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    Summary
    EudraCT Number:2019-003048-63
    Sponsor's Protocol Code Number:MK-3655-001
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-09-18
    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 ConcernedFrance - ANSM
    A.2EudraCT number2019-003048-63
    A.3Full title of the trial
    A Phase 2b Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of MK-3655 in Individuals With Pre-cirrhotic Nonalcoholic Steatohepatitis.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 2b Study of MK-3655 in Individuals with Pre cirrhotic Nonalcoholic Steatohepatitis (NASH)
    A.4.1Sponsor's protocol code numberMK-3655-001
    A.5.4Other Identifiers
    Name:INDNumber:134888
    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 SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.5.2Functional name of contact pointGlobal Clinical Trials Operations
    B.5.3 Address:
    B.5.3.1Street AddressOne Merck Drive P.O. Box 100
    B.5.3.2Town/ cityWhitehouse Station, New Jersey
    B.5.3.3Post code08889-0100
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1732-594-4437
    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 No
    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 nameMK-3655
    D.3.2Product code MK-3655
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNnot available
    D.3.9.2Current sponsor codeMK-3655
    D.3.9.3Other descriptive nameBTPH-040, NP313, NGM313
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number33.3
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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 No
    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 nameMK-3655
    D.3.2Product code MK-3655
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMK-3655
    D.3.9.2Current sponsor codeMK-3655
    D.3.9.3Other descriptive nameBTPH-040, NP313, NGM313
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    E.1.1.1Medical condition in easily understood language
    Nonalcoholic Steatohepatitis (NASH)
    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 22.0
    E.1.2Level PT
    E.1.2Classification code 10053219
    E.1.2Term Non-alcoholic steatohepatitis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To evaluate the effect of each dose of MK-3655 versus placebo on the proportion of individuals with nonalcoholic steatohepatitis (NASH) resolution without worsening of fibrosis after 52 weeks.
    2. To evaluate the safety and tolerability of MK-3655 compared with placebo.
    E.2.2Secondary objectives of the trial
    1. To evaluate the effect of each dose of MK-3655 versus placebo on mean percent relative reduction from baseline in liver fat content (LFC) after 24 weeks.
    2. To evaluate the effect of each dose of MK-3655 versus placebo on the proportion of individuals with ≥1 stage improvement in fibrosis without worsening of steatohepatitis after 52 weeks.
    3. To evaluate the effect of each dose of MK-3655 versus placebo on the proportion of individuals with ≥2 point improvement in the Nonalcoholic Fatty Liver Disease Activity Score (NAS) without worsening of fibrosis after 52 weeks.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Has histological confirmation of NASH based upon a liver biopsy obtained ≤6 months before Visit 1/Screening. If no acceptable biopsy performed ≤6 months before Visit 1/Screening is available, a liver biopsy will be performed at Visit 3/Liver Biopsy.
    Histological criteria for study entry include:
    - NAS ≥4 with a score ≥1 point in each component (steatosis, ballooning, and lobular inflammation),
    AND
    - NASH CRN fibrosis score of Stage 2 or 3.
    2. Has an MRI-PDFF ≥8% as assessed at Visit 2/MRI-PDFF.
    3. Has a baseline MELD-Na score ≤12 at Visit 1/Screening.
    4. Is a male or a postmenopausal female aged 18 years to 80 years (in Japan, aged 20 to 80 years), at the time of signing the ICF.
    5. Has a BMI ≥25 kg/m2 and ≤50 kg/m2 at the time of Visit 1/Screening.
    6. Has stable weight (based on self-reporting) defined as ≤5% gain or loss of body weight for at least 3 months before Visit 1/Screening.
    7. Meets one of the following criteria:
    - Has no history of T2DM.
    OR
    - Has a history of T2DM with an A1C ≤9.0% at Visit 1/Screening and controlled by diet or stable doses of AHAs.
    8. Has a systolic blood pressure of ≤160 mm Hg and a diastolic blood pressure ≤90 mm Hg (after at least a 10-minute seated rest) based on the mean of 3 measurements at Visit 5/Randomization.
    9. Be willing and able to comply with scheduled visits, treatment plan, laboratory tests,and/or other study procedures.
    10. Contraceptive use by male participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    11. Is a postmenopausal female.
    12. The participant (or legally acceptable representative, if applicable) provides written informed consent for the study. The participant may also provide consent for FBR. However, the participant may participate in the main study without participating in FBR.
    E.4Principal exclusion criteria
    1. Has presence of cirrhosis on liver biopsy.
    2. Has Type 1 diabetes.
    3. Has a history of malignancy, unless cancer free ≥5 years, or is under evaluation for active or suspected malignancy before signing the ICF except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
    4. Has a history of bariatric surgery ≤5 years before Visit 1/Screening.
    5. Has undergone a major surgical procedure ≤3 months before signing the ICF or has major surgery planned during the study.
