Clinical trial NCT00162266: Abatacept With Methotrexate- Phase IIB
Official title: A Phase IIB, Multi-Center, Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Safety and Clinical Efficacy of Two Different Doses of BMS-188667 Administered Intravenously to Subjects With Active Rheumatoid Arthritis While Receiving Methotrexate
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rheumatoid Arthritis
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2005-09-13
Enrollment: 524
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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

Primary outcomes:
measure: Number of Responders to American College of Rheumatology 20% Improvement Criteria (ACR 20) at Day 180 of the Double-Blind (DB) Period
timeFrame: Day 180
measure: Participants Receiving Concomitant Disease Modifying Rheumatic Drugs and Biologics in Open-Label (OL) Period
timeFrame: Day 360 to Day 3,060
measure: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) in OL Period
timeFrame: Day 360 to Day 3060
measure: Number of Participants With AEs of Special Interest in OL Period
timeFrame: Day 360 to Day 3060
measure: Baseline Serum Immunoglobulin A (IgA) Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720,1080, 1440, and 1800
measure: Mean Change From Baseline (BL) in IgA Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, and 1800
measure: Baseline Immunoglobulin G (IgG) Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440 and 1800
measure: Mean Change From Baseline (BL) in IgG Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, and 1800
measure: Baseline Immunoglobulin M (IgM) Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720,1080,1440, and 1800
measure: Mean Change From Baseline (BL) in IgM in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, and 1800
measure: Number of Participants With Hematology Values Meeting Marked Abnormality Criteria in OL Period
timeFrame: Day 360 to Day 3060
measure: Number of Participants With Liver and Kidney Function Values Meeting Marked Abnormality Criteria in OL Period
timeFrame: Day 360 to Day 3060
measure: Number of Participants With Electrolyte Values Meeting Marked Abnormality Criteria in OL Period
timeFrame: Day 360 to Day 3060
measure: Number of Participants With Glucose, Protein, Metabolites, and Urinalysis Values Meeting Marked Abnormality Criteria in OL Period
timeFrame: Day 360 to Day 3060
Secondary outcomes:
measure: Number of ACR 20 Responders in DB Period
timeFrame: Days 15, 30, 60, 90, 120, 150,180, 240, 300, and 360
measure: Number of ACR 50 Responders in DB Period
timeFrame: Day 15; Day 30; Day 60; Day 90; Day 120; Day 150; Day 180; Day 240; Day 300; Day 360
measure: Number of ACR 70 Responders in DB Period
timeFrame: Day 15; Day 30; Day 60; Day 90; Day 120; Day 150; Day 180; Day 240; Day 300; Day 360
measure: ACR Numeric Values (ACR-N)
timeFrame: Day 15; Day 30; Day 60; Day 90; Day 120; Day 150; Day 180; Day 240; Day 300; Day 360
measure: ACR-N Area Under The Curve (AUC) on Day 180 and Day 360
timeFrame: Baseline and Day 180; Baseline and Day 360
measure: Individual Components of ACR Criteria--Mean Percentage Change From Baseline at Day 180
timeFrame: Baseline, Day 180
measure: Individual Components of ACR Criteria--Mean Percentage Change From Baseline at Day 360
timeFrame: Baseline, Day 360
measure: Mean Changes From Baseline in the Short Form 36 (SF-36) Physical and Mental Health Component Summary Scores (PCS and MCS) at Day 180 and Day 360
timeFrame: Baseline, Day 180, Day 360
measure: Adjusted Mean Percent Changes From Baseline in the Modified Health Assessment Questionnaire (mHAQ) at Day 180 and Day 360
timeFrame: Baseline, Day 180, Day 360
measure: Number of Participants With At Least One New Active Joint (Tender Joints and Swollen Joints) at Day 180 and Day 360
timeFrame: Day 180, Day 360
measure: Participants Who Experienced Death, Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations During the Double-Blind Period
timeFrame: From the start of study through the end of the double-blind period (at 12 months)
measure: Participants With Laboratory Abnormalities Meeting the Marked Abnormality Criteria for Selected Blood Chemistry Values During Double-Blind Therapy
timeFrame: From the start of study up to 60 days post the end of the 12-month double-blind period
measure: Participants With Laboratory Abnormalities Meeting the Marked Abnormality Criteria for Selected Hematologic Values During Double-Blind Therapy
timeFrame: From the start of study up to 60 days post the end of the 12-month double-blind period
measure: Number of Participants Who Discontinued Due to Lack of Efficacy in the DB and OL Periods
timeFrame: Day 1 to Day 360 (Double-Blind Period), Day 361 to Day 3060 (Open-Label Period)
measure: Immunogenicity Data: Anti-CTLA4Ig Antibodies With Immunoglobulin (IG) Region
timeFrame: Baseline, Days 30, 90, 180, 270, 360
measure: Immunogenicity Data: Anti-CTLA4Ig Antibodies Without IG Region
timeFrame: Baseline, Days 30, 90, 180, 270, 360
