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    Summary
    EudraCT Number:2007-005434-37
    Sponsor's Protocol Code Number:IM101-174
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-05-26
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2007-005434-37
    A.3Full title of the trial
    A Phase IIIB Multicenter, Randomized, Double-Blind, Double-Dummy Study to
    Compare the Efficacy and Safety of Abatacept Administered Subcutaneously and
    Intravenously in Subjects with Rheumatoid Arthritis, Receiving Background
    Methotrexate, and Experiencing an Inadequate Response to Methotrexate. (Short title: MTX-IR Study)

    Revised Protocol 04 incorporating Protocol amendment 11 (v1.0 date 15-Jun-2010) and Administrative Letter 01. And Pharmacogenetics Blood sample Amendment - Site Specific (v1.0, date 07-Sep-2007).
    A.3.2Name or abbreviated title of the trial where available
    MTX-IR Study
    A.4.1Sponsor's protocol code numberIM101-174
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBristol Myers Squibb International Corporation
    B.1.3.4CountryBelgium
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Orencia
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Company
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameAbatacept (IV)
    D.3.2Product code BMS-188667
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAbatacept
    D.3.9.1CAS number 332348-12-6
    D.3.9.2Current sponsor codeBMS-188667
    D.3.9.3Other descriptive nameCTLA4Ig
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Yes
    D.3.11.13.1Other medicinal product typeFusion protein
    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 nameAbatacept (SC)
    D.3.2Product code BMS-188667
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNAbatacept
    D.3.9.1CAS number 332348-12-6
    D.3.9.2Current sponsor codeBMS-188667
    D.3.9.3Other descriptive nameCTLA4Ig
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number125
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Yes
    D.3.11.13.1Other medicinal product typeFusion protein
    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 infusion
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 2
    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
    RHEUMATOID ARTHRITIS, NOS
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    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 for this study is to demonstrate that subcutaneous (SC)
    injections of abatacept are non-inferior to intravenous (IV) infusions of abatacept in ACR 20 responses after 6 months of treatment in subjects who have active RA, are receiving methotrexate and experiencing an inadequate response to methotrexate.
    E.2.2Secondary objectives of the trial
    1) Assess the proportion of subjects with ACR 50 response at month 6 (Day 169).
    2) Assess the proportion of subjects with ACR 70 response at month 6 (Day 169).
    3) Assess the pharmacokinetics of SC injections of abatacept.
    4) Assess the immunogenicity of abatacept.
    5) Assess the change in physical function as measured by the HAQ disability index at
    Month 6 (Day 169).
    6) Assess the proportion of subjects with a HAQ response as measured by a reduction of at least 0.3 unit from baseline in the HAQ disability index at Month 6 (Day 169)
    7) Assess the safety and tolerability of SC injections of abatacept.

    Subjects receiving SC injections of abatacept will be assessed relative to subjects
    receiving IV infusions of abatacept.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Signed Written Informed Consent
    a) Subject is willing to participate in the study and signed the informed consent.

    2) Target Population
    a) Subjects must meet the criteria of the American Rheumatism Association (1987)
    for the diagnosis of rheumatoid arthritis and the American College of Rheumatology (1991) functional Classes I, II, or III. (Protocol Appendices 3 and 4).
    b) Subjects must have had rheumatoid arthritis for more than 1 year from the initial
    diagnosis. Not Applicable per Amendment 03.
    c) Subjects with stable renal, endocrine, hepatic, hematological, gastrointestinal,
    pulmonary, cardiac, neurological or cerebral disease(s) (eg, diabetes mellitus,
    congestive heart failure, chronic obstructive pulmonary disease) will be allowed
    to participate in this study.
    d) Subjects who are considered methotrexate inadequate responders by a treating
    physician or investigator. Subjects must have been taking methotrexate for at least
    3 months at a minimal weekly dose of 15 mg, and at a stable dose for 28 days
    prior to randomization (Day 1). A methotrexate weekly dose as low as 10 mg is
    permitted for subjects who can not tolerate higher doses. In this circumstance, the
    10 mg weekly dose will be permitted if there is verifiable documentation in the
    medical record prior to entry into the study that the subject could not tolerate
    higher doses. Use of parenteral methotrexate is acceptable as clinically indicated.

