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    Summary
    EudraCT Number:2016-001448-21
    Sponsor's Protocol Code Number:MS200527-0086
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-02-14
    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 ConcernedBulgarian Drug Agency
    A.2EudraCT number2016-001448-21
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled Phase II Study of M2951 with a Parallel, Open-Label, Active Control Group (Tecfidera), in Patients with Relapsing Multiple Sclerosis to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics, and Biological Activity.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Efficacy and Safety of M2951 in Relapsing Multiple Sclerosis
    A.4.1Sponsor's protocol code numberMS200527-0086
    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 KGaA
    B.1.3.4CountryGermany
    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 KGaA
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck KGaA
    B.5.2Functional name of contact pointCommunication Center
    B.5.3 Address:
    B.5.3.1Street AddressFrankfurter Strasse 250
    B.5.3.2Town/ cityDarmstadt
    B.5.3.3Post code64293
    B.5.3.4CountryGermany
    B.5.4Telephone number+496151725200
    B.5.5Fax number+496151722000
    B.5.6E-mailservice@merckgroup.com
    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 nameM2951
    D.3.2Product code M2951
    D.3.4Pharmaceutical form 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 INNM2951
    D.3.9.2Current sponsor codeM2951
    D.3.9.3Other descriptive nameM2951
    D.3.9.4EV Substance CodeSUB180032
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 RoleComparator
    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 Tecfidera
    D.2.1.1.2Name of the Marketing Authorisation holderBiogen Idec Ltd
    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 nameTecfidera
    D.3.4Pharmaceutical form Capsule, hard
    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 INNTecfidera
    D.3.9.1CAS number 624-49-7
    D.3.9.3Other descriptive nameDIMETHYL FUMARATE
    D.3.9.4EV Substance CodeSUB13608MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number120
    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 RoleComparator
    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 Tecfidera
    D.2.1.1.2Name of the Marketing Authorisation holderBiogen Idec Ltd
    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 nameTecfidera
    D.3.4Pharmaceutical form Capsule, hard
    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 INNTecfidera
    D.3.9.1CAS number 624-49-7
    D.3.9.3Other descriptive nameDIMETHYL FUMARATE
    D.3.9.4EV Substance CodeSUB13608MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number240
    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 placeboTablet
    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
    Relapsing Multiple Sclerosis
    E.1.1.1Medical condition in easily understood language
    Relapsing Multiple Sclerosis
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10028245
    E.1.2Term Multiple sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10048393
    E.1.2Term Multiple sclerosis relapse
    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
    The primary objective of the main study is to evaluate the efficacy and dose-response of M2951 on the number of gadolinium-positive (Gd+) T1 MRI lesions versus placebo after 24 weeks of treatment.

    The primary objective of the open-label extension period is to evaluate
    the long-term safety, efficacy, and HRQoL of M2951 for an additional 2
    years, at an initial dose of 75 mg once daily which is eventually switched
    to 75 mg twice daily.
    E.2.2Secondary objectives of the trial
    The key secondary objectives are as follows:
    - To evaluate the efficacy and dose-response of M2951 on clinical endpoints over 24 weeks versus placebo
    - To evaluate the safety of M2951

    Additional secondary objectives are as follows:
    - To evaluate the efficacy of M2951 on additional MRI parameters over 24 weeks versus placebo
    - To evaluate the efficacy of M2951 on clinical and MRI endpoints from Week 24 to 48
    - To evaluate the efficacy of Tecfidera on clinical and MRI endpoints over 24 weeks
    - To evaluate the efficacy of Tecfidera on clinical and MRI endpoints from Week 24 to 48
    - To evaluate the safety of Tecfidera
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacodynamics Bruton’s tyrosine kinase (BTK) occupancy (version and date as per current protocol).

    Bruton’s tyrosine kinase (BTK) occupancy samples will be taken from a subset of approximately 30 evaluable subjects treated with M2951 or placebo from selected sites capable of providing samples.

    Objective: To determine the Change from Baseline in percent BTK occupancy to predose on Days 28, 84 and 168 and 2 hours postdose on Days 1, 28, 84 and 168.
    E.3Principal inclusion criteria
    1. Subjects with a diagnosis of relapsing multiple sclerosis (may include subjects with Secondary PMS [SPMS] with superimposed relapses provided they meet the other criteria) in accordance with revised McDonald criteria for MS and Lublin and Reingold
    2. Male or female aged 18 to 65 years
    3. One or more documented relapses within the 2 years before Screening with either: a) One relapse which occurred within the last year prior to randomization or b) the presence of at least 1 Gd+ T1 lesion within 6 months prior to randomization would make the patient eligible.
    4. Expanded Disability Status Scale score of 0 to 6 at Baseline
    5. Women of childbearing potential must use a supplementary barrier method together with a highly effective method of contraception for 4 weeks prior to randomization, throughout the trial, and for 90 days after the last dose of IMP. Male subjects and their female partners must also use the above.
    6. Signed and dated informed consent (subject must be able to understand the informed consent) indicating that the subject has been informed of all the pertinent aspects of the trial prior to enrolment and will comply with the requirements of the protocol.

