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    Summary
    EudraCT Number:2017-000384-32
    Sponsor's Protocol Code Number:MS200527-0060
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-07-12
    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 ConcernedBulgarian Drug Agency
    A.2EudraCT number2017-000384-32
    A.3Full title of the trial
    A Phase IIb, Randomized, Double blind Study in Subjects with Rheumatoid Arthritis Evaluating the Safety and Efficacy of Evobrutinib Compared with Placebo in Subjects with an Inadequate Response to Methotrexate
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase IIb in Rheumatoid Arthritis
    A.3.2Name or abbreviated title of the trial where available
    N/A
    A.4.1Sponsor's protocol code numberMS200527-0060
    A.5.4Other Identifiers
    Name:N/ANumber:N/A
    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.4.1Name of organisation providing supportEMD Serono Research & Development Institute, Inc.
    B.4.2CountryUnited States
    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 nameEvobrutinib
    D.3.2Product code M2951
    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 INNEvobrutinib
    D.3.9.1CAS number N/A
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    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
    Rheumatoid Arthritis
    E.1.1.1Medical condition in easily understood language
    Rheumatoid Arthritis
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy and dose response of 12 weeks of treatment with evobrutinib compared with placebo in subjects with rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX-IR) on stable MTX therapy by assessment of the signs and symptoms of RA, as measured by American College of Rheumatology (ACR) 20% (ACR20) response assessed using high-sensitivity C-reactive protein (hsCRP) at Week 12
    E.2.2Secondary objectives of the trial
    • To further evaluate the efficacy and dose response of 12 weeks of treatment with evobrutinib in MTX-IR subjects with RA on stable MTX therapy by assessment of the signs and symptoms of RA, as measured by DAS28-hsCRP low disease activity (DAS28 < 3.2) rate at Week 12
    • To further evaluate the efficacy of 12 weeks of treatment with evobrutinib compared to placebo in MTX-IR subjects with RA on stable MTX therapy by assessment of the signs and symptoms of RA, as measured by DAS28-hsCRP remission (DAS28 < 2.6) rate at Week 12
    • To further evaluate the efficacy and dose response of 12 weeks of treatment with evobrutinib in MTX-IR subjects with RA on stable MTX therapy by assessment of the signs and symptoms of RA, as measured by ACR50 and ACR70 at Week 12
    • To evaluate the safety of evobrutinib in MTX-IR subjects with RA on stable MTX thera
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    MRI sub-study (date and version of protocol)
    Approximately 50% of subjects in selected sites will participate in a substudy using magnetic resonance imaging (MRI) to evaluate the ability of Evobrutinib to prevent the progression of joint structural damage. These subjects will have hand and wrist MRI images
    Objectives
    • To evaluate the effect of evobrutinib on joint structures and inflammation, at Week 4 and Week 12 in the MRI substudy, as assessed by magnetic resonance imaging (MRI)
    E.3Principal inclusion criteria
    The current trial will enroll subjects who fulfill the following key inclusion criteria:
    • Consenting male or female subjects, 18 to 75 years of age
    • Confirmed diagnosis of RA according to 2010 ACR/EULAR RA classification criteria of at least 6 months duration prior to Screening
    • Persistently active moderate to severe RA at both Screening and Randomization (if significant surgical treatment of a joint has been performed, that joint cannot be counted for entry or enrollment purposes), as defined by:
    o ≥ 6 swollen joints (of 66 assessed) and
    o ≥ 6 tender joints (of 68 assessed).
    • An hsCRP ≥ 5.0 mg/L (≥ 0.50 mg/dL) at Screening
    • Treatment for ≥ 16 weeks with 7.5 to 25 mg/week MTX at a stable dose and route of administration (oral or parenteral) for at least 8 weeks prior to dosing with the IMP and maintained throughout the trial
    • For subjects entering the trial on MTX doses < 15 mg/week, there must be clear documentation in the medical record that higher doses of MTX were not tolerated or that the dose of MTX is the highest acceptable dose based on local clinical practice guidelines.
    MRI Substudy Subjects:
    In addition to meeting the inclusion criteria for the study, subjects must have palpable synovitis of the wrist and/or ≥ 1 of MCP joints #1 to #5, defined as loss of bony contours with palpable joint effusion and/or swelling, in the MRI-designated hand (i.e., the hand being used in MRI assessments).
    E.4Principal exclusion criteria
    Subjects who fulfill any of the following key exclusion criteria should not be enrolled into this trial:
    • ACR functional class IV as defined by the ACR classification of functional status or wheelchair/bedbound
    • Use of oral corticosteroids > 10 mg daily prednisone equivalent, or change in dose of corticosteroids within 2 weeks prior to Screening or during Screening
    • Use of injectable corticosteroids (including intra-articular corticosteroids) or intra-articular hyaluronic acid within 4 weeks prior to Screening or during Screening
    • Initiation or change in dose for nonsteroidal anti-inflammatory drugs (NSAIDs) (including low-dose aspirin and COX-2 inhibitors) within 2 weeks prior to dosing with the IMP
    • High potency opioid analgesics are prohibited within 2 weeks prior to Screening and during the trial; other analgesics are allowed (e.g., acetaminophen, codeine, hydrocodone, propoxyphene, or tramadol), although not within 24 hours of study visits with clinical assessments.
