Study of Abatacept Versus Placebo to Assess the Prevention of Rheumatoid Arthritis (RA) in Adult Patients

Study Overview
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Brief Summary
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The purpose of this study is to assess if Abatacept given for six months will prevent rheumatoid arthritis (RA) in patients who are at risk for the development of RA in comparison to placebo. High risk patients are defined as those having a positive laboratory test for anti-cyclic citrullinated peptide (anti-CCP2).

Official Title
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A Phase II Study of Abatacept Versus Placebo to Assess the Prevention of Rheumatoid Arthritis (RA) in Adult Patients With Undifferentiated Arthritis Who Are at High Risk for the Development of RA

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: Abatacept
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of undifferentiated arthritis Clinical synovitis of two or more joints At least one but not more than three of the criteria for diagnosis of RA (1987). No prior disease modifying anti-rheumatic drugs (DMARDs)/biologics. Duration of disease must be 18 months or less. Positive for antibodies against cyclic citrullinated peptides. Exclusion Criteria: Women of child bearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy. Active vasculitis of a major organ system. Severe or recurrent bacterial infection. History of cancer in the last five years except certain skin cancers. Herpes zoster that resolved less than 2 months prior to enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br> | Drug: Abatacept<br>* solution, intravenous injection, monthly, 169 days weight based: <60 kg = 500 mg 60 to 100 kg = 750 mg >100 kg = 1 g<br>* Other names: Orencia;|
| Placebo Comparator: 2<br> | Drug: placebo<br>* solution, intravenous injection, 0 mg, monthly, 169 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Diagnosis of Rheumatoid Arthritis (RA) by American Rheumatism Association (ARA) Criteria and/or Discontinued Due to Lack of Efficacy | ARA criteria is a 7-item tool for RA classification purposes; a patient is said to have RA (meeting endpoint) if he or she has satisfied at least 4 of the 7 criteria. If a participant discontinued due to lack of efficacy, he/she was regarded as meeting primary endpoint also. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Diagnosis of RA by 1987 ARA Criteria and/or Discontinued Due to Lack of Efficacy | ARA criteria is a 7-item tool for classification purposes; a patient is said to have RA (meeting endpoint) if he or she has satisfied at least 4 of the 7 criteria. If a participant discontinued due to lack of efficacy, he/she was regarded as meeting endpoint also. | 24 months | 
| Number of Participants With Undifferentiated Inflammatory Arthritis (UA) Who Develop Another Rheumatic Disease | Clinical diagnosis of other rheumatic diseases at 12 and 24 months. If a participant discontinued due to lack of efficacy, he/she was regarded as meeting endpoint also. | 12 months, 24 months | 
| Change From Baseline in Radiographic Erosion and Joint Space Narrowing Score at 6 Months, 12 Months, and 24 Months | Mean change from baseline using the Genant-Modified Sharp Score. Erosion score=assessment of 14 sites in each hand and wrist + 6 joints in each foot, using an 8-point scale from 0 (no erosions) to 3.5 (erosions of 100% or articular surfaces). Joint score= assessment of 13 sites in each wrist and hand + 6 sites in each foot using a 9-point scale from 0 (normal) to 4.0 (definite ankylosis). As-observed data. Change from Baseline=postbaseline score at timepoint (6 or 12 or 24 months) minus baseline score; a lower value signifies improvement. | Baseline, 6 months, 12 months, 24 months | 
| Change From Baseline in Total Erosion, Edema, Synovitis Scores at 6 Months, 12 Months, and 24 Months | Mean change from baseline. Degree of synovitis and structural joint damage (erosion, edema) of the carpal and metacarpophalangeal joints, as measured by magnetic resonance imaging (MRI) scores using the European League Against Rheumatism (EULAR)-Outcome Measures in Rheumatology Clinical Trials (OMERACT) assessment. Edema scale=0 (no bone involved) to 3 (67% to 100% of bone involved). Synovitis scale=0 (normal) and 1-3 (mild, moderate, severe. Bone erosion scale=0 (0% of bone involved) to 10 (91% to 100% of bone involved). Change from baseline=postbaseline score at timepoint - baseline score. | Baseline, 6 months, 12 months, 24 months | 
| Number of Participants With Persistent Symptomatic Clinical Synovitis | Synovitis, assessed by clinical signs and symptoms | 6, 12, and 24 months | 
| Short Form-36 (SF-36) Physical and Mental Component Summary (PCS and MCS) Scores - Mean Change From Baseline | SF-36, a 36-item instrument that covers 8 quality of life domains, which were used to derive the physical and mental component summary scores, which ranged from 0 to 100, with higher scores indicating a better quality of life. Change from baseline=postbaseline - baseline value; a higher value signifies improvement. | 6 months, 12 months, 24 months | 
| Change From Baseline in Cytokine Levels and Second Generation Anti-cyclic Citrullinated Peptide (Anti-CCP2) Antibodies at 6 Months, 12 Months, and 24 Months | To assess pharmacodynamic effect of abatacept on serum levels of autoantibodies, mean change from baseline in cytokines (interleukin-6 [IL-6], interleukin-1B [IL-1B], tumor necrosis factor Alpha [TNF-Alpha], Matrix Metalloproteinase 3T [MMP3T], and anti-CCP2), as measured by standard laboratory investigations, were assessed. Change from baseline=postbaseline value at timepoint (6