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    Summary
    EudraCT Number:2012-002181-12
    Sponsor's Protocol Code Number:8457-010
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-07-09
    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 ConcernedSweden - MPA
    A.2EudraCT number2012-002181-12
    A.3Full title of the trial
    A Phase IIa, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Worldwide, Proof-of-Concept Clinical Trial to Evaluate the Safety, Tolerability, and Efficacy of MK-8457 in Subjects with Active Rheumatoid Arthritis and an Inadequate Response or Intolerance to Anti-TNF-α Therapy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase IIa POC study to evaluate Safety, Tolerability and Efficacy in Subjects with RA
    A.3.2Name or abbreviated title of the trial where available
    A Phase IIa POC study to evaluate Safety, Tolerability and Efficacy in Subjects with RA
    A.4.1Sponsor's protocol code number8457-010
    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. (hereafter referred to as
    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
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck
    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, NJ
    B.5.3.3Post code08889-0100
    B.5.3.4CountryUnited States
    B.5.4Telephone number908740-7324
    B.5.6E-mailHaoling.weng@merck.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 nameMK-8457
    D.3.2Product code MK-8457
    D.3.4Pharmaceutical form Capsule
    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 INNNone
    D.3.9.3Other descriptive nameMK-8457
    D.3.9.4EV Substance CodeSUB89445
    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 placeboCapsule
    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
    Active rheumatoid arthritis
    E.1.1.1Medical condition in easily understood language
    Rheumatoid Arthritis due to overactive immune system
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    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 determine the effects of MK-8457 100 mg BID compared to placebo over 12 weeks of treatment as measured by ACR20 response.
    To determine the safety and tolerability of MK-8457 100 mg BID compared to placebo over 12 weeks of treatment.
    E.2.2Secondary objectives of the trial
    Key Secondary: To determine the effects of MK-8457 100 mg BID compared to placebo as measured by ACR20 at Week 24; DAS28CRP change from baseline at Week 12; and ACR50 at Week 12.

    - Base Study: To determine the effects of MK-8457 100 mg BID compared to placebo as measured by
    change from baseline in DAS28CRP at Week 24; ACR50 at Week 24; and HAQ change
    from baseline at Weeks 12 and 24.

    Safety Extension: To assess the safety and tolerability of MK-8457 during the safety extension period
    through Week 100.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Subject has a diagnosis of RA for at least 6 months prior to screening.
    • Subject has active RA as defined by the presence of 6 swollen joints (of 66 joint count) AND 6 tender joints (of 68 joint count) at screening (Visit 1) and baseline (Visit 2).
    • Subject has a C-reactive protein (CRP) blood level > 0.9 mg/dL from the central reference laboratory at screening.
    • Subject is anti-cyclic citrullinated antibody positive and/or rheumatoid factor positive at screening.
    • Subject is ACR functional Class I, II, or III.
    • Subject must have received MTX for a minimum of 3 months prior to screening with a regionally appropriate stable weekly dose for at least 4 weeks prior to screening (15-25 mg/wk for regions outside of Asia, and 6-25 mg/week for Asia). The subject’s dose of weekly MTX must remain stable through week 24 of the study.
    • Subject must have either failed treatment with 1 or 2 anti-TNFtherapies or was intolerant to anti-TNFtherapy prior to screening. For subjects who have failed therapy, the treatment with anti-TNF therapies must have been for at least 3 months.

    Note: The inadequate response or intolerance to anti-TNF therapy will be defined by the Investigator’s assessment and will be recorded. Typically, an inadequate response is based on clinical reasons (e.g., no improvement or worsening of RA). Lack of access to the medication or financial reasons are not considered an inadequate response
    E.4Principal exclusion criteria
    • Subject has inflammatory disease other than RA, including but not limited to psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, or Lyme disease.
    • Previous exposure to fostamatinib or other splenic tyrosine kinase (SYK) inhibitors.
    • Previous exposure to any biological agents other than anti-TNF therapeutic agents, including but not limited to abatacept, tocilizumab, rituximab or other biological agents used for the treatment of RA.

    • Subject has received any treatment (listed in the table below) more recently than the indicated washout period prior to randomization.
    Washout Period for Medications Prior to Randomization

    Medications, Supplements, and Other Substances Washout Period Prior to Randomization
    Anti-TNF-α Therapies:
    Adalimumab
    Certolizumab
    Etanercept
    Golimumab
    Infliximab
    8 weeks
    8 weeks
    4 weeks
    8 weeks
    8 weeks
    Cyclosporine, corticosteroids¹ (parenteral, intra-articular), azathioprine, sulfasalazine, hydroxychloroquine 4 weeks
    Leflunomide² 8 weeks unless subject undergoes standard cholestyramine or activated charcoal washout in which case 4 weeks washout is required.
    Cytotoxic agents including chlorambucil, cyclophosphamide, nitrogen mustard, or other alkylating agents 3 months
    Live vaccinations 1 month
    Investigational medications 30 days or 5 half lives of the investigational agent whichever is longer
    Bacille Calmette-Guerin (BCG) vaccination 1 month

    1 Subjects will be allowed to take stable doses of oral corticosteroids as specified in inclusion criterion #10; i.e., subjects must be on a stable dose of ≤10 mg prednisone per day (or equivalent) for at least 2 weeks prior to first administration of study medications.
    2 Subjects may be allowed to use leflunomide instead of methotrexate on or after Week 24 of study treatment.
    E.5 End points
    E.5.1Primary end point(s)
    • The primary efficacy endpoint is the proportion of subjects achieving ACR20 response at Week 12.
    The primary safety endpoints are:
    • Percentage of subjects with adverse experiences;
    • Change from baseline in laboratory parameters;
    • Change from baseline in vital signs parameters;
    • Change in blood pressure from predose to 1 hour, 2 hours and 3 hours after the morning study drug dose at Week 2 and Week 12; and
    • Average change in blood pressure from predose in the 3 hours time period after am study drug dose at Week 2 and Week 12
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 12
    E.5.2Secondary end point(s)
    The key secondary efficacy endpoints are:

    • Proportion of subjects achieving ACR20 response at Week 24;
    • Change from baseline in DAS28CRP at Week 12; and
    • Proportion of subjects achieving ACR50 response at Week 12.

    Other secondary efficacy endpoints that will be evaluated include:
    • Change from baseline in DAS28CRP at Week 24;
    • Proportion of subjects achieving ACR50 response at Week 24; and
    • Change from baseline in HAQ at Weeks 12 and 24.
    Safety endpoints will also be evaluated through Week 100 of the safety extension.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Weeks 12 and 24
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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 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
    All patients will take background methotrexate (MTX).
    E.8.2.4Number of treatment arms in the trial2
    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 EEA23
    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
    Australia
    Brazil
    Colombia
    Denmark
    France
    Greece
    Hungary
    Italy
    New Zealand
    Peru
    Poland
    South Africa
    Spain
    Sweden
    United Kingdom
    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 (Post-Study Visit is the scheduled last visit for patients.)
    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 months9
    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 months2
    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: 178
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 92
    F.4.2.2In the whole clinical trial 178
    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)
    No additional follow up monitoring or treatment is planned after the patient completes the Post-Study Visit, performed 14 days after the last dose of study medication.
    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 Decision2013-04-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-08-19
    P. End of Trial
    P.End of Trial StatusCompleted
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