A Phase III Study of Abatacept in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00409838
First received: December 8, 2006
Last updated: August 6, 2013
Last verified: August 2013
  Purpose

The purpose of the study is to demonstrate the clinical efficacy of abatacept (body-weight tiered dose approximating 10 mg/kg) compared with placebo on a background of methotrexate after 6 months (Day 169) of treatment in Korean patients with active rheumatoid arthritis and an inadequate clinical response to methotrexate


Condition Intervention Phase
Rheumatoid Arthritis
Drug: Abatacept
Drug: Methotrexate
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III, Multi-center, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Abatacept Administered Intravenously in Korean Subjects With Active Rheumatoid Arthritis While Receiving Methotrexate

Resource links provided by NLM:


Further study details as provided by Bristol-Myers Squibb:

Primary Outcome Measures:
  • Percentage of Participants Meeting the Criteria of the American College of Rheumatology for 20% Improvement (ACR20) [ Time Frame: At Day 169 ] [ Designated as safety issue: No ]
    The ACR 20 is based on 20% improvement (compared with baseline values) in tender and swollen joint counts and on 20% improvement in 3 of the remaining 5 core set measures (participant global assessment of pain, participant global assessment of disease activity, physician global assessment of disease activity, participant assessment of physical function) and 1 acute phase reactant value.

  • Long-term Extension (LTE) (Open-Label) Period: Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Related SAEs, Discontinuatons Due to SAEs, Adverse Events (AEs), Related AEs, and Discontinuations Due to AEs [ Time Frame: Day 169 to up to 56 days post the last dose (Day 1485) in the LTE period ] [ Designated as safety issue: Yes ]
    AE=any new untoward medical occurrence or worsening of a preexisting medical condition which does not necessarily have a causal relationship with this treatment. Related AE=relationship of certain, probable, possible, or missing. 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 the development of drug dependency or drug abuse, is an important medical event.


Secondary Outcome Measures:
  • Percentage of Participants With American College of Rheumatology (ACR) ACR50 and ACR70 Response at Day 169 [ Time Frame: At Day 169 ] [ Designated as safety issue: No ]
    The ACR defines ACR 50 and ACR70 response as a 50% or 70% improvement (compared with baseline values) in tender and swollen joint counts and 50% or 70% improvement in 3 of the remaining 5 core set measures (patient global assessment of pain, patient global assessment of disease activity, physician global assessment of disease activity, subject assessment of physical function) and 1 acute phase reactant value (C-reactive protein).

  • Percentage of Participants With at Least 20%, 50%, or 70% Improvement From Baseline in American College of Rheumatology (ACR) Core Components [ Time Frame: From Baseline to Day 169 ] [ Designated as safety issue: No ]
    The ACR defines improvement in core components as 20%, 50%, or 70% improvement in tender and swollen joint counts and 3 of the remaining core components: patient global assessment of disease activity, physician global assessment of disease activity, patient assessment of pain, patient self-assessed disability (Health Assessment Questionnaire Disability Index [HAQ-DI]), and levels of 1 acute phase reactant (C-reactive protein levels or erythrocyte sedimentation rate.) The HAQ-DI assesses a patient's level of functional ability via 20 questions in 8 categories of functioning; scale=0 (no disability) to 3 (completely disabled); total possible score=24. The higher the score, the greater the disability.

  • Change From Baseline in Disease Activity Scores (DAS) Based on C-reactive Protein (DAS 28 [CRP]) Levels or Erythrocyte Sedimentation Rate (DAS 28[ESR]) [ Time Frame: From Baseline to Days 169 and 1485 ] [ Designated as safety issue: No ]
    Adjusted mean change from baseline. The DAS28 provides a score on a scale from 0 to 10 indicating the current activity of rheumatoid arthritis (>5.1=high disease activity; <3.2=low disease activity; <2.6=remission). CRP or ESR give estimations of DAS28 values on a group level. Change from Baseline=Postbaseline - Baseline value.

  • Change From Baseline to Day 169 in Health Assessment Questionnaire Disability Index (HAQ-DI) Score [ Time Frame: From Baseline to Day 169 ] [ Designated as safety issue: No ]
    Adjusted mean change from baseline. The HAQ-DI assesses a patient's level of functional ability via 20 questions in 8 categories of functioning. Patients respond on a scale from 0 (no disability) to 3 (completely disabled); total possible score=24. Higher score indicates greater disability. Change from baseline= postbaseline - baseline value.

