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    Summary
    EudraCT Number:2012-003817-32
    Sponsor's Protocol Code Number:LOLA-Merz:WMDHP39937
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-11-28
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2012-003817-32
    A.3Full title of the trial
    Brain muscle axis during treatment of hepatic encephalopathy with L-ornithine L-aspartate
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Investigation of brain and muscle function in patients with chronic liver disease: A study using L-ornithine l-aspartate
    A.3.2Name or abbreviated title of the trial where available
    LOLA in Hepatic Encephalopathy
    A.4.1Sponsor's protocol code numberLOLA-Merz:WMDHP39937
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorImperial College London
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerz Pharmaceuticals
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationImperial College London
    B.5.2Functional name of contact pointProfessor Simon Taylor-Robinson
    B.5.3 Address:
    B.5.3.1Street AddressDepartment of Medicine, 10th Floor QEQM Wing, St Mary's Hospital, Praed Street
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeW2 1NY
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02078866454
    B.5.5Fax number02079249369
    B.5.6E-mails.taylor-robinson@imperial.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Hepa-Merz® Granulat 3000
    D.2.1.1.2Name of the Marketing Authorisation holderMerz Pharmaceuticals GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameHepa-Merz® Granulat 3000
    D.3.4Pharmaceutical form Granules for oral solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNL-ornithine L-aspartate
    D.3.9.1CAS number 3230-94-2
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboGranules for oral solution
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hepatic Encephalopathy
    E.1.1.1Medical condition in easily understood language
    The state of confusion or memory loss experienced by many patients with advanced liver disease, caused by the liver not filtering out toxins in the blood efficiently (including ammonia).
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10019660
    E.1.2Term Hepatic encephalopathy
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objective: Improvement in mental state by paper-and-pencil-based Psychometric Hepatic Encephalopathy Score (PHES) and Cogstate Research test(computer-based cognitive assessment research tool)
    E.2.2Secondary objectives of the trial
    1. Brain volume reduction (reduction in brain swelling) measured by magnetic resonance imaging (MRI) of the brain and improvement in the chemical structure of the brain (cerebral osmolytes) measured by in vivo MR spectroscopy (MRS) scanning of the brain

    2. Improvement in brain function through assessment of key areas of the brain involved in attention and memory (the default mode network [DMN] measured by functional MRI of the Brain (fMRI)

    3. Improvement in muscle function (muscle metabolome normalisation) and increase muscle size (fat free mass), measured by in vivo MRS scanning and MR imaging scans of the leg and by vitro NMR spectroscopy, mass spectroscopy, histology on muscle biopsy samples.

    4. Improvement in the profile of key chemicals in the blood and urine (plasma and urinary metabolome), measured with in vitro NMR spectroscopy to assess for biomarkers of treatment response and to determine the amino acids changed in hepatic encephalopathy.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients with established cirrhosis and previously documented minimal hepatic encephalopathy, either untreated or treated with standard of care, lactulose.
    E.4Principal exclusion criteria
    1. Current excess alcohol use or within 1 month,
    2. Recent use of psychiatric medication within 1 month
    3. Affective disorder
    4. Severe coagulopathy (INR greater than 2, platelet count less than 60,000)
    5. Known myopathy or myositis
    6. Trauma to the lower extremities within 3 months
    7. Recent intestinal haemorrhage within 1 month
    8. Ferromagnetic implant or foreign body
    9. Claustophobia or previous inability to tolerate MRI scanning.
    10. Age over 65
    E.5 End points
    E.5.1Primary end point(s)
    Improvement in mental state of patients with hepatic encephalopathy measured by paper-and-pencil-based Psychometric Hepatic Encephalopathy Score (PHES) and Cogstate Research computer-based psychometric battery after 12 weeks treatment with L-ornithine L-aspartate
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 12 weeks of treatment with L-ornithine L-aspartate
    E.5.2Secondary end point(s)
    1. Detection of small changes in brain size following alterations in degree of encephalopathy in patients during and after LOLA administration using in vivo T1-weighted magnetic resonance imaging (MRI).

    2. Detection of improvement in cerebral osmolytes (creatinine, choline, N-acetylaspartate, myoinosotol, glutamine/glutamate, lactate) in patients during and after LOLA administration using in vivo 1H MR spectroscopy (MRS).

    3. Detection of improvement in brain function in patients during and after LOLA administration through assessment of the default mode network (DMN) on functional MRI of the brain (fMRI).

    4. Detection of improvement in health-related quality of life (HRQoL) as measured by CLDQ and SF-36 in patients during and after LOLA administration.

    5. Detection of normalisation of the muscle metabolome, function (detected by in vitro NMR spectroscopy, and mass spectroscopy), mass (detected by in vivo imaging of muscle) and increase in fat free histology on muscle biopsy samples can be measured in patients during and after LOLA administration.

    6. Correlation of the histological, NMR spectroscopic and energetic functions of muscle with the ammonia levels and degree of hepatic encephalopathy.

    7. Improvement in the plasma and urinary metabolome (measured with in vitro NMR spectroscopy) for biomarkers of response and amino acids changed in hepatic encephalopathy in patients during and after LOLA therapy.
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 12 weeks of treatment with L-ornithine L-aspartate
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months11
    E.8.9.2In all countries concerned by the trial days30
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 34
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state34
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 34
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients will continued to be monitored in the cirrhosis clinic at St Mary's Hospital as part of their routine clinical service. If patients find LOLA to be beneficial from a cognitive and quality of life perspective, we shall approach Merz in Germany, the company that produces it, to supply the drug on a named patient basis from Germany.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-01-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-01-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-06-19
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