Clinical Trials/NCT00048581

NCT00048581

Completed

Phase 3

A Phase III, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of BMS-188667 in Subjects With Active Rheumatoid Arthritis on Background Disease Modifying Anti-Rheumatic Drugs (DMARDS) Who Have Failed Anti-Tumor Necrosis Factor (TNF) Therapy

Bristol-Myers Squibb1 site in 1 country738 target enrollmentDecember 2002

ConditionsRheumatoid Arthritis

InterventionsAbatacept Placebo

DrugsAbatacept Placebo

Overview

Phase: Phase 3
Intervention: Abatacept
Conditions: Rheumatoid Arthritis
Sponsor: Bristol-Myers Squibb
Enrollment: 738
Locations: 1
Primary Endpoint: DB; Number of Participants Achieving Clinically Meaningful Improvement in Health Assessment Questionnaire (HAQ)
Status: Completed
Last Updated: 14 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

The purpose of this clinical research study is to determine whether abatacept treatment on a background of Disease Modifying Antirheumatic Drugs (DMARDs) will relieve the symptoms of rheumatoid arthritis (RA) in participants who are currently receiving anti-tumor necrosis factor (TNF) therapy for at least 3 months and are not responding or have taken anti-TNF therapy in the last 3 months and did not respond. The safety of treatment with abatacept will also be evaluated. This study also has a 4.5-year long-term extension beginning 6 months after the start of the study.

Registry

clinicaltrials.gov

Start Date

December 2002

End Date

September 2009

Last Updated

14 years ago

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

Bristol-Myers Squibb

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

Not provided

Exclusion Criteria

•Women who are pregnant or breast feeding
•Current symptoms of serious medical disease
•History of cancer in last 5 years other than non-melanoma skin cancer
•Chronic serious infection
•Active TB requiring treatment in last 5 years
•Herpes zoster in last 2 months
•Any active viral infection including Human Immunodeficiency Virus (HIV)
•Serious side effects associated with previous anti-TNF therapy

Arms & Interventions

Abatacept

Short Term Portion of Study

Intervention: Abatacept

Placebo

Short Term Portion of Study

Intervention: Placebo

Abatacept (Long Term)

Long Term Portion of Study: All participants receive Active Drug

Intervention: Abatacept

Outcomes

Primary Outcomes

DB; Number of Participants Achieving Clinically Meaningful Improvement in Health Assessment Questionnaire (HAQ)

Time Frame: Day 169

The disability section of the full HAQ includes 20 questions to assess physical functions in 8 domains: dressing, arising, eating, walking, hygiene, reach, grip and common activities. The questions are evaluated on a 4-point scale: 0=without any difficulty, 1= with some difficulty, 2= with much difficulty, and 3= unable to do. Higher scores= greater dysfunction. A disability index was calculated by summing the worst scores in each domain and dividing by the number of domains answered. Clinically meaningful HAQ response=an improvement of at least 0.3 units from baseline in HAQ disability Index.

OL; Mean Time-matched Baseline Immunoglobulin (Ig) Levels Over the OL

Time Frame: Baseline and Days 169, 365, 729, and 1093

Serum samples collected from participants were used to determine serum levels of IgA, IgM, and IgG. Time-matched baseline values were presented by visit and represented the mean baseline value for only that cohort of participants with serum samples available at that visit.

