Abatacept With Methotrexate- Phase IIB

This study was conducted to assess the safety and tolerability of Abatacept combined with Methotrexate in participants with active rheumatoid arthritis (RA). The secondary objectives were to assess efficacy, pharmacodynamic marker activity, and immunogenicity of Abatacept combined with Methotrexate.

All participants who completed the 12-month double-blind study period were eligible to continue in the open-label study. Participants received placebo, Abatacept 2 mg/kg, or Abatacept 10 mg/kg in the double-blind study. Participants receiving placebo in the double-blind study were switched 1:1 to continued treatment with placebo or Abatacept 2 mg/kg. Participants receiving Abatacept 2 mg/kg or Abatacept 10 mg/kg continued at the double-blind study dosage. After results from the double-blind period became available, all participants were switched to a weight-tiered 10 mg/kg dose of Abatacept.

Open label study design: Single group assignment, Single arm, Open label,

Eligibility Criteria:
Inclusion Criteria:

Double blind study phase:

1. Males or females (not nursing and not pregnant), at least 18 years of age. Women of child bearing potential (WOCBP) are eligible if they are practicing effective contraceptive measures
2. 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
3. Subjects have been taking Methotrexate (10-30 mg weekly) for at least 6 months, and at a stable dose for 28 days prior to treatment
4. Washout/drug stabilization requirements (except Methotrexate) \[Informed consent must be signed before making any changes in RA therapy if those changes are solely for the purpose of this study\].

   * Leflunomide or Infliximab have already been discontinued at least 60 days prior to enrollment (prior to signing of informed consent) and a total of 90 days prior to treatment. All other Disease Modifying Anti-Rheumatic Drugs (DMARDs) (except Methotrexate) have been withdrawn at least 28 days prior to treatment
   * Oral corticosteroid treatment has been reduced to the equivalent of 10 mg or less prednisone daily and stabilized for at least 28 days prior to enrollment
5. Eligibility of subjects for the study is based on their disease activity and anti-rheumatic treatment at the initial visit:

   * Methotrexate monotherapy: Subject is receiving only Methotrexate, steroids, Non-steroidal anti-inflammatory drugs (NSAIDs) and will not require washout
   * Combination therapy: Subject is receiving Methotrexate in combination with another DMARD(s) and will require washout

   At entry, Methotrexate monotherapy must have a disease activity:
   * 10 or more swollen joints (66 joint count)
   * 12 or more tender joints (68 joint count)
   * C reactive protein (CRP) ≥.1 mg/dL (10 mg/L) at "Screening" visit

   At entry, combination therapy must have a disease activity (if subject does not satisfy the above):
   * 6 or more swollen joints (66 joint count)
   * 8 or more tender joints (68 joint count)
   * No restriction on C-reactive protein (CRP)

   In addition

   All subjects who were on combination therapy at entry must undergo a 28 day washout period of DMARDs other than Methotrexate. After the washout/drug stabilization and prior to randomization such subjects must have:
   * 10 or more swollen joints (66 joint count)
   * 12 or more tender joints (68 joint count)
   * C reactive protein (CRP) ≥ 1 mg/dL (10 mg/L)
6. Subject is willing to participate in the study and willing to sign the informed consent

Open label study phase:

* Participants that have completed the initial short term portion (double blind) of the study

Exclusion Criteria:

Double blind study phase:

1. Subjects who have at any time received treatment with BMS-188667 (Abatacept)
2. Subjects who within 30 days of the Day 1 visit have received treatment with any investigational drug
3. Subjects with active vasculitis of a major organ system (except for subcutaneous rheumatoid nodules)
4. Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, neurological, or cerebral disease. Concomitant medical conditions that in the opinion of the investigator might place the subject at unacceptable risk for participation in this study
5. Mammogram requiring further investigation or biopsies leading to the diagnosis of a clinically significant abnormality. Complete evaluation of lesion is required before initiation of dosing
6. Subjects with a history of cancer within the last five years (other than non-melanoma skin cell cancers cured by local resection)
7. Subjects who have a history of clinically significant drug or alcohol abuse, or admit to consumption of more than 1 alcoholic drink per day
8. Subjects with evidence (as assessed by the investigator) of active or latent bacterial or viral infections at the time of potential enrollment, including subjects with evidence of Human Immunodeficiency Virus (HIV) infection, or hepatitis B or C infection
9. Subjects with any serious or chronic infections such as pneumonia, pyelo-nephritis, renal infection, chest infection with bronchiectasis, or sinusitis in the previous 3 months
10. Subjects with active tuberculosis requiring treatment within the previous 3 years
11. Subjects with any opportunistic infections such as herpes zoster or cytomegalovirus (CMV) within the previous 2 months
12. Subjects with severe asthma defined as \> 3 emergency room admissions in the last year or \> 3 treatments with oral steroids for asthma in the last year
13. A history of either angioedema or anaphylaxis that was associated with a reaction to a drug
14. Subjects with the following laboratory values:

    * Hemoglobin \< 8.5 g/dL
    * White blood cells \< 3000/mm3
    * Platelets \< 100,000/mm3
    * Serum creatinine \> 2 times upper limit of normal
    * Serum Alanine aminotransferase (ALAT) or Aspartate aminotransferase (ASAT) \> 2 times upper limit of normal
    * Any other lab values that in the opinion of the investigator might place the subject at unacceptable risk for participation in this study

Open label study phase:

* Participants must continue to meet inclusion/exclusion criteria as in the short term (double blind) phase of the protocol except subjects who have receiving other than Abatacept