    3) Age and Sex
    a) Men and women, ages ≥ 18
    Women of childbearing potential (WOCBP) must be using an adequate method of
    contraception to avoid pregnancy throughout the study and for up to 10 weeks after the last dose of abatacept in such a manner that the risk of pregnancy is minimized.

    4) Concomitant medication
    Informed consent must be signed before making any changes in RA therapy, if those
    are solely for the purpose of this study.
    a) Drug stabilization requirements:
    Oral corticosteriod treatment must have been reduced to the equivalent of ≤ 10 mg
    prednisone daily for 28 days and stabilized for at least 25 out of 28 days prior to treatment (Day 1). No intra-articular or IM injections of corticosteriods are permitted
    within 28 days prior to treatment (Day 1).
    b) Washout requirements:
    Subjects receiving methotrexate monotherapy will not require a washout. Subjects
    receiving combination RA therapy should discontinue their DMARDs (other than methotrexate) at least 28 days prior to treatment (Day 1).
    Required washout periods (prior to Day 1):
    At least 4 weeks for
    − Gold
    − Azathioprine
    − Cyclosporin A and other Calcineurin inhibitors
    − D-Penicillamine
    − mycophenylate mofetil (CellCept®)
    − Immunoadsorption columns
    At least 8 weeks for
    − Leflunomide (or perform active wash-out with cholestyramine according to
    the manufacturer’s recommendations).

    5) Disease Activity Requirements
    The disease activity requirements will depend on whether the subject requires a
    washout period (see Inclusion Criteria #4).
    a) For subjects receiving methotrexate monotherapy (no washout):
    At randomization (Day 1), subjects must have the following disease activity:
    i) 10 or more swollen joints (66 joint count) and
    ii) 12 or more tender joints (68 joint count) and
    iii) C reactive protein (hsCRP) ≥ 0.8 mg/dL (result used from screening visit).
    b) For subjects receiving methotrexate plus other DMARDs (washout):
    At screening visit, subjects must have the following disease activity:
    i) 6 or more swollen joints (66 joint count) and
    ii) 8 or more tender joints (68 joint count) and
    iii) no restriction on hsCRP
    After washout, at randomization (Day 1), subjects must have the following disease
    activity:
    i) 10 or more swollen joints (66 joint count) and
    ii) 12 or more tender joints (68 joint count) and
    iii) Creactive protein (hsCRP) ≥ 0.8 mg/dL (result used from screening or Day -3
    visit).

    6) Subjects must be willing to self-inject or allow a caregiver to do it for them.

    7) Subjects must be able to adhere to the study visit schedule, understand, and comply with other protocol requirements.
    E.4Principal exclusion criteria
    1)Sex & Reproductive Status
    a)WOCBP unwilling or unable to use an acceptable method to avoid
    pregnancy for entire study period & up to 10 weeks after last dose of
    investigational product
    b)pregnant or breastfeeding Women
    c)Women with positive pregnancy test on enrollment or prior to IMP administration

    2)Target Disease Exceptions
    a)Subjects who meet diagnostic criteria for any other rheumatic disease (eg, lupus
    erythematous)
    b)Subjects with active vasculitis of a major organ system (except for subcutaneous
    rheumatoid nodules)