OL; Number of Participants With Hematology Laboratories Meeting Marked Abnormality Criteria

Time Frame: From first day of OL to 5.5 years

Upper Normal Limit (ULN), Lower Normal Limit (LLN), Baseline (BL). Marked abnormality criteria are: Hemoglobin (HGB): \>3 g/dL decrease from BL; Hematocrit: \<0.75 \* BL; Erythrocytes: \<0.75 \* BL; Platelets (PLT): \<0.67 \* LLN/\>1.5 \* ULN, or if BL \< LLN then use 0.5 \* BL/\<100,000 mm\^3; Leukocytes: \<0.75 \* LLN/ \>1.25 \* ULN, or if BL\<LLN then use \<0.8 \* BL/\>ULN, or if BL\>ULN then use \>1.2 \* BL/\<LLN; neutrophils+bands: \<1.0 \* 10\^3 c/uL; eosinophils: \>0.750 \* 10\^3 c/uL; basophils: \> 400 mm\^3; monocytes: \>2000 mm\^3; lymphocytes: \<0.750 \* 10\^3 c/uL/ \>7.50 \* 10\^3 c/uL.

Open-Label Period (OL); Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, or AEs Leading to Discontinuation

Time Frame: From first day of OL to 5.5 years

AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with treatment. SAE=any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event.Related AE/SAE=Certain,Probable,Possible,or Missing relationship to Drug

OL; Number of Participants AEs of Special Interest

Time Frame: From first day of OL to 5.5 years

AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. AEs of special interest are those AEs that may be associated with the use of immunomodulatory drugs, including all infections, serious infections, and opportunistic infections; autoimmune disorders; neoplasms; acute infusional AEs (pre-specified AEs occurring within 1 hour of start of infusion) and peri-infusional AEs (pre-specified AEs occurring within 24 hours of the start of infusion).

OL; Number of Participants With Blood Chemistry Laboratories Meeting Marked Abnormality Criteria

Time Frame: From first day of OL to 5.5 years

Marked abnormality criteria: Alkaline phosphatase (ALP): \>2\* ULN, or if BL\>ULN then use \>3\* BL; aspartate aminotransferase (AST): \>3\* ULN, or if BL\>ULN then use \>4\* BL; alanine aminotransferase (ALT): \>3\* ULN, or if BL\>ULN then use \>4\* BL; G-Glutamyl transferase (GGT): \>2\* ULN, or if BL\>ULN then use \>3\* BL; Bilirubin: \>2\* ULN, or if BL\>ULN then use \>4\* BL; blood urea nitrogen (BUN): \>2\* BL; creatinine: \>1.5\* BL

Double-blind Period (DB); Number of Participants With American College of Rheumatology (ACR) 20 Response at Day 169

Time Frame: Day 169

ACR 20 response requires a participant to have a 20% reduction in the number of swollen and tender joints, and a reduction of 20% in three of the following five parameters: physician global assessment of disease, participant global assessment of disease, participant assessment of pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in Health Assessment Questionnaire (HAQ) score. A participant achieved a sustained ACR 20 response if the participant had ACR 20 observed for at least 2 consecutive study visits.

OL; Mean Time-matched Change From Baseline in Immunoglobulin (Ig) Levels Over the OL

Time Frame: BL, Days 169, 365, 729, and 1093

Serum samples collected from participants were used to determine serum levels of IgA, IgM, and IgG. Time-matched mean change from baseline = Post-baseline value - time-matched baseline value, where the time-matched baseline value represents the mean baseline value for only that cohort of participants with serum samples available at that visit.

