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    Summary
    EudraCT Number:2016-003575-21
    Sponsor's Protocol Code Number:
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-05-09
    Trial 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 number2016-003575-21
    A.3Full title of the trial
    A multicentre, 48 week randomised controlled factorial trial of adding maraviroc and/or metformin for hepatic steatosis in HIV-1-infected adults on combination antiretroviral therapy.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    MAVMET: A research study exploring whether MAraViroc, a licensed treatment for HIV infection and METformin, a licensed treatment for diabetes, are effective and safe at reducing the amount of fat in the liver.
    A.3.2Name or abbreviated title of the trial where available
    MAVMET
    A.4.1Sponsor's protocol code number
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03129113
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMRC Clinical Trials Unit at UCL
    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 supportViiv Healthcare
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity College London
    B.5.2Functional name of contact pointChief Investigator for MAVMET Trial
    B.5.3 Address:
    B.5.3.1Street AddressAviation House, 125 Kingsway
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeWC1B 6NH
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number07983806215
    B.5.5Fax number02076704718
    B.5.6E-mails.pett@ucl.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 Metformin
    D.2.1.1.2Name of the Marketing Authorisation holderTEVA UK Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameMetformin
    D.3.2Product code metformin
    D.3.4Pharmaceutical form Film-coated tablet
    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.3.9.4EV Substance CodeAS1
    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.IMP: 2
    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 Celsentri
    D.2.1.1.2Name of the Marketing Authorisation holderViiV Healthcare UK
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameCelsentri
    D.3.2Product code maraviroc
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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.IMP: 3
    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 metformin
    D.2.1.1.2Name of the Marketing Authorisation holderSpecial Concept Development UK
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 namemetformin
    D.3.2Product code metformin
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hepatic steatosis in adults with chronic HIV-1 infection
    E.1.1.1Medical condition in easily understood language
    HIV-1- infected patients with non-alcoholic fatty liver disease
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10029530
    E.1.2Term Non-alcoholic fatty liver
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    MAVMET is trying to find out if maraviroc, metformin or a combination of both results in a change in percentage of liver fat as measured by MR PDFF a type of MRI imaging over 48 weeks.
    E.2.2Secondary objectives of the trial
    Secondary outcomes over 48 weeks are as follows:

    1) Grade of hepatic steatosis as measured by MR PDFF
    2) Liver enzymes: ALT, AST, ALP and GGT
    3) Absolute and percentage CD4+ and CD8+ T-cells
    4) plasma HIV RNA;
    5) SAE
    6) Grade 3 and 4 AEs
    7) Treatment-limiting toxicity of any grade
    8) Quality of life (QoL) as measured by EQ-5D-QL
    9) Adherence to trial drugs
    10) Use of all potentially hepatotoxic medications, including over-the-counter medication such as paracetamol


    There are a number of other exploratory objectives including measuring the levels of inflammation in blood, looking at greater details of the exact changes in immune cells during the trial, and in a subset of people enrolling at Mortimer Market Centre, there is the option to have a brain MRI scan at the beginning of the trial and at the end.

