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

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Abatacept
* Drug: Methotrexate
* Drug: Placebo
* Drug: Abatacept
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Abatacept and Methotrexate<br> | Drug: Abatacept<br>* 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<br>* Other names: BMS-188667;Drug: Methotrexate<br>* Tablets, Oral, ≥ 15 mg, weekly, 6 months<br>|
| Placebo Comparator: Placebo and Methotrexate<br>(standard of care) | Drug: Methotrexate<br>* Tablets, Oral, ≥ 15 mg, weekly, 6 months<br>Drug: Placebo<br>* IV solution, Intravenous, D5W, Day 1, Day 15, Day 29; every 28 days thereafter, 6 months<br>|
| Experimental: Abatacept - Open Label<br>Open-label extension phase | Drug: Abatacept<br>* Solution, intravenous, 10 mg/kg, every 28 days<br>* Other names: BMS-188667;Drug: Methotrexate<br>* Tablets, oral, 15 mg weekly to be adjusted according to patient condition<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Meeting the Criteria of the American College of Rheumatology for 20% Improvement (ACR20) | 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. | At Day 169 | 
| 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 | 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. | Day 169 to up to 56 days post the last dose (Day 1485) in the LTE period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With American College of Rheumatology (ACR) ACR50 and ACR70 Response at Day 169 | 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). | At Day 169 | 
| Percentage of Participants With at Least 20%, 50%, or 70% Improvement From Baseline in American College of Rheumatology (ACR) Core Components | 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. | From Baseline to Day 169 | 
| Change From Baseline in Disease Activity Scores (DAS) Based on C-reactive Protein (DAS 28 [CRP]) Levels or Erythrocyte Sedimentation Rate (DAS 28[ESR]) | 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. | From Baseline to Days 169 and 1485 | 
| Change From Baseline to Day 169 in Health Assessment Questionnaire Disability Index (HAQ-DI) Score | 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. | From Baseline to Day 169 | 
| Change From Baseline to Day 169 in Analysis of Short-Form 36 (SF-36) Health Survey Questionnaire Domains | 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. | From Baseline to Day 169 | 
| 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 | 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. | 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. | 
| Abatacept Pharmacokinetic (PK) Parameters: Time to Maximum Concentration (Tmax) and Half-Life of Elimination (T-Half) | 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. | 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 | 
| Abatacept Pharmacokinetic (PK) Parameters - Maximum Concentration (Cmax) | 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. | 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 | 
| Abatacept Pharmacokinetic (PK) Parameters - Area Under the Curve (AUC) | 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. | 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 | 
| Abatacept Pharmacokinetic (PK) Parameters: Total Body Clearance (CLT) | 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. | Day 29, every 28 days until Day 141 | 
| Abatacept Pharmacokinetic (PK) Parameters: Volume at Steady State (VSS) | 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. | 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 | 
| Summary Statistics of Minimum Observed Serum Concentration (Cmin) for Abatacept | Minimum concentration (Cmin) of Abatacept 500 mg and 750 mg at given time points | At the end of infusion and 2 to 4 hours after the start of the infusion on Day 85 | 
| Immunogenicity of Abatacept- Number of Participants With Reactivity Toward CTLA4-IG and CTLA4-T at Day 169 | Immunogenicity was determined by measuring adult subject sera for reactivity against the whole Abatacept molecule (CTLA4Ig) and CTLA4-T (CTLA4 without the Ig regions). | Day 169 | 
| Change From Baseline in Surrogate Marker Erythrocyte Sedimentation Rate (ESR) at Day 169 | Mean change in surrogate marker mean ESR. A surrogate marker is an indirect measurement of effectiveness. Change from Baseline = postbaseline - baseline value. | From Baseline to Day 169 | 
| Change From Baseline in Surrogate Marker Rheumatoid Factor (RF) at Day 169 | Mean change in RF. A surrogate marker is an indirect measurement of effectiveness. Mean change from Baseline = postbaseline - baseline value. | Baseline, Day 169 | 
| LTE Period: Overall Number of Participants With Positive Results of Immunogenicity Samples | 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. | 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 | 
| Percentage of Participants Achieving ACR20, ACR50, and ACR70 Over Time | 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. | Days 15 through 1569 | 
| Percentage of Participants With Physical Function Response as Assessed Using the Health Assessment Questionnaire Disability Index (HAQ-DI) | 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. | At Day 1485 | 
| Change From Baseline in Health Assessment Questionnaire Disability Index (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. | Day 1485 | 
| Changes From Baseline in Short-Form 36 (SF-36) Physical and Mental Health Summaries | 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. | At Day 1485 | 
| Percentage of Participants With European League Against Rheumatism (EULAR)-Defined Low Disease Activity Score (LDAS) and With EULAR-defined Remission | 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 | At Days 169 and 1485 | 
| Changes From Baseline in the Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI) Scores | 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. | At Days 169 and 1569 | 
| Percentage of Participants With Low Disease Activity Score (LDAS) or Who Are in Remission | 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. | At Days 169, 337, 729, 1149, and 1485 | 
| Change From Baseline in Levels of C-reactive Protein (CRP) |  | Days 169 to 1569 | 
| Change From Baseline in Erythrocyte Sedimentation Rate |  | Days 169 to 1569 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid Arthritis, with inadequate response to methotrexate