measure: Immunogenicity Data: Categories of Post Baseline Value to Baseline Value (VA/PRE) Ratios and Number of Participants With Sero-conversion (Anti-CTLA4Ig Antibodies With IG Region)
timeFrame: Baseline, Days 30, 90, 180, 270, 360
measure: Immunogenicity Data: Categories of Post Baseline Value to Baseline Value (VA/PRE) Ratios and Number of Participants With Sero-conversion(Anti-CTLA4Ig Antibodies Without IG Region)
timeFrame: Baseline, Days 30, 90, 180, 270, 360
measure: Pharmacodynamic Measure: Mean Changes From Baseline in Rheumatoid Factor at Day 180 and Day 360
timeFrame: Baseline, Day 180, Day 360
measure: Pharmacodynamic Measure: Mean Changes From Baseline in Interleukin-6 at Day 180 and Day 360
timeFrame: Baseline, Day 180, Day 360
measure: Pharmacodynamic Measure: Mean Changes From Baseline in Plasma Soluble Interleukin-2 Receptor (sIL-2R) at Day 180 and Day 360
timeFrame: Baseline, Day 180, Day 360
measure: Pharmacodynamic Measure: Mean Changes From Baseline in E-Selectin at Day 180 and Day 360
timeFrame: Baseline, Day 180, Day 360
measure: Pharmacodynamic Measure: Mean Changes From Baseline in Soluble Inter-Cellular Adhesion Molecule 1 (sICAM-1) at Day 180 and Day 360
timeFrame: Baseline, Day 180, Day 360
measure: Pharmacodynamic Measure: Mean Changes From Baseline in Tumor Necrosis Factor (TNF)-Alpha at Day 180 and Day 360
timeFrame: Baseline, Day 180, Day 360
measure: Number of ACR 20 Responders in OL Period
timeFrame: Days 360, 450, 540, 630, 720, 810, 900, 1080, 1350, 1440, 1530, 1620, 1710, 1800, 1980, 2160, 2340, 2520, 2700, 2880, and 3060
measure: Number of ACR 50 Responders in the OL Period
timeFrame: Days 360, 450, 540, 630, 720, 810, 900, 1080, 1350, 1440, 1530, 1620, 1710, 1800, 1980, 2160, 2340, 2520, 2700, 2880, and 3060
measure: Number of ACR 70 Responders in the OL Period
timeFrame: Days 360, 450, 540, 630, 720, 810, 900, 1080, 1350, 1440, 1530, 1620, 1710, 1800, 1980, 2160, 2340, 2520, 2700, 2880, and 3060
measure: Number of Participants With a Clinically Meaningful Improvement on the Modified Health Assessment Questionnaire (mHAQ) in OL Period
timeFrame: Days 360, 720,1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Baseline Level of Serum Rheumatoid Factor Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720,1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Change From Baseline in Serum Rheumatoid Factor Level Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720,1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Baseline Soluble Serum Interleukin-2 Receptor Level (sIL2-r) Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720,1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Change From Baseline in sIL2-r Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, and 1800
measure: Mean Baseline Serum C-Reactive Protein Level Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080,1440,1800, 2160, 2520, 2880, 3060
measure: Mean Change From Baseline in Level of C Reactive Protein Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, 3060
measure: Mean Baseline Physical Component Summary (PCS) of the Short-Form 36 (SF-36) Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2880, and 3060
measure: Mean Change From Baseline (BL) in the Physical Component Summary (PCS) of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2880, and 3060
measure: Mean Baseline Mental Component Summary (MCS) of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2880, and 3060
measure: Mean Change From Baseline (BL) in the MCS of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 450, 540, 630, 720, 810, 900, 1080, 1350, 1440, 1530, 1620, 1710, 1800, 1980, 2160, 2340, 2520, 2700, 2880, and 3060
measure: Mean Baseline (BL) Physical Functioning Domain of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Change From Baseline (BL) in the Physical Functioning Domain of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Baseline Role-Physical Domain of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Change From Baseline (BL) in the Role-Physical Domain of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Baseline Bodily Pain Domain of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Change From BL in the Bodily Pain Domain of the SF-36 Over Time in OL Period
timeFrame: BL (Day 0); Day 360; Day 720; Day 1,080; Day 1,440; Day 1,800; Day 2,160; Day 2,520; Day 2,880; Day 3,060
measure: Mean BL General Health Domain of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Change From Baseline (BL) in the General Health Domain of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Baseline Vitality Domain of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Change From Baseline (BL) in the Vitality Domain of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Baseline Social Functioning Domain of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Change From Baseline (BL) in the Social Functioning Domain of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Baseline Role-Emotional Domain of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Change From Baseline (BL) in the Role-Emotional Domain of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Baseline Mental Health Domain of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060