    3)Medical History & Concurrent Diseases
    a)Subjects who are impaired, incapacitated, or incapable of completing study
    related assessments
    b)Current symptoms of severe, progressive, or uncontrolled renal, hepatic,
    hematological, gastrointestinal, pulmonary, cardiac, neurological, or cerebral
    disease. Concomitant medical conditions that, in opinion of the investigator,
    might place subject at unacceptable risk for participation in this study
    c)Female subjects who have had breast cancer screening study that is suspicious
    for malignancy & in whom the possibility of malignancy cannot be reasonably
    excluded following additional clinical, laboratory or other diagnostic evaluations
    (Protocol Section 6.3.6)
    d)Subjects with history of cancer within the last 5 years (other than nonmelanoma skin cell cancers cured by local resection). Existing non-melanoma
    skin cell cancers must be removed prior to dosing. Subjects with carcinoma in
    situ, treated with definitive surgical intervention prior to study entry, are allowed
    e)Subjects who have clinically significant drug or alcohol abuse
    f)Subjects with serious acute bacterial infection (such as pneumonia or
    pyelonephritis unless treated & completely resolved with antibiotics)
    g)Subjects with severe chronic or recurrent bacterial infections (such as recurrent
    pneumonia, chronic bronchiectasis)
    h)Subjects at risk for TB. Specifically subjects with:
    i)Current clinical, radiographic or laboratory evidence of active or latent TB
    ii)A history of active TB within the last 3 years even if it was treated.
    iii)A history of active TB > 3 years ago unless there is documentation
    that prior anti-TB treatment was appropriate in duration & type
    iv)Latent TB which was not successfully treated. Subjects with a positive TB
    screening test indicative of latent TB will not be eligible for the study unless
    active TB infection has been ruled out & they have initiated treatment for
    latent TB with isoniazid (INH) for at least 4 weeks prior to dosing of study
    drug and they have a negative chest X-ray at enrollment. Such subjects should
    complete 9 months of INH treatment
    i)Subjects with herpes zoster that resolved < 2 months prior to enrollment
    j)Subjects with evidence (as assessed by investigator) of active or latent
    bacterial or viral infections at time of potential enrollment, including subjects
    with evidence of HIV infection

    4)Physical & Laboratory Test Findings
    a)Hepatitis B surface antigen-positive subjects
    b)Hepatitis C antibody-positive subjects who are also RIBA-positive or PCR
    positive
    c)Subjects with any of following laboratory values:
    i)Hgb <8.5 g/dL
    ii)WBC <3,000/mm³
    iii)Platelets <100,000/mm³
    iv)Serum creatinine >2 x upper limit of normal
    v)Serum ALT or AST >2 x upper limit of normal
    vi)Any other laboratory test results that might place subject at unacceptable risk
    for participation in this study

    5)Allergies & Adverse Drug Reactions
    None

    6)Prohibited Treatments &/or Therapies
    a)Subjects who have received treatment with rituximab
    b)Subjects who have had prior exposure to abatacept (CTLA4-Ig)
    c)Subjects exposed to any investigational drug within 4 weeks or 5 half-lives, whichever is longer
    d)Subjects currently (or in last 3 months) receiving treatment with azathioprine,
    gold, leflunomide, immunoadsorption columns (such as Prosorba columns),
    mycophenylate mofetil (CellCept®), cyclosporin A, other calcineurin inhibitors or
    D-Penicillamine. Not applicable per Amendment 03.
    e)Subjects who have received any live vaccines within 3 months of study drug
    administration or are scheduled to receive live vaccines
    f)Subjects currently (at time of informed consent) treated with an anti-TNF
    therapy, such as Adalimumab and Infliximab (within 8 weeks of last dose), or
    Etanercept (within 4 weeks of last dose)
    g)Subjects having discontinued an anti-TNF therapy due to lack of efficacy in the
    past
    h)Subjects exposed to multiple anti-TNF therapies
    i)Subjects currently treated with anakinra unless a minimum 4-week wash-out
    period has been completed before Day 1
    j)Subjects that received prior treatment with any investigational biologic not
    currently approved

    7)Other
    a)Involuntarily incarcerated subjects or prisoners
    b)Subjects who are compulsorily detained for treatment of either psychiatric or
    physical (eg infectious disease) illness
    c)Illiterate Subjects
    E.5 End points
    E.5.1Primary end point(s)
    The primary analysis will assess the proportion of subjects meeting the ACR criteria of 20% improvement (ACR 20) after 6 months (Day 169). The ACR 50, ACR 70 and HAQ will also be assessed.

    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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
    Immunogenicity
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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
    comparison of 2 different administration routes of Abatacept
    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 EEA75
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    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 Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 517
    F.4.2.2In the whole clinical trial 2400
    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 Decision2008-07-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-06-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-09-12
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