  • Change From Baseline to Day 169 in Analysis of Short-Form 36 (SF-36) Health Survey Questionnaire Domains [ Time Frame: From Baseline to Day 169 ] [ Designated as safety issue: No ]
    Adjusted mean change from baseline. The SF-36 is a 36-item self-administered questionnaire developed to assess health-related quality of life and comprised of 8 domains( including 4 physical and 4 mental subscales) used to derive the physical and mental component summary scores. All subscales were scored using norm-based methods that standardized the scores to a mean of 50 and a standard deviation of 10 in the general population. The scores range from 0 to 100, with a higher score indicating better quality of life. Change from baseline=postbaseline - baseline value.

  • Percentage of Participants Experiencing Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), Related SAEs and AEs, and Discontinuations Due to SAEs and AEs During the Double-Blind Period [ Time Frame: Throughout double-blind study period (up to Day 169); table includes data up to 56 days past double-blind period or start of the open-label period, whichever occurred first. ] [ Designated as safety issue: Yes ]
    AE=any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. Related AE=relationship of certain, probable, possible, or missing. 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 the development of drug dependency or drug abuse, is an important medical event.

  • Abatacept Pharmacokinetic (PK) Parameters: Time to Maximum Concentration (Tmax) and Half-Life of Elimination (T-Half) [ Time Frame: At the end of infusion and 2 to 4 hours after the start of infusion on Day 85, at anytime between Day 92 and 96, and pre-dose on Day 113 ] [ Designated as safety issue: No ]
    Steady-state PK parameters following administration of body-weight tiered doses approximating 10 mg/kg. Tmax = the time after administration of a drug when the maximum plasma concentration is reached; when the rate of absorption equals the rate of elimination. T-Half = the biological half-life or elimination half life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity.

  • Abatacept Pharmacokinetic (PK) Parameters - Maximum Concentration (Cmax) [ Time Frame: At the end of infusion and 2 to 4 hours after the start of the infusion on Day 85, at anytime between Day 92 and 96, and pre-dose on Day 113 ] [ Designated as safety issue: No ]
    Steady-state PK parameters following administration of body-weight tiered doses approximating 10 mg/kg. Maximum Concentration (Cmax)= the maximum plasma concentration of the drug.

  • Abatacept Pharmacokinetic (PK) Parameters - Area Under the Curve (AUC) [ Time Frame: At the end of infusion, 2 to 4 hours after the start of infusion on Day 85, anytime between Day 92 and 96, and predose on Day 113 ] [ Designated as safety issue: No ]
    Area Under the Plasma Concentration-Time Curve (AUC), a measure of drug absorption, in a dosing interval of 28 days from Day 85 to Day 113. Steady-state PK parameters following administration of body-weight tiered doses approximating 10 mg/kg.

  • Abatacept Pharmacokinetic (PK) Parameters: Total Body Clearance (CLT) [ Time Frame: Day 29, every 28 days until Day 141 ] [ Designated as safety issue: No ]
    Steady-state PK parameters following administration of body-weight tiered doses approximating 10 mg/kg. Clearance is a pharmacokinetic parameter that describes how quickly drugs are eliminated, metabolized or distributed throughout the body.

  • Abatacept Pharmacokinetic (PK) Parameters: Volume at Steady State (VSS) [ Time Frame: At the end of infusion, 2 to 4 hours after the start of infusion on Day 85, anytime between Day 92 and 96, and predose on Day 113 ] [ Designated as safety issue: No ]
    The volume of distribution of drug at steady state (VSS). Steady-state PK parameters following administration of body-weight tiered doses approximating 10 mg/kg.

  • Summary Statistics of Minimum Observed Serum Concentration (Cmin) for Abatacept [ Time Frame: At the end of infusion and 2 to 4 hours after the start of the infusion on Day 85 ] [ Designated as safety issue: No ]
    Minimum concentration (Cmin) of Abatacept 500 mg and 750 mg at given time points

  • Immunogenicity of Abatacept- Number of Participants With Reactivity Toward CTLA4-IG and CTLA4-T at Day 169 [ Time Frame: Day 169 ] [ Designated as safety issue: No ]
    Immunogenicity was determined by measuring adult subject sera for reactivity against the whole Abatacept molecule (CTLA4Ig) and CTLA4-T (CTLA4 without the Ig regions).