measure: Mean Change From Baseline (BL) in the Mental Health Domain of the SF-36 Over Time in OL Period
timeFrame: Baseline (Day 0) and Days 360, 720, 1080, 1440, 1800, 2160, 2520, 2880, and 3060
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Local Institution
state: Alabama
city: Huntsville
country: United States
facility: Local Institution
state: Alabama
city: Long Beach
country: United States
facility: Local Institution
state: California
city: Highlands Ranch
country: United States
facility: Local Institution
state: Colorado
city: Largo
country: United States
facility: Local Institution
state: Florida
city: Titusville
country: United States
facility: Local Institution
state: Florida
city: West Palm Beach
country: United States
facility: Local Institution
state: Florida
city: Rome
country: United States
facility: Local Institution
state: Georgia
city: Chicago
country: United States
facility: Local Institution
state: Illinois
city: Wichita
country: United States
facility: Local Institution
state: Kansas
city: Cumberland
country: United States
facility: Local Institution
state: Maryland
city: Springfield
country: United States
facility: Local Institution
state: Massachusetts
city: Worcester
country: United States
facility: Local Institution
state: Massachusetts
city: Duluth
country: United States
facility: Local Institution
state: Minnesota
city: Lincoln
country: United States
facility: Local Institution
state: Nebraska
city: Albuquerque
country: United States
facility: Local Institution
state: New Mexico
city: Los Alamos
country: United States
facility: Local Institution
state: New Mexico
city: Albany
country: United States
facility: Local Institution
state: New York
city: Binghamton
country: United States
facility: Local Institution
state: New York
city: Bronx
country: United States
facility: Local Institution
state: New York
city: Portland
country: United States
facility: Local Institution
state: Oregon
city: Duncansville
country: United States
facility: Local Institution
state: Pennsylvania
city: Sellersville
country: United States
facility: Local Institution
state: Pennsylvania
city: Amarillo
country: United States
facility: Local Institution
state: Texas
city: Austin
country: United States
facility: Local Institution
state: Texas
city: Dallas
country: United States
facility: Local Institution
state: Texas
city: Quilmes
country: Argentina
facility: Local Institution
state: Burenos Aires
city: Buenos Aries
country: Argentina
facility: Local Institution
city: Adelaide
country: Australia
facility: Local Institution
state: South Australia
city: Malvern
country: Australia
facility: Local Institution
state: Victoria
city: Perth
country: Australia
facility: Local Institution
state: Western Australia
city: Antwerpen
country: Belgium
facility: Local Institution
city: Bruxelles
country: Belgium
facility: Local Institution
city: Gent
country: Belgium
facility: Local Institution
city: Leuven
country: Belgium
facility: Local Institution
city: Mons
country: Belgium
facility: Local Institution
city: Edmonton
country: Canada
facility: Local Institution
state: Alberta
city: Ottawa
country: Canada
facility: Local Institution
state: Ontario
city: Toronto
country: Canada
facility: Local Institution
state: Ontario
city: Montreal
country: Canada
facility: Local Institution
state: Quebec
city: Sherbrooke
country: Canada
facility: Local Institution
state: Quebec
city: Ste-Foy
country: Canada
facility: Local Institution
state: Quebec
city: St. John
country: Canada
facility: Local Institution
city: Montpellier
country: France
facility: Local Institution
state: Cedex
city: Strasbourg
country: France
facility: Local Institution
state: Cedex
city: Paris
country: France
facility: Local Institution
city: Berlin
country: Germany
facility: Local Institution
city: Freiburg
country: Germany
facility: Local Institution
city: Jena
country: Germany
facility: Local Institution
city: Cork
country: Ireland
facility: Local Institution
city: Nijmegen
country: Netherlands
facility: Local Institution
city: Muckleneuk
country: South Africa
facility: Local Institution
state: Gauteng
city: Cape Town
country: South Africa
facility: Local Institution
state: Western Cape
city: Cambridge
country: United Kingdom
facility: Local Institution
state: Cambridgeshire
city: Manchester
country: United Kingdom
facility: Local Institution
state: Greater Manchester
city: Maidstone
country: United Kingdom
facility: Local Institution
state: Kent
city: Leeds
country: United Kingdom
facility: Local Institution
state: Yorkshire
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: Westhovens R, Kremer JM, Emery P, Russell AS, Alten R, Barre E, Dougados M. Long-term safety and efficacy of abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: a 7-year extended study. Clin Exp Rheumatol. 2014 Jul-Aug;32(4):553-62. Epub 2014 Jul 8.