Secondary Outcomes

DB; Mean Change From Baseline to Day 169 in Levels of Disease Biomarkers (IL-6, sIL-2R, and TNF-alpha) in Participants With Measurements at Day 169(BL, Day 169)
DB; Mean Time-Matched Percentage of Change From Baseline in TJC Over Time: ACR Core Component(BL, Days 15, 29, 57, 85, 113, 141, and 169)
DB; Mean Time-matched Baseline Swollen Joint Count (SJC) and Post-Baseline SJCs Over Time: ACR Core Component(Days 15, 29, 57, 85, 113, 141, and 169)
DB; Mean Time-Matched Percentage of Change From Baseline in Participant Global Assessment Over Time: ACR Core Component(BL, Days 15, 29, 57, 85, 113, 141, and 169)
DB; Mean Time-Matched Percentage of Change From Baseline in Physician Global Assessment Over Time: ACR Core Component(BL, Days 15, 29, 57, 85, 113, 141, and 169)
DB; Mean Time-matched Baseline Tender Joint Counts (TJCs) and Post-Baseline TJCs Over Time: ACR Core Component(BL)
DB; Mean Time-matched Baseline Participant Pain Assessment Over Time: ACR Core Component(BL)
DB; Mean Time-matched Baseline Participant Global Assessment Over Time: ACR Core Component(BL)
DB; Mean Time-Matched Percentage of Change From Baseline in CRP Levels Over Time: ACR Core Component(Days 15, 29, 57, 85, 113, 141, and 169)
DB; Mean Baseline Levels of Disease Biomarkers (Interleukin-6 (IL-6), Soluble IL-2 Receptor [sIL-2R], and Tumor Necrosing Factor [TNF]-Alpha) in Participants With Measurements at Day 169(BL)
DB; Number of Participants With ACR 20, ACR 50, and ACR 70 Responses Over Time(Days 15, 29, 57, 85, 113, 141, and 169)
DB; Mean Time-matched Baseline HAQ-DI Over Time: ACR Core Component(BL)
DB; Mean Time-Matched Percentage of Change From Baseline in HAQ-DI Over Time: ACR Core Component(BL, Days 15, 29, 57, 85, 113, 141, and 169)
DB; Mean Time-matched Baseline Physician Global Assessment Over Time: ACR Core Component(BL)
DB; Adjusted Mean Change From Baseline to Day 85 in Short SF-36 PCS, MCS, and SF-36 Individual Component Scores(BL, Day 85)
DB; Mean Time-Matched Percentage of Change From Baseline in SJC Over Time: ACR Core Component(Days 15, 29, 57, 85, 113, 141, and 169)
DB; Mean Time-Matched Percentage of Change From Baseline in Participant Pain Assessment Over Time: ACR Core Component(BL, Days 15, 29, 57, 85, 113, 141, and 169)
DB; Mean Baseline Levels of Disease Biomarkers (E-Selectin, Soluble Inter-Cellular Adhesion Molecule 1 [sICAM-1], and Matrix Metalloproteinase-3 [MMP-3]) in Participants With Measurements at Day 169(BL)
DB; Mean Change From Baseline to Day 169 in Rheumatoid Factor (RF) Status(BL, Day 169)
DB; Mean Baseline Short Form 36 (SF-36) Quality of Life Physical Component Summary (PCS), Mental Component Summary (MCS), and SF-36 Individual Component Scores For Participants With Measurements at Day 85(BL)
DB; Mean Baseline HAQ-DI and HAQ Component Scores in Participants With Assessments at Day 169(BL)
DB; Mean Time-matched Baseline C-Reactive Protein (CRP) Levels Over Time: ACR Core Component(BL)
DB; Adjusted Mean Change From Baseline to Day 169 in SF-36 PCS, MCS, and SF-36 Individual Component Scores For Participants With Measurements at Day 169(BL, Day 169)
DB; Mean Disease Activity Score (DAS)28 (C-Reactive Protein [CRP]) and Mean Disease Activity Score (Erythrocyte Sedimentation Rate [ESR]) at Day 169(BL, Day 169)
DB; Adjusted Mean Change From Baseline to Day 169 in DAS28 (CRP) and DAS28 (ESR)(BL, Day 169)
OL; Number of Participants With Low Disease Activity (LDAS) or Remission For Participants Treated in the OL(Days 15, 29, 57, 85, 113, 141, 169, 253, 365, 449, 533, 617, 729, 813, 897, 981, 1093, 1261, 1457, 1625, and 1821)
