Substudy - Low Dose of Abatacept in Subjects With Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of this exploratory sub-study was to evaluate from a clinical perspective the impact on disease activity of lowering the dose of abatacept from 10 mg/kg to 5 mg/kg in subjects who had achieved remission (Disease Activity Score 28 [DAS 28]-erythrocyte sedimentation rate [ESR] < 2.6) at Day 701 of study IM101023.

Official Title
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A Phase 3B, Multi-Center, Randomized, Double-blind Study to Evaluate Remission and Joint Damage Progression in Methotrexate-naïve Early Erosive Rheumatoid Arthritis Subjects Treated With Abatacept Plus Methotrexate Compared With Methotrexate - Low Dose Sub-Study

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Abatacept
* Drug: Abatacept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who have completed the main study, are willing to participate and have a DAS 28 ESR score of < 2.6 on Day 701 of the main study Exclusion Criteria: None

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 |
| --- | --- |
| Active Comparator: Abatacept (10 mg/Kg)<br> | Drug: Abatacept<br>* IV solution, IV, 10 mg/Kg, Once monthly, 1 year<br>* Other names: BMS-188667;|
| Active Comparator: Abatacept (5 mg/Kg)<br> | Drug: Abatacept<br>* IV solution, IV, 5 mg/Kg, Once monthly, 1 year<br>* Other names: BMS-188667;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Disease Relapse Through Month 12 (Kaplan-Meier Cumulative Percentage of Events of Disease Relapse) | An event of disease relapse was defined as additional Disease-modifying antirheumatic drug (DMARD) therapy given, or 2 or more courses of high steroids given, or return to abatacept 10 mg/kg (rescue medication given), or DAS28 C-reactive protein (CRP) score >=3.2 at 2 consecutive visits. Time to disease relapse was evaluated using life tables (Kaplan-Meier Cumulative Percentage of Events of Disease Relapse). | Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Disease Relapse | Disease relapse is defined as additional DMARD therapy given, or 2 or more courses of high steroids given, or return to abatacept 10 mg/kg (rescue medication given), or DAS28 CRP score >= 3.2 at 2 consecutive visits. | After 12 Months of treatment | 
| Mean Time-Matched Baseline DAS28 CRP Scores | Mean baseline DAS28 CRP values for the cohort of participants with serum samples available at that timepoint. DAS 28 is a continuous variable which is a composite of 4 variables: number of tender joints out of 28, number of swollen joints out of 28 joints, CRP in mg/L and subject assessment of disease activity measure on a visual analogue scale (VAS) of 100 mm. The DAS28 provides a score on a scale from 0 to 10 indicating the current activity of the rheumatoid arthritis (>5.1=high disease activity; <3.2=low disease activity; <2.6=remission). | Baseline | 
| Adjusted Mean Change From Baseline in DAS28 CRP During Double-Blind Treatment | Mean baseline DAS28 CRP values for the cohort of participants with serum samples available at that timepoint. DAS 28 is a continuous variable which is a composite of 4 variables: number of tender joints out of 28, number of swollen joints out of 28 joints, CRP in mg/L and subject assessment of disease activity measure on a VAS of 100 mm. The DAS28 provides a score on a scale from 0 to 10 indicating the current activity of the rheumatoid arthritis (>5.1=high disease activity; <3.2=low disease activity; <2.6=remission). | Baseline, Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365 | 
| Percentage of Participants With 2 Consecutive DAS 28 CRP Scores ≥ 3.2 (Loss of Low Disease Activity Status) | DAS 28 is a continuous variable which is a composite of 4 variables: number of tender joints out of 28, number of swollen joints out of 28 joints, CRP in mg/L and subject assessment of disease activity measure on a VAS of 100 mm. The DAS28 provides a score on a scale from 0 to 10 indicating the current activity of the rheumatoid arthritis (>5.1=high disease activity; <3.2=low disease activity; <2.6=remission). | After 12 months of treatment | 
| Percentage of Participants Given Additional DMARD Therapy During Double-Blind Treatment | Additional DMARD therapy is defined as a re-introduction of methotrexate (MTX), an increase of at least 2.5 mg of MTX, or the addition of at least 1 DMARD. | After 12 months of treatment | 
| Percentage of Participants Who at Any Time During Double-Blind Treatment Were Given 2 or More Courses of High-Dose Steroids | A course of high dose steroids is defined as a course of intramuscular, intravenous, or high dose oral corticosteroids (use of > 10 mg/day equivalent of prednisone for a minimum of 3 consecutive days or for those subjects who had continued use for long durations of time, each course was determined by 28 day intervals). | After 12 months of treatment | 
| Percentage of Participants Given Rescue Medication Therapy During Double-Blind Treatment | All subjects in the sub-study randomized to receive double-blind abatacept 5 mg/kg or 10 mg/kg. Subjects rescued to open-label treatment received abatacept 10 mg/kg. | After 12 months of treatment | 
| Percentage of Participants Who Modified Therapy During Double-Blind Treatment | Modified therapy=additional DMARD therapy, 2 or more courses of high dose steroids or rescue medication. Additional DMARD therapy=re-introduction of methotrexate (MTX), an increase of at least 2.5 mg of MTX, or the addition of at least 1 DMARD. A course of high dose steroids=a course of intramuscular, intravenous, or high dose oral corticosteroids (use of > 10 mg/day equivalent of prednisone for a minimum of 3 consecutive days or for those subjects who had continued use for long durations of time, each course was determined by 28 day intervals). Rescue medication=abatacept 10 mg/kg. | After 12 months of treatment | 
