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

Sperimentale: Abatacept and Methotrexate

Droga: 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

Altri nomi:

• Orencia
• BMS-188667

Droga: Methotrexate

Tablets, Oral, ≥ 15 mg, weekly, 6 months

Droga: Abatacept

Solution, intravenous, 10 mg/kg, every 28 days

Altri nomi:

• Orencia
• BMS-188667

Droga: Methotrexate

Tablets, oral, 15 mg weekly to be adjusted according to patient condition

Comparatore placebo: Placebo and Methotrexate

(standard of care)

Droga: Methotrexate

Tablets, Oral, ≥ 15 mg, weekly, 6 months

Droga: Methotrexate

Tablets, oral, 15 mg weekly to be adjusted according to patient condition

Droga: Placebo

IV solution, Intravenous, D5W, Day 1, Day 15, Day 29; every 28 days thereafter, 6 months

Sperimentale: Abatacept - Open Label

Open-label extension phase

Droga: 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

Altri nomi:

• Orencia
• BMS-188667

Droga: Methotrexate

Tablets, Oral, ≥ 15 mg, weekly, 6 months

Droga: Abatacept

Solution, intravenous, 10 mg/kg, every 28 days

Altri nomi:

• Orencia
• BMS-188667

Droga: Methotrexate

Tablets, oral, 15 mg weekly to be adjusted according to patient condition

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Summary Statistics of Minimum Observed Serum Concentration (Cmin) for Abatacept

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

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

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

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

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

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)

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

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

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

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

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

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)

Change From Baseline in Erythrocyte Sedimentation Rate