, W2 1NY
About this study
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
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.
Read the 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
- 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
- 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.
- Improvement in brain function
- 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.
- Improvement in the chemical profile of key chemicals in the blood and urine, measured with in vitro NMR spectroscopy
- Being tested
- Vastus Muscle Biopsy, LOLA or placebo, Cognitive assessment (PHES), Cognitive Assessement (Cogstate), blood and urine sampling
- 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
- Medical subject headings
- Hepatic Encephalopathy, Fibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Vastus Muscle BiopsyProcedure or surgery
Both Arms, all 3 visits at 0, 4 and 12 weeks
LOLA or placeboDrug
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
Cognitive assessment (PHES)Other
Both Arms, all 3 visits at 0, 4 and 12 weeks
Cognitive Assessement (Cogstate)Other
Both Arms, all 3 visits at 0, 4 and 12 weeks
blood and urine samplingOther
Both Arms, all 3 visits at 0, 4 and 12 weeks
Nutritional assessmentOther
Both Arms, all 3 visits at 0, 4 and 12 weeks
MRI brain and spectroscopyOther
Both Arms, all 3 visits at 0, 4 and 12 weeks
MRI leg cross sectionOther
Both Arms, all 3 visits at 0, 4 and 12 weeks
Functional MRI (working memory and attention tasks)Other
Both Arms, all 3 visits at 0, 4 and 12 weeks
| Study group | Role | What they receive |
|---|---|---|
| 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) Receives: 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 | Not described Receives: 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) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Improvement in mental state on paper and pencil Hepatic Encephalopathy score (PHES) testing and Cogstate testing (computer based cognitive assessment research tool)
Measured: At 0, 4 and 12 weeks
Secondary outcomes (5)
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)
Measured: At 0 , 4 and 12 weeks
Brain chemical structure
Improvement in brain chemical structure (by measuring cerebral osmolytes) will be assessed by in-vivo MR spectroscopy
Measured: 0, 4, 12 weeks
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
Measured: 0, 4, 12 weeks
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.
Measured: 0, 4 and 12 weeks
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.
Measured: 0, 4 and 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 May 2013 (estimated)
- Study startAug 2013
- Primary completionJun 2015
- Study completionJun 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hepatic EncephalopathyStudies of the same condition, open and under way.
- More trials run by Imperial College LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 42 participants (actual)
Sponsor and investigators
- Lead sponsor
- Imperial College London
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Simon D Taylor-Robinson, MD FRCP, Principal investigator, Imperial College London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01847651
- Sponsor's protocol ID
- LOLA-Merz WMDH P39937
- Other IDs
- 2012-003817-32, 12/LO/1937, CRO2033
- Status last verified
- May 2013
- First submitted
- 2 May 2013
- Last updated
- 22 Oct 2015
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 22 Oct 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01847651
- Acronym / sponsor ID
- LOLA-Merz WMDH P39937
- Keywords
- hepatic encephalopathy, minimal hepatic encephalopathy, cirrhosis, lateral vastus, muscle biopsy, L ornithine L aspartate, functional magnetic resonance imaging, magnetic resonance spectroscopy
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 42 participants (actual)
- Lead sponsor
- Imperial College LondonUniversity, hospital or other
- Study start
- Aug 2013
- Primary completion
- Jun 2015 (actual)
- Study completion
- Jun 2015 (actual)
- First posted
- 7 May 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
- 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
- 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.
- Improvement in brain function
- 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.
- Improvement in the chemical profile of key chemicals in the blood and urine, measured with in vitro NMR spectroscopy
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| LOLA | Active 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)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) |
| 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) |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Ambulant patients of any Child-Pugh stage cirrhosi and PHEs defined MHe or grade 1 encephalopathy
Key exclusion criteria (12 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Vastus Muscle BiopsyBoth Arms, all 3 visits at 0, 4 and 12 weeks | Procedure or surgery | LOLA, Placebo |
| LOLA or placeboHepa-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 | Drug | LOLA, Placebo |
| Cognitive assessment (PHES)Both Arms, all 3 visits at 0, 4 and 12 weeks | Other | LOLA, Placebo |
| Cognitive Assessement (Cogstate)Both Arms, all 3 visits at 0, 4 and 12 weeks | Other | LOLA, Placebo |
| blood and urine samplingBoth Arms, all 3 visits at 0, 4 and 12 weeks | Other | LOLA, Placebo |
| Nutritional assessmentBoth Arms, all 3 visits at 0, 4 and 12 weeks | Other | LOLA, Placebo |
| MRI brain and spectroscopyBoth Arms, all 3 visits at 0, 4 and 12 weeks | Other | LOLA, Placebo |
| MRI leg cross sectionBoth Arms, all 3 visits at 0, 4 and 12 weeks | Other | LOLA, Placebo |
| Functional MRI (working memory and attention tasks)Both Arms, all 3 visits at 0, 4 and 12 weeks | Other | LOLA, Placebo |
Primary outcome
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
5 secondary outcomes
Brain Volume
Time frame: At 0 , 4 and 12 weeks
Brain chemical structure
Time frame: 0, 4, 12 weeks
Improvement in brain function measured by functional MRI
Time frame: 0, 4, 12 weeks
Improvement in Muscle Function and increase in muscle size
Time frame: 0, 4 and 12 weeks
Improvement of plasma and urine metabolome
Time frame: 0, 4 and 12 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Oct 2015.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Simon D Taylor-Robinson, MD FRCP principal investigator
Imperial College London
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Vastus Muscle Biopsy, Cognitive assessment (PHES) and Cognitive Assessement (Cogstate) in people with Hepatic Encephalopathy and Minimal Hepatic Encephalopathy, run by Imperial College London at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Oct 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Oct 2015.