DB; Mean Change From Baseline to Day 169 in Levels of Disease Biomarkers (E-Selectin, sICAM-1, and MMP-3) in Participants With Measurements at Day 169(BL, Day 169)
DB; Number of Participants With Blood Chemistry Laboratories Meeting MA Criteria(From BL up to database lock for DB period (6/2/2004))
OL; Mean Time-matched Baseline DAS28 (ESR) Over Time For Participants Treated in the OL(BL)
OL; Mean Time-matched Change From Baseline in Levels of RF Over Time For Participants Treated in the OL(BL, Days 169, 365, 729, 1093, 1261, 1457, and 1821)
OL; Mean Time-matched Change From Baseline in ESR Over Time For Participants Treated in the OL(BL, Days 169, 365, 729, 1093, 1261, 1457, and 1821)
OL; Mean Time-matched Baseline SF-36 PCS and MCS Over Time For Participants Treated in OL(BL)
DB; Mean Baseline SF-36 PCS, MCS, and SF-36 Individual Component Scores For Participants With Measurements at Day 169(BL)
DB; Adjusted Mean Change From Baseline to Day 169 in HAQ-DI and HAQ Component Scores in Participants With Assessments at Day 169(BL, Day 169)
DB; Number of Participants With Death, Serious Adverse Events (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs, Related AEs, or AEs Leading to Discontinuation(From BL up to database lock for DB period (6/2/2004))
DB; Number of Participants With Hematology Laboratories Meeting Marked Abnormality (MA) Criteria(From BL up to database lock for DB period (6/2/2004))
DB; Number of Participants With Positive Anti-Abatacept or Anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) Responses by Enzyme-Linked Immunosorbant Assay (ELISA)(From BL to Day 169)
OL; Mean Time-matched Baseline DAS28 (CRP) Over Time For Participants Treated in the OL(BL)
DB; Number of Participants AEs of Special Interest(From BL up to database lock for DB period (6/2/2004))
OL; Mean Time-matched Change From Baseline in DAS28 (CRP) Over Time For Participants Treated in the OL(BL, Days 15, 29, 57, 85, 113, 141, 169, 253, 365, 449, 533, 617, 729, 813, 897, 981, 1093, 1261, 1457, 1625, and 1821)
OL; Number of Participants Achieving HAQ Response Over Time In Participants Treated in the OL(Days 15, 29, 57, 85, 113, 141, 169, 253, 365, 449, 533, 617, 729, 813, 897, 981, 1093, 1261, 1457, 1625, and 1821)
OL; Mean Time-matched Change From Baseline in Levels of CRP Over Time For Participants Treated in the OL(BL, Days 169, 365, 729, 1093, 1261, 1457, and 1821)
OL; Mean Time-matched Baseline Erythrocyte Sedimentation Rate (ESR) Over Time For Participants Treated in the OL(BL)
OL; Mean Time-matched Baseline Levels of Soluble Interleukin 2 Receptor (sIL-2R) Over Time For Participants Treated in the OL(BL)
OL; Mean Time-matched Baseline Role-Physical Score Over Time For Participants Treated in the OL(BL)
OL; Number of Participants With ACR 20, ACR 50, and ACR 70 Responses Over Time For Participants Treated in the OL(Days 15, 29, 57, 85, 113, 141, 169, 253, 365, 449, 533, 617, 729, 813, 897, 981, 1093, 1261, 1457, 1625, and 1821)
OL; Mean Time-matched Change From Baseline in DAS28 (ESR) Over Time For Participants Treated in the OL(BL, Days 169, 253, 365, 449, 533, 617, 729, 813, 897, 981, 1093, 1261, 1457, 1625, and 1821)
OL; Mean Time-matched Baseline HAQ-DI and HAQ Component Scores Over Time For Participants Treated in the OL(BL)
OL; Mean Time-matched Baseline Levels of Rheumatoid Factor (RF) Over Time For Participants Treated in the OL(BL)
OL; Mean Time-matched Baseline Levels of C-Reactive Protein (CRP) Over Time For Participants Treated in the OL(BL)