    Optional stored blood samples: these will be collected, stored and later tested to help understand how genes affect the amount of fat in liver, for example to measure the e.g. PNP3A g
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Signed informed consent
    2) Age ≥35 years of age
    3) Chronic HIV-1-infection for ≥5 years
    4) On combination antiretroviral therapy (cART) and with virological suppression (<50 copies/mL) for ≥1 year
    5) i)>1 abnormal (above the upper limit) of LFTS (ALT or AST) in the last 2 years with no other explanation (e.g. secondary syphilis) and/or
    ii) increased waist circumference ≥94 cm (≥90cm if South Asian origin) in men, ≥80cm in women and/or
    iii) a confirmed diagnosis of NAFLD on liver imaging (CT/MRI/ultrasound), FibroScan and/or
    iv) liver biopsy confirmed diagnosis of NALFD
    6) For females of child bearing potential (CBP) agree to avoid pregnancy for the duration of the study
    7) Able to comply with protocol requirements
    E.4Principal exclusion criteria
    1. Co-infection with hepatitis B or C
    2. Confirmed chronic liver disease from any other cause (e.g. hepatitis C, hepatitis B)
    3. Daily intake of alcohol >20g in women and >30g in men
    4. Current illicit drug use that in the opinion of the investigator would interfere with patient’s ability to comply with the protocol
    5. On metformin or another biguanide agent
    6. Currently on maraviroc
    7. Any contraindication to the receipt of maraviroc and/or metformin
    8. Known B12 deficiency
    9. Pregnant or breast feeding
    10. Contraindication to MRI scanning
    11. Peanut or soya allergy
    12. eGFR <60 ml/min/1.73m2
    13. ALT ≥10 x ULN
    14. History of cardiovascular (ischaemic heart disease) or cerebrovascular disease.
    15. Any other condition that in the opinion of the investigator would not make the patient suitable for the trial.




    E.5 End points
    E.5.1Primary end point(s)
    Change in percentage of liver fat as measured by MR PDFF between baseline and week 48.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline and 48 weeks
    E.5.2Secondary end point(s)
    1) Grade of hepatic steatosis as measured by MR PDFF
    2) Liver enzymes: ALT, AST, ALP and GGT
    3) Absolute and percentage CD4+ and CD8+ T-cells
    4) Plasma HIV RNA
    5) SAE
    6) Grade 3 and 4 AEs
    7) Treatment-limiting toxicity of any grade
    8) Quality of life (QoL) as measured by EQ-5D-QL
    9) Adherence to trial drugs
    10) Use of all potentially hepatotoxic medications, including over-the-counter medication such as paracetamol.

    Exploratory outcomes over 48 weeks
    All participants
    1) Sleep quality and quantity as captured on the sleep questionnaire
    2) Fasting HOMA-IR and lipids
    3) BMI
    4) Anthropometric measures
    5) Framingham 10-year cardiovascular risk score
    6) Alcohol use
    7) NALFD fibrosis score
    8) Percentage of liver fat as measured by 1H MRS
    9) Liver T1 MRI scan determined change in grade of liver fibrosis
    10) Percentage of pancreatic fat as measured by MR PDFF
    11) Percentage of total body fat as measured by MR PDFF
    12) Abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) area as assessed by MR PDFF.


    In those consenting to stored blood collection and/or a *participant at Mortimer Market Centre, the change in the following over 48 weeks
    1) *Absolute and percentage activated CD4+ and CD8+ T-cells (CD38+HLA-DR+);
    2) Plasma levels of ligands for CCR5, changes in LPS and sCD14; leptin and adiponectin;
    3) Inflammatory biomarkers (e.g. IL-6, hsCRP; D-dimer);
    4) Liver specific inflammatory biomarkers e.g. hyaluronic acid;
    5) Ultrasensitive HIV RNA.


    Exploratory neuroimaging outcomes*

    1) Total volume of white matter hyperintensities of presumed vascular origin on brain MRI
    2) Sodium concentration in supratentorial white matter and deep grey matter
    3) Fractional anisotropy and mean diffusivity in supratentorial white matter and deep grey matter

    *In a subset of patients at Mortimer Market Centre only (maximum enrollment is 32), optional scans over 48 weeks.

    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline to week 48
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    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
    The end of the trial will be defined as when the last patient recruited has attended their week 48 visit, and key data queries have been considered to be resolved.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    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: 83
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 state88
    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)
    Continued provision of maraviroc or metformin will not be possible outside of the trial once the research has finished.

    Patients will take the trial medication for a total of 48 weeks. Until the trial is completed and the results are known, and it has been shown (perhaps with further additional studies) that maraviroc and or metformin is effective, it cannot be recommended as a treatment.
    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 Decision2017-07-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-20
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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