    For the open-label extension period;
    Subject who have withdrawn after randomization (eg, due to AEs or lack of efficacy) will not be replaced and will not eligible to participate in the OLE Period. Only subjects who have completed the 48-week main study are eligible to participate.
    E.4Principal exclusion criteria
    • Progressive MS
    • Disease duration > 15 years in subjects with EDSS of 2 or less
    • Use of the following, as determined in the protocol ; rituximab, ocrelizumab, mitoxantrone, or lymphocyte-depleting therapies, lymphocyte trafficking blockers (eg, natalizumab, fingolimod), intravenous (IV) immunoglobulins (Ig), plasmapheresis, immunosuppressive treatments, B-interferons or glatiramer acetate, Systemic glucocorticoids, teriflunomide, daclizumab
    • Exposure to Tecfidera within 6 months prior to randomization
    • Any allergy, contraindication, or inability to tolerate Tecfidera
    • Treatment with dalfampridine (fampridine, Ampyra) unless on a stable dose for ≥ 30 days prior to randomization
    • Inability to comply with MRI scanning
    • Immunologic disorder other than MS, with the exception of secondary well-controlled diabetes or thyroid disorder, or any other condition requiring oral, IV, intramuscular, or intra-articular corticosteroid therapy
    • Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening
    • Severe drug allergy or history of anaphylaxis, or allergy to the IMP or any of its incipients
    • Active, clinically significant viral, bacterial, or fungal infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks of Screening, or completion of oral anti-infectives within 2 weeks before or during Screening, or a history of recurrent infections (ie, 3 or more of the same type of infection in a 12-month rolling period). Vaginal candidiasis, onychomycosis, and genital or oral herpes simplex virus considered by the Investigator to be sufficiently controlled would not be exclusionary.
    • History of or positive testing for human immunodeficiency virus (HIV), hepatitis C (HCV) antibody and/or polymerase chain reaction, hepatitis B surface antigen (HBsAg) (+) and/or hepatitis B core total, and/or IgM antibody (+) at Screening.
    • The subject: • Has a history of or current diagnosis of active tuberculosis (TB) or • Is currently undergoing treatment for latent TB infection (LTBI) or • Has an untreated LTBI or • Has a positive QuantiFERON®-TB test at Screening.
    • Indeterminate QuantiFERON
    • Subjects with current household contacts with active TB will also be excluded
    • History of splenectomy or any major surgery within 2 months prior to Screening
    • History of myocardial infarction or cerebrovascular event as per the protocol
    • History of attempted suicide within 6 months prior to Screening or a positive response to items 4 or 5 of Columbia-Suicide Severity Rating Scale (C-SSRS)
    • An episode of major depression within the last 6 months prior to Screening
    • On anticoagulation, fish oil supplements, or antiplatelet therapy other than daily aspirin for cardioprotection and treatment of Tecfidera induced flushing
    • History of cancer, except adequately treated basal cell or squamous cell carcinoma of the skin
    • Breastfeeding/lactating or pregnant women
    • Participation in any investigational drug trial within 1 month or 5 half-lives of the investigational drug, whichever is longest, prior to Screening
    • Subjects currently receiving (or unable to stop using prior to receiving the first dose of IMP) medications or herbal supplements known to be potent inhibitors of cytochrome P450 3A (CYP3A)
    • History of or current alcohol or substance abuse
    • Clinically significant abnormality on electrocardiogram or screening chest X-ray
    • Clinically significant laboratory abnormality

    Note: for subjects participating in the OLE Period after receiving Tecfidera during the 48-week main study, absolute lympchocyte count <800/mm^3 is considered an exclusion criterion
    E.5 End points
    E.5.1Primary end point(s)
    Main Study
    Total number of gadolinium-enhancing T1 lesions at Weeks 12, 16, 20, and 24

    Ole Period
    •Efficacy and HRQoL endpoints at Week 48 and 96.
    •Safety as assessed by the nature, severity, and occurrence of AEs; vital signs; ECGs; absolute concentrations and change from Baseline in Ig levels; absolute numbers and change from Baseline in B cells; and clinical laboratory safety parameters.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 12, 16, 20 and 24

    Week 48 and 96

    AEs are evaluated throughout the study
    E.5.2Secondary end point(s)
    Key secondary endpoints to evaluate the efficacy and safety of M2951 compared to placebo:
    • Annualized relapse rate (ARR), based on protocol-defined qualified relapses, at Week 24
    • Qualified relapse-free status at Week 24
    • Change from Baseline in Expanded Disability Status Scale (EDSS) at Week 24
    • Safety as assessed by the nature, severity, and of AEs; vital signs; ECGs; absolute concentrations and change from Baseline in Ig levels; absolute numbers and change from Baseline in B cells; and clinical laboratory safety parameters (duration of placebo treatment group limited to 24 weeks).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 24 for the key secondary endpoints

    AEs are evaluated throughout the study
    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 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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    tolerability; determine the potential correlation between gene expression signatures and PD/efficacy
    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) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial5
    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 concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA41
    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
    Bulgaria
    Croatia
    Czech Republic
    Poland
    Russian Federation
    Serbia
    Slovakia
    Spain
    Turkey
    Ukraine
    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
    LSLV
    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 months3
    E.8.9.1In the Member State concerned days28
    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.1.1.1In 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: 248
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state120
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 250
    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)
    4 week safety follow up after treatment. A separate open-label extension protocol will be developed allowing continued dosing, provided that safety and tolerability are acceptable.
    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 Decision2017-04-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-04-11
    P. End of Trial
    P.End of Trial StatusOngoing
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