OL; Mean Time-matched Baseline Physical Function Score Over Time For Participants Treated in the OL(BL)
OL; Mean Time-matched Change From Baseline in Role-Emotional Score Over Time For Participants Treated in the OL(BL, Days 169, 365, 729, 1093, 1457, and 1821)
OL; Mean Time-matched Change From Baseline in HAQ-DI and HAQ Component Scores For Participants Treated in the OL(BL, Days 169, 253, 365, 449, 533, 617, 729, 813, 897, 981, 1093, 1261, 1457, 1625, and 1821)
OL; Mean Time-matched Change From Baseline in Levels of sIL-2R Over Time For Participants Treated in the OL(BL, Days 169, 365, 729, 1093, 1261, 1457, and 1821)
OL; Mean Time-matched Baseline Bodily Pain Score Over Time For Participants Treated in the OL(BL)
OL; Mean Time-matched Change From Baseline in General Health Score Over Time For Participants Treated in the OL(BL, Days 169, 365, 729, 1093, 1457, and 1821)
OL; Mean Time-matched Baseline Vitality Score Over Time For Participants Treated in the OL(BL)
OL; Mean Time-matched Baseline Medical Outcomes Study Sleep Module (MOS-sleep) Score Over Time For Participants Treated in the OL(BL)
OL; Mean Time-matched Change From Baseline in MOS-Sleep Score Over Time For Participants Treated in the OL(BL, Days 169, 365, 729, 1093, 1457, and 1821)
OL; Mean Time-matched Change From Baseline in Fatigue VAS Over Time For Participants Treated in the OL(BL, Days 169, 365, 729, 1093, 1457, and 1821)
OL; Mean Time-matched Change From Baseline in SF-36 PCS and MCS Over Time For Participants Treated in OL(BL, Days 169, 365, 729, 1093, 1457, and 1821)
OL; Mean Time-matched Change From Baseline in Physical Function Score Over Time For Participants Treated in the OL(BL, Days 169, 365, 729, 1093, 1457, and 1821)
OL; Mean Time-matched Baseline Social Functioning Score Over Time For Participants Treated in the OL(BL)
OL; Mean Time-matched Change From Baseline in Role-Physical Score Over Time For Participants Treated in the OL(BL, Days 169, 365, 729, 1093, 1457, and 1821)
OL; Mean Time-matched Change From Baseline in Bodily Pain Score Over Time For Participants Treated in the OL(BL, Days 169, 365, 729, 1093, 1457, and 1821)
OL; Mean Time-matched Change From Baseline in Social Functioning Score Over Time For Participants Treated in the OL(BL, Days 169, 365, 729, 1093, 1457, and 1821)
OL; Mean Time-matched Baseline Mental Health Score Over Time For Participants Treated in the OL(BL)
OL; Mean Time-matched Baseline General Health Score Over Time For Participants Treated in the OL(BL)
OL; Mean Time-matched Change From Baseline in Vitality Score Over Time For Participants Treated in the OL(BL, Days 169, 365, 729, 1093, 1457, and 1821)
OL; Mean Time-matched Baseline Role-Emotional Score Over Time For Participants Treated in the OL(BL)
OL; Mean Time-matched Change From Baseline in Mental Health Score Over Time For Participants Treated in the OL(BL, Days 169, 365, 729, 1093, 1457, and 1821)
OL; Mean Time-matched Baseline Fatigue Visual Analog Score (VAS) Over Time For Participants Treated in the OL(BL)
OL; Mean Time-matched Baseline Activity Limitation Score Over Time For Participants Treated in the OL(BL)
Cumulative Analysis (DB + OL); Number of Participants With Positive Anti-Abatacept or Anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) Responses by Enzyme-Linked Immunosorbent Assay (ELISA)(From BL (Day 1) to Day 1821)
OL; Mean Change From Baseline in Activity Limitation Score Over Time For Participants Treated in the OL(Days 169, 365, 729, 1093, 1457, and 1821)