| Percentage of Participants Who Lost Remission Status | Loss of remission is defined as DAS 28 CRP >=2.6. | After 12 months of treatment | 
| Steady-state Trough Serum Concentration (Cmin) of Abatacept During Double-Blind Treatment |  | Day 701 of the main study; sub-study Days 1, 85, 169, 253 | 
| Percentage of Participants With Adverse Events (AEs), Serious AEs (SAEs), Deaths, and Discontinuations During Double-Blind Treatment | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. Related AE/SAE=Certain, Probable, Possible, or Missing. SAE=any untoward medical occurrence that results in death, is life-threatening, requires or prolongs inpatient hospitalization (including elective surgery), results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. | From start of substudy up to 56 days post last dose in the double-blind period or start of the open-label rescue period, whichever occurred first until end of study (study duration was 115 weeks) | 
| Percentage of Participants With Infection and Infestation AEs Reported During Double-Blind Treatment | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. Infection and Infestation AEs = any AE within the System Organ Class Infection and Infestation. | From start of substudy up to 56 days post last dose in the double-blind period or start of the open-label rescue period, whichever occurred first until end of study (study duration was 115 weeks) | 
| Percentage of Participants With Malignant Neoplasms Reported During Double-Blind Treatment | All neoplasms were assessed by medical review as to whether or not the event was malignant. | From start of substudy up to 56 days post last dose in the double-blind period or start of the open-label rescue period, whichever occurred first until end of study (study duration was 115 weeks) | 
| Percentage of Participants With Prespecified Acute Infusional Adverse Events (AIAEs) During Double-Blind Treatment, by Intensity | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. Acute Infusional AE= a subset of the peri-infusional AEs with onset during the first hour after the start of the study drug infusion. A total of 105 infusional events were prespecified in the protocol. | From start of substudy up to 56 days post last dose in the double-blind period or start of the open-label rescue period, whichever occurred first until end of study (study duration was 115 weeks) | 
| Percentage of Participants With Prespecified Peri-Infusional Adverse Events (PAIAEs) During Double-Blind Treatment, by Intensity | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. Peri-infusional AE=a pre-specified infusional AE occuring during the first 24 hours after the start of study drug infusion.A total of 105 infusional events were prespecified in the protocol. GDASC=General Disorders and Administration Site Conditions, RTMD=Respiratory, Thoracic and Mediastinal Disorders. | From start of substudy up to 56 days post last dose in the double-blind period or start of the open-label rescue period, whichever occurred first until end of study (study duration was 115 weeks) | 
| Percentage of Participants With Pre-specified Autoimmune Disorders (ADs) Reported During Double-Blind Treatment, by Intensity | A total of 127 autoimmune disorders were prespecified in the protocol. MCTD=Musculoskeletal and Connective Tissue Disorders | From start of substudy up to 56 days post last dose in the double-blind period or start of the open-label rescue period, whichever occurred first until end of study (study duration was 115 weeks) | 
| Percentage of Participants With Laboratory Values Meeting the Marked Abnormality Criteria During Double-Blind Treatment | Not evaluated: high hemoglobin,high hematocrit,high erythrocytes,high neutrophils+bands(N+B),low monocytes,low basophils,low eosinophils,low alkaline phosphatase(ALP),low aspartate aminotransferase(AST),low alanine aminotransferase(ALT),low G-Glutamyl transferase(GGT),low total bilirubin,low blood urea nitrogen,low creatinine,high albumin,low uric acid,low urine protein,low urine glucose,low urine blood,low urine leukocyte esterase,low urine white blood cells,low red blood cells.Pre Rx=pretreatment,(*)Lymphocytes(c/uL):Low<.750x10^3,High>7.50x10^3.(*)Eosinophils:>.750x10^3 c/uL. | From start of substudy up to 56 days post last dose in the double-blind period or start of the open-label rescue period, whichever occurred first until end of study (study duration was 115 weeks) | 
| Clinically Significant Changes in Vital Signs and Physical Findings | Clinical significance was determined by investigator. Parameters include blood pressure, heart rate, respiration rate, and temperature. | From start of substudy up to 56 days post last dose in the double-blind period or start of the open-label rescue period, whichever occurred first until end of study (study duration was 115 weeks) | 
| Participants With Positive Antibody Responses to Abatacept (Electrochemiluminescence [ECL] Method) During Double-Blind Treatment | A positive antibody response to Abatacept (measured by the ECL assay) is further classified as a positive response for either Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Possibly immunoglobulin (Ig)' or 'Ig and/or Junction Region' | After 12 months of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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