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    Summary
    EudraCT Number:2004-000922-59
    Sponsor's Protocol Code Number:IM101-043
    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:2004-10-13
    Trial results Removed from public view
    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 number2004-000922-59
    A.3Full title of the trial
    A Phase III, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Comparative
    Study of Abatacept or Infliximab in Combination with Methotrexate in Controlling
    Disease Activity in Subjects with Rheumatoid Arthritis Having an Inadequate Clinical
    Response to Methotrexate.

    Revised Protocol 1 , incorporating Amendment 02 (v5.0).
    Pharmacogenomic Amendment 01.
    Protocol Amendment 03 - Long-Term Extension.
    Protocol Amendment 05 - Long Term Extension Site Specific (V2.0, Date 23-Dec-2006).
    A.4.1Sponsor's protocol code numberIM101-043
    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 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
    D.3.2Product code BMS-188667
    D.3.4Pharmaceutical form Powder for solution for injection
    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 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 Remicade
    D.2.1.1.2Name of the Marketing Authorisation holderCentocor B.V. - Einsteinweg 101 - 2333 CB Leiden - Netherlands
    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 nameRemicade
    D.3.4Pharmaceutical form Powder for solution for injection
    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 INNInfliximab
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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) 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 typeChimeric IgCl Monodonal Antibody
    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 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 placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Rheumatoid Arthrithis, Nos
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate that the abatacept in combination with methotrexate will demonstrate a greater reduction in disease activity than placebo in combination with methotrexate as measured by the disease activity score (DAS28) at 6 months (Day 197).

    Long-Term extension (amendment 03)

    To assess the safety and long-term tolerability of abatacept in subjects who have completed the initial 12-month double-blind treatment period.

    Secondary objectives will be to assess efficacy and immunogenicity of abatacept in combination with background DMARDs during this long-term extension phase (see protocol amendment 03 - section 2.2).

    Long-Term extension (amendment 05)

    to assess the safety and long-term tolerability of abatacept in subjects who will continue in the long-term extension.

    Secondary objectives will be to assess the immunogenicity of abatacept in combination with methotrexate.
    E.2.2Secondary objectives of the trial
    * To demonstrate that infliximab in combination with methotrexate will demonstrate a greater reduction in disease activity than placebo in combination with methotrexate as measured by the disease activity score (DAS28) at 6 months.
    * Compare the reduction in disease activity over time as measured by the DAS28 area under the curve (DAS28AUC) over 12 months in subjects receiving abatacept versus infliximab in combination with methotrexate.
    * Assess the change in physical function and the subject’s health-related quality of life as measured by the disability index of the HAQ and the SF-36 questionnaire
    respectively, in subjects receiving placebo, abatacept, or infliximab in combination
    with methotrexate at 6 months and 12 months
    * Determine the proportion of subjects treated with abatacept or infliximab at
    12 months who demonstrate a good, moderate or no response according to the EULAR response criteria.
    (see protocol for additional secondary objectives).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    * Subject is willing to participate in the study and signed the informed consent.
    * 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. (Refer to protocol appendices 1 and 2.)
    * Subjects must have been taking methotrexate for at least 3 months at a weekly dose of at least 15 mg, and at a stable dose for 28 days prior to treatment (Day 1)
    * Men and women, ages 18 ≤ 75 years old. Men and Women of childbearing potential are eligible if they are practicing effective contraceptive measures.
    * Methotrexate alone: Subjects who are treated only with methotrexate will not require washout.
    * Methotrexate plus other DMARDs: Subjects who are treated with methotrexate in
    combination with another anti-rheumatic treatment (DMARD) will require washout
    of the other DMARD.
    * Drug stabilization requirements (except methotrexate)
    a) All DMARDs (except methotrexate) should be discontinued at least 28 days prior
    to treatment (Day 1).
    i) In the case of leflunomide, the subject can be washed out with cholestyramine
    according to manufacturer recommendations.
    b) Oral corticosteroid 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).
    For Subjects Receiving Methotrexate Alone:
    At randomization (Day 1), subjects must have the following disease activity:
    a) 10 or more swollen joints (66 joint count) and
    b) 12 or more tender joints (68 joint count) and
    c) C-reactive protein (CRP) ≥ 1 mg/dL (Result used from screening visit)
    For Subjects Receiving Other DMARDs Plus Methotrexate:
    At screening visit, subjects must have the following disease activity:
    a) 6 or more swollen joints (66 joint count) and
    b) 8 or more tender joints (68 joint count) and
    c) No restriction on CRP
    IN ADDITION
    All subjects who are receiving other DMARDs plus methotrexate therapy at the screening visit must undergo a 28 day washout period of their other anti-rheumatic treatment (DMARD) (other than methotrexate).
    After washout at randomization (Day 1), subjects must have the following disease
    activity:

    a) 10 or more swollen joints (66 joint count) and
    b) 12 or more tender joints (68 joint count) and
    c) C reactive protein (CRP) ≥ 1 mg/dL. (Result used from Day -3 visit).

    Long-Term Extension (Protocol Amendment 03)

    Subjects must be willing to participate in the long term extension and sign consent. Subjects who enter the long term extension must continue to meet Inclusion/ Exclusion criteria as outlined in Protocol IM101043 and/or all subsequent amendments, with the exception of tender and swollen joint counts, CRP, dose of methotrexate, PPD skin testing, and male contraception use requirement.
    E.4Principal exclusion criteria
    * WOCBP who are unwilling or unable to use an acceptable method to avoid
    pregnancy for the entire study period and for up to 10 weeks after the last infusion of abatacept
    * Any previous or current medical conditions that are contraindications to the use of
    TNF blocking agents. (Please refer to Appendix 11 and 12 Remicade Labels)
    * Subjects who have previously received treatment with an approved biologic RA
    therapy (Infliximab, Etanercept, Anakinra, Adalimumab).
    * Subjects who have failed more than 4 DMARDs (including methotrexate) due to lack
    of efficacy (DMARDs approved for the treatment of RA include methotrexate,hydroxycholoroquine, sulfasalzine, leflunomide, azathioprine, and gold).
    * Subjects with active vasculitis of a major organ system (except for subcutaneous
    rheumatoid nodules).
    * Current symptoms of severe, progressive, or uncontrolled renal, hepatic,
    hematological, gastrointestinal, pulmonary, cardiac, neurological, or cerebral disease.
    * Female subjects, who have not had age and/or risk factor appropriate breast cancer screening or who have had a breast cancer screening study that is suspicious for malignancy, and in whom the possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory or other diagnostic evaluations
    * Subjects with a history of cancer within the last five years (other than non-melanoma skin cell cancers cured by local resection). Existing non-melanoma skin cell cancers must be removed prior to dosing.
    * Subjects with active tuberculosis (TB) requiring treatment within the previous
    3 years. Subjects with a positive PPD at screening will not be eligible for the study
    unless active TB infection has been ruled out, they have initiated treatment for latent
    TB for at least 4 weeks prior to dosing of study drug, and they have a negative chest
    x-ray at enrollment.
    * Hepatitis B surface antigen-positive subjects.
    * Hepatitis C antibody-positive subjects who are also RIBA-positive or PCR-positive.
    * Subjects with any of the following laboratory values:
    • Hgb < 8.5 g/dL.
    • WBC < 3,000/mm3 (3 x 109/L)
    • Platelets < 100,000/mm3 (100 x 109/L).
    • Serum creatinine > 2 times upper limit of normal.
    • Serum ALT or AST > 2 times upper limit of normal.
    E.5 End points
    E.5.1Primary end point(s)
    The primary end point will be the comparison of abatacept versus placebo for changes from baseline to 6 months (Day 197) in the DAS28.

    Long-Term Extension (Protocol Amendment 03)

    Efficacy analyses will be done in 3-month intervals over the course of the long term extension.
    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 No
    E.6.7Pharmacodynamic Yes
    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 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) 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 Yes
    E.8.1.7.1Other trial design description
    Placebo arm for 6 months+ Double dummy design.
    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.8.3 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 EEA10
    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 years3
    E.8.9.1In the Member State concerned months8
    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 months8
    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.1.3Elderly (>=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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 660
    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 Decision2004-11-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2004-12-01
    P. End of Trial
    P.End of Trial StatusCompleted
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