    • Current or prior treatment with ANY of the following:
    o Biologic DMARDs (approved or investigational), including but not limited to:
    -TNF antagonists or biosimilars of these agents (approved or investigational), or any investigational TNF antagonist
    - Interleukin-6 antagonists
    - Abatacept (CTLA4-Fc)
    - Anakinra (IL-1 receptor antagonist)
    - B cell-depleting antibodies (e.g., rituximab, ocrelizumab, ofatumumab, obinutuzumab, ocaratuzumab, veltuzumab, or any biosimilars of these agents [approved or investigational])
    - Anti-BLyS (B lymphocyte stimulator) agents (e.g., belimumab, tabalumab)
    - Dual BLyS/A proliferation-inducing ligand (APRIL) neutralizing agents (e.g., atacicept, RCT-18).
    o Targeted synthetic DMARDs (approved or investigational), specifically:
    - Janus kinase inhibitors
    - Other Bruton’s tyrosine kinase (BTK) inhibitors
    o Alkylating agents (e.g., chlorambucil, cyclophosphamide).
    • The following restrictions on non-biologic DMARD must be followed, otherwise the subject is excluded:
    o Auranofin (Ridaura®), minocycline, penicillamine, sulfasalazine, cyclosporine, mycophenolate, tacrolimus, azathioprine: must have been discontinued for 4 weeks prior to dosing with the IMP
    o Leflunomide (Arava®) must have been discontinued 12 weeks prior to dosing with the IMP if no elimination procedure is followed. Alternately, it should have been discontinued with the following elimination procedure at least 4 weeks prior to dosing with the IMP: Cholestyramine at a dosage of 8 g 3 times a day for at least 24 hours, or activated charcoal at a dosage of 50 g 4 times a day for at least 24 hours.
    o Injectable Gold (aurothiglucose or aurothiomalate): must have been discontinued for 8 weeks prior to dosing with the IMP
    o Anti-malarials (hydroxychloroquine, chloroquine) will be allowed in this trial. Subjects may be taking oral hydroxychloroquine (≤ 400 mg/day) or chloroquine (≤ 250 mg/day), doses must have been stable for at least 12 weeks prior to dosing with the IMP, and will need to be continued at that stable dose for the duration of the trial. If discontinued prior to this trial, they must have been discontinued for 4 weeks prior to dosing with the IMP.
    MRI Substudy Subjects:
    • Inability to comply with MRI scanning, including contraindications to MRI such as known allergy to gadolinium contrast media, claustrophobia (if the site does not have ability to scan extremities only), presence of a pacemaker, cochlear implants, ferromagnetic devices or clips, intracranial vascular clips, insulin pumps, and nerve stimulators
    • More than 25% of applicable joints of the target hand and wrist having had prior surgery or showing maximum Genant-modified Sharp erosion (3.0) or joint-space narrowing (4.0) scores, based on single posteroanterior radiographs of target hand and wrist read centrally.
    E.5 End points
    E.5.1Primary end point(s)
    Number of Subjects With ACR20 response assessed using hsCRP (ACR20-CRP)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 12
    E.5.2Secondary end point(s)
    1) Number of subjects With DAS28-hsCRP low disease activity (DAS28 < 3.2) rate
    2) Number of subjects With DAS28-hsCRP remission (DAS28 < 2.6) rate
    3) Number of subjects with ACR 50% (ACR50) response assessed using hsCRP (ACR50-CRP)
    4) Number of subjects with ACR 70% (ACR70) response assessed using hsCRP (ACR70-CRP)
    5) Nature, severity and Occurrences of Subjects With of AEs and serious AEs (SAEs)
    6)Absolute value in vital signs
    7) Absolute value in ECG parameters including RR interval, PR interval,
    QRS duration, QT interval, and QTcF interval
    8) Absolute value in Serum Ig levels (IgG, IgA, IgM)
    9) Absolute value in Total B cell counts
    10) Absolute value in Clinical laboratory parameters
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-4:Week 12
    5-10 Baseline up to Week 12
    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 Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarker, quality of life; Health resource utilization (HRU), Imaging
    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 Yes
    E.8.2.3.1Comparator description
    Different dosage of IMP (25mg QD, 75 mg QD, 50 mg BID)
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA66
    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
    Brazil
    Bulgaria
    Chile
    Colombia
    Czech Republic
    Germany
    Japan
    Mexico
    Poland
    Russian Federation
    Serbia
    South Africa
    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
    Last subject’s end of trial visit
    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 months11
    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 months11
    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: 308
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 55
    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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    the elderly
    F.4 Planned number of subjects to be included
    F.4.1In the member state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 199
    F.4.2.2In the whole clinical trial 363
    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)
    After a subject has completed the trial or has withdrawn early, the subject is free to access further treatment as deemed appropriate by the Treating Investigator
    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 Decision2017-09-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-02
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-09-23
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