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    Summary
    EudraCT Number:2017-003172-32
    Sponsor's Protocol Code Number:MASHVs1.118-08-17
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-05-16
    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 number2017-003172-32
    A.3Full title of the trial
    Maraviroc Add-on Therapy for Steatohepatitis in HIV
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The MASH Trial
    A.3.2Name or abbreviated title of the trial where available
    The MASH Trial
    A.4.1Sponsor's protocol code numberMASHVs1.118-08-17
    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 support
    B.4.2Country
    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 pointJames Maurice
    B.5.3 Address:
    B.5.3.1Street AddressSt Mary's Hospital
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeW21NY
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailjames.maurice@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 Celsentri
    D.2.1.1.2Name of the Marketing Authorisation holderViiV Healthcare UK Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical 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.3.8INN - Proposed INNMaraviroc
    D.3.9.1CAS number 376348-65-1
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number150 to 300
    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
    Non alcoholic steatohepatitis (NASH) in patients with HIV mono-infection.
    E.1.1.1Medical condition in easily understood language
    Fatty liver disease in patients with HIV infection.
    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 20.1
    E.1.2Level PT
    E.1.2Classification code 10053219
    E.1.2Term Non-alcoholic steatohepatitis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10008919
    E.1.2Term Chronic HIV infection
    E.1.2System Organ Class 100000004862
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Does maraviroc change the inflammatory cell infiltrate in the livers of patients with HIV infection and non-alcoholic steatohepatitis?
    E.2.2Secondary objectives of the trial
    Does Maraviroc have an impact on:
    1. metabolic parameters e.g. insulin resistance and diabetes, blood pressure
    2. Circulating inflammatory signals in the blood (cytokines and adiopkines)
    3. The severity of non-alcoholic steatohepatitis on the liver biopsy, scored by histopathologists using a score called the NAFLD Activity Score ('NAS' Score)
    4. Non- invasive markers of liver fibrosis
    5. Levels of liver enzymes in the blood (the standard clinical biochemical tests to assess liver function)
    6. Create a high- quality biobank repository of samples from patients with well characteristed NAFLD and HIV mono-infection.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. HIV-1 infected individuals (males and females) aged 18-75 years
    2. Stable antiretroviral therapy for at least one year on a regimen that is unlikely to change in the next 12 months.
    3. At least two consecutive undetectable HIV viral loads defined by HIV RNA ≤50 copies/mm3 for ≥ 6 months from the date of inclusion.
    4. CD4 count ≥ 200 cells/mm3
    5. Histological evidence of NASH based on liver histology performed within 12 months prior to enrollment with a NAFLD activity score (NAS) ≥ 4 with a score of at least 1 in each component (steatosis, lobular inflammation, and hepatocyte ballooning)[19] and <10% weight loss since the time of liver biopsy
    6. Consent to second liver biopsy after 48 weeks treatment with MVC.
    7. Patient able to understand and signed a consent form
    E.4Principal exclusion criteria
    1) Liver co-morbidities:
    1. Positive HBs antigen (HBsAg)
    2. Positive HCV antibody (HCVAb), with the exception of subjects with the presence of HCVAb but negative hepatitis C virus RNA without treatment (i.e. spontaneous clearance following acute infection).
    3. Underlying acute or chronic liver disease including non- B non- C viral hepatitis (A & E), autoimmune liver disease, biliary disease, hemochromatosis, Wilson´s disease, alpha-1-antitrypsin deficiency.
    4. History of decompensated cirrhosis including ascites, hepatic encephalopathy, or variceal bleeding.
    5. Suspicion of drug-related toxicity defined by abnormal LFTs following the recent introduction of a new medication.

    2) Additional co-morbidities:
    1. Active, serious infections that require parenteral antibiotic or antifungal therapy within 30 days prior to screening visit.
    2. Active AIDS-defining disease other than oesophageal candidiasis.
    3. Any active life- threatening disease
    4. Active malignancy (except for early dysplastic lesions eg anal dysplasia)
    5. Congestive cardiac failure
    6. Platelet count <100x103 cells/mm3 and/or INR >1.4
    7. Severe renal impairment with CrCl<30mL/min

    3) Lifestyle:
    1. Excessive alcohol consumption during the last 6 months prior inclusion defined by more than 14 units/week for women or 21 units/week for men

    4) Concomitant medications:
    1. Patients actively treated with Maraviroc or having received Maraviroc over the last 12 months.
    2. Weight reduction through bariatric surgery in the past 5 years or planned during the conduct of the study.
    3. Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic agents or immunomodulating agents.
    4. Receiving any experimental medications within 30 days prior to screening or anticipated use during the trial.
    5. Patients receiving pioglitazone, rosiglitazone, vitamin E 800 IU/day, , and/or ursodeoxycholic acid since these drugs may have confounding effect on efficacy of MVC

    5) Others
    1. Females who are pregnant or breastfeeding
    2. Allergy to the study drug or its components (including peanut and soya)
    3. Participation in any other clinical trial at Screening without approval from the Sponsor
    E.5 End points
    E.5.1Primary end point(s)
    A change in hepatic immune cells- including CD3+, CD4+, CD8+, T-bet+, CD56, CD68, CD163 and myeloperoxidase positive cells identified on liver biopsy tissue using immunohistochemistry- following 48 weeks MVC therapy.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Compare values at baseline (within 12 months before enrollment) with values after 48 weeks treatment.
    E.5.2Secondary end point(s)
    1. Improvement in biochemical (fasting glucose, lipids and HOMA index) metabolic parameters at EOT as compared to baseline.
    2. Modification of circulating inflammatory cytokines, adipokines and markers of macrophage activation (high sensitive IL6, sTNFR1 /2, sCD14, sCD163, hsCRP, Leptin, Total and High molecular weight adiponectin) at EOT as compared to baseline.
    3. Number of subjects with a reduction in the NAS score by ≥2 points without worsening of fibrosis at EOT as compared to baseline.
    4. Number of subjects with a reduction in the degree of liver steatosis, inflammation and/or ballooning at EOT as compared to baseline
    5. Number of subjects with a reduction of at least one stage of liver fibrosis in patients with fibrosis at EOT as compared to baseline
    6. Number of subjects with a reduction of Fibroscan® values and biochemical markers of fibrosis (APRI, Fib-4, NAFLD Fibrosis Score[5]) from at EOT as compared to baseline
    7. Number of subjects with normalization of Fibroscan values at the EOT
    8. Number of subjects with a reduction in liver transaminases (ALT and AST) levels during the course and the EOT
    9. Additional stool and urine samples will be collected at baseline and EOT and stored in Imperial College Gastroenterology and Hepatology Biobank for analysis of the impact of the intestinal microbiome and associated metabolic biomarkers on the progression of NAFLD/NASH in HIV.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Compare values at baseline with values after 48 weeks treatment.
    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 No
    E.6.4Safety No
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA6
    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 No
    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 years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days7
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days7
    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: 28
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 30
    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)
    The findings will need to be confirmed with a larger randomised controlled trial.

    Therefore there will be no provision for further treatment with maraviroc after the trial outside of the current license indications.
    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 Decision2017-11-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-10-30
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2020-06-30
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