  • Change From Baseline in Surrogate Marker Erythrocyte Sedimentation Rate (ESR) at Day 169 [ Time Frame: From Baseline to Day 169 ] [ Designated as safety issue: No ]
    Mean change in surrogate marker mean ESR. A surrogate marker is an indirect measurement of effectiveness. Change from Baseline = postbaseline - baseline value.

  • Change From Baseline in Surrogate Marker Rheumatoid Factor (RF) at Day 169 [ Time Frame: Baseline, Day 169 ] [ Designated as safety issue: No ]
    Mean change in RF. A surrogate marker is an indirect measurement of effectiveness. Mean change from Baseline = postbaseline - baseline value.

  • LTE Period: Overall Number of Participants With Positive Results of Immunogenicity Samples [ Time Frame: Days 169, at 6-month intervals on-treatment, and at Days 28, 56, and 85 after the last infusion of study medication in the LTE period ] [ Designated as safety issue: No ]
    Positive antibody titers were identified by validated enzyme-linked immunosorbent assay results. On-treatment samples were obtained during the LTE period, and posttreatment samples were following the last infusion of study medication.

  • Percentage of Participants Achieving ACR20, ACR50, and ACR70 Over Time [ Time Frame: Days 15 through 1569 ] [ Designated as safety issue: No ]
    The ACR 20, ACR50, and ACR70 are based on 20%, 50% and 70% improvement, respectively, (compared with baseline values) in tender and swollen joint counts and on 20%, 50% and 70%, respectively, improvement in 3 of the remaining 5 core set measures (participant global assessment of pain, participant global assessment of disease activity, physician global assessment of disease activity, participant assessment of physical function) and 1 acute phase reactant value.

  • Percentage of Participants With Physical Function Response as Assessed Using the Health Assessment Questionnaire Disability Index (HAQ-DI) [ Time Frame: At Day 1485 ] [ Designated as safety issue: No ]
    Improvement is measured by an improved response of at least 0.3 units from baseline on the HAQ-DI score. The HAQ-DI assesses a patient's level of functional ability via 20 questions in 8 categories of functioning. Patients respond on a scale from 0 (no disability) to 3 (completely disabled); total possible score=24. Higher score indicates greater disability. Change from baseline= postbaseline - baseline value.

  • Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score [ Time Frame: Day 1485 ] [ Designated as safety issue: No ]
    The HAQ-DI assesses a patient's level of functional ability via 20 questions in 8 categories of functioning. Patients respond on a scale from 0 (no disability) to 3 (completely disabled); total possible score=24. Higher score indicates greater disability. Change from baseline= postbaseline - baseline value.

  • Changes From Baseline in Short-Form 36 (SF-36) Physical and Mental Health Summaries [ Time Frame: At Day 1485 ] [ Designated as safety issue: No ]
    The SF-36 is a 36-item questionnaire used to measure Quality of Life over 8 physically and emotionally based areas: physical functioning, role limitations due to physical health, role limitations due to emotional problems, energy/fatigue, emotional well-being, social functioning, pain, and general health. Answers to each question correspond to a precoded numeric value. An aggregate percentage score is reached for each of the 8 sections and is based on answers to questions. The mean average is worked out for each section. Scores range from 0% (lowest level of functioning) to 100% (highest level of functioning, with higher score indicated increasing levels of functioning.

  • Percentage of Participants With European League Against Rheumatism (EULAR)-Defined Low Disease Activity Score (LDAS) and With EULAR-defined Remission [ Time Frame: At Days 169 and 1485 ] [ Designated as safety issue: No ]
    EULAR defines LDAS as a disease activity score as measured by c-reactive protein (DAS28-CRP) ≤3.2 and remission as DAS28-CRP <2.6

  • Changes From Baseline in the Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI) Scores [ Time Frame: At Days 169 and 1569 ] [ Designated as safety issue: No ]
    The SDAI is the sum of 5 parameters: Tender joint (TJC) and swollen joint(SJC)counts, based on a 28-joint assessment; patient global (PtGA)and physician global assessments (PGA), assessed on 0-10 cm visual analog scale (VAS), on which higher scores=greater affection due to disease activity DA); and C-reactive protein level. SDAI total score=0-86. SDAI <=3.3 indicates disease remission, >3.4 to 11=low DA, >11 to 26=moderate DA, and >26=high DA. SJC is assessed at each visit, with no swelling=0, swelling=1. TJC is assessed through identification of joints painful under pressure or to passive motion at each visit, with no tenderness=0, tenderness=1. Higher score=greater affection due to DA. CDAI is sum of 4 parameters: TJC and SJC (based on a 28-joint assessment), PtGA and PGA (assessed on 0-10 cm VAS; higher scores=greater affection due to disease activity). CDAI total score=0-76. CDAI <=2.8 indicates disease remission, >2.8 to 10=low DA, >10 to 22=moderate DA, and >22=high DA.

  • Percentage of Participants With Low Disease Activity Score (LDAS) or Who Are in Remission [ Time Frame: At Days 169, 337, 729, 1149, and 1485 ] [ Designated as safety issue: No ]
    LDAS is defined as a Disease Activity Score C-reactive protein (DAS28-CRP) level <=3.2. Remission is defined as a DAS28-CRP level <2.6.

  • Change From Baseline in Levels of C-reactive Protein (CRP) [ Time Frame: Days 169 to 1569 ] [ Designated as safety issue: No ]
  • Change From Baseline in Erythrocyte Sedimentation Rate [ Time Frame: Days 169 to 1569 ] [ Designated as safety issue: No ]

Enrollment: 113
Study Start Date: April 2007
Study Completion Date: December 2011
Primary Completion Date: July 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Abatacept and Methotrexate Drug: Abatacept
Intravenous (IV) solution, - weight tiered (500 mg <60 kg); (750 mg 60-100 kg); (1 gram > 100 kg), Day 1, Day 15, Day 29; every 28 days thereafter, 6 months
Other Names:
  • Orencia
  • BMS-188667
Drug: Methotrexate
Tablets, Oral, ≥ 15 mg, weekly, 6 months
Placebo Comparator: Placebo and Methotrexate
(standard of care)
Drug: Methotrexate
Tablets, Oral, ≥ 15 mg, weekly, 6 months
Drug: Placebo
IV solution, Intravenous, D5W, Day 1, Day 15, Day 29; every 28 days thereafter, 6 months
Experimental: Abatacept - Open Label
Open-label extension phase
Drug: Abatacept
Solution, intravenous, 10 mg/kg, every 28 days
Other Names:
  • Orencia
  • BMS-188667
Drug: Methotrexate
Tablets, oral, 15 mg weekly to be adjusted according to patient condition

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Rheumatoid arthritis (RA) for longer than 1 year from the time of the initial diagnosis of RA
  • Patients must have been taking methotrexate for at least 3 months with at least a weekly dose of 15 mg, and a stable dose for 28 days prior to treatment (Day 1)
  • Methotrexate weekly dose as low as 10 mg is permitted for patients who cannot tolerate higher doses

Key Exclusion Criteria:

  • Evidence (as assessed by the Investigator) of active or latent bacterial or viral infections at the time of potential enrollment
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00409838

Locations
Korea, Republic of
Local Institution
Seoul, Sungdong-Gu, Korea, Republic of, 133-792
Local Institution
Anyang, Korea, Republic of, 431-070
Local Institution
Daegu, Korea, Republic of, 705-718
Local Institution
Daejeon, Korea, Republic of, 302-799
Local Institution
Seoul, Korea, Republic of, 138-736
Local Institution
Seoul, Korea, Republic of, 137-040
Local Institution
Seoul, Korea, Republic of, 110-744
Sponsors and Collaborators
Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
No publications provided

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00409838     History of Changes
Other Study ID Numbers: IM101-124
Study First Received: December 8, 2006
Results First Received: November 16, 2009
Last Updated: August 6, 2013
Health Authority: Korea: Food and Drug Administration

Keywords provided by Bristol-Myers Squibb:
Rheumatoid Arthritis, with inadequate response to methotrexate

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Abatacept
Methotrexate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on September 30, 2014