    6. Has a history or evidence of:
    - Chronic liver disease other than NASH
    - Hepatitis B as defined by the presence of HBsAg
    - Hepatitis C as defined by the presence of HCV RNA or positive hepatitis C antibody (anti-HCV); participants with a history of HCV infection may be included if HCV PCR is negative ≥3 years
    - Drug-induced liver disease
    - Ongoing autoimmune liver disease
    - Decompensated liver disease
    - HIV
    - Primary biliary cirrhosis
    - Primary sclerosing cholangitis
    - Reye Syndrome
    - Splenomegaly
    - Wilson’s disease
    - Documented Cushing disease, Cushing syndrome, or any condition associated with hypercortisolism
    - Hypothyroidism, hyperthyroidism, or subclinical thyroid disease
    - Alpha-1-antitrypsin deficiency
    - Hemochromatosis or iron overload
    - Spontaneous bacterial peritonitis
    - Known bile duct obstruction
    - Hepatocellular carcinoma
    - Untreated obstructive sleep apnea
    - Hemostasis disorder
    - Hematological disorder
    7. Has significant systemic or major illnesses other than liver disease, including recent events (≤6 months before Visit 1/Screening) of congestive heart failure, unstable coronary artery disease, arterial revascularization, pulmonary disease, renal failure, stroke, transient ischemic attack, or organ transplantation.
    8. Has a known hypersensitivity to any of the ingredients or excipients of the IMP.
    9. Has experienced any bone trauma, fracture, or bone surgery ≤2 months before Visit 1/Screening.
    10. Has a history of osteoporosis or an indication that requires treatment with a bone-active pharmacological agent in the classes listed in exclusion criterion #18 at Visit 1/Screening.
    11. Has current or history of significant alcohol consumption for a period of more than 3 consecutive months ≤24 months before Visit 1/Screening.
    12. Has an inability to reliably quantify alcohol consumption.
    13. Has a recent history of drug abuse (defined as ≤3 years) or is a current user of recreational or illicit drugs at the time of Visit 1/Screening.
    14. Has a known psychiatric or any other cognitive disorder per the opinion of the investigator, that would interfere with the participant’s ability to cooperate with the requirements of the study.
    15. Is at imminent risk of self-harm, based on clinical interview and responses on the C-SSRS, or of harm to others in the opinion of the investigator.
    16. Has a total score >12 on the PHQ-9.
    17. Is on treatment with or has used the following agents ≤24 months before Visit 1/Screening:
    - Thiazolidinediones
    - Fibric acid derivatives
    - Obeticholic acid
    - High dose vitamin E (>400 IU/day)
    - L-ornithine L-aspartate
    18. Is on treatment with or has used bone-active agents in the classes listed below ≤24 months before Visit 1/Screening.
    - Bisphosphonates
    - Calcitonin
    - Selective estrogen receptor modulator (estrogen receptor agonist/antagonist)
    - PTH and PTH analogs
    - RANK ligand inhibitor
    - Anti-sclerostin antibody
    - Aromatase inhibitors
    - GnRH agonists
    19. Is on treatment with or has used drugs associated with NAFLD ≤6 months before Visit 1/Screening:
    - Amiodarone
    - Anabolic steroids
    - Chemotherapeutic agents
    - Cocaine
    - Dronedarone
    - Estrogens at doses greater than those used for hormone replacement or contraception
    - Methotrexate
    - Nucleoside reverse transcriptase inhibitors
    - Tetracycline (intravenous administration at high doses)
    - Valproic acid
    - Other known hepatotoxins
    20. Is on treatment or likely to require treatment for ≥14 consecutive days or repeated courses of pharmacologic doses of corticosteroids.
    21. Is on treatment with anticoagulants.
    22. Is on treatment with an AHA or other medications indicated in the protocol.
    23. Is currently participating in or has participated in an interventional clinical study with an investigational compound or device ≤6 months of participating in this current study.
    24. Has exclusionary laboratory values.
    25. Has poor venous access that precludes routine peripheral blood sampling required for this study.
    26. Has received blood products ≤2 months before Visit 1/Screening and/or donated blood products ≤1 month before Visit 1/Screening.
    27. Has a clinically significant ECG abnormality that requires further diagnostic evaluation or intervention.
    28. Has claustrophobia to a degree that prevents tolerance of MRI scanning procedure.
    29. Has a metallic implant of any sort that prevents MRI examination, or any other contraindication to MRI examination.
    E.5 End points
    E.5.1Primary end point(s)
    1. Percentage of participants with NASH resolution without worsening fibrosis assessed with the NASH Clinical Research Network (CRN) scoring system (evaluated by blinded independent central review [BICR]) after 52 weeks
    2. Percentage of participants with adverse events (AEs) up to 56 weeks
    3. Percentage of participants discontinuing study intervention due to adverse events (AEs) up to 52 weeks
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. At 52 weeks
    2. Up to 56 weeks
    3. Up to 52 weeks
    E.5.2Secondary end point(s)
    1. Change from baseline in liver fat content (LFC) (%) measured by Magnetic Resonance Imaging-Estimated Proton Density Fat Fraction (MRI-PDFF) (evaluated by BICR) after 24 weeks
    2. Percentage of participants with ≥1 stage improvement in fibrosis without worsening of steatohepatitis assessed with the NASH CRN scoring system (evaluated by BICR) after 52 weeks
    3. Percentage of participants with ≥2 point improvement (PI) in the Nonalcoholic Fatty Liver Disease Activity Score (NAS) with ≥1 PI in inflammation/ballooning without worsening fibrosis by NASH CRN scoring system (evaluated by BICR) after 52 weeks
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Baseline and 24 Weeks
    2. At 52 weeks
    3. At 52 weeks
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 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 concerned15
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA49
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Canada
    Chile
    China
    France
    Germany
    Hong Kong
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    New Zealand
    Russian Federation
    Spain
    Taiwan
    Turkey
    United States
    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 months3
    E.8.9.1In the Member State concerned days15
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days15
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 230
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 98
    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 state36
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 328
    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)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-11-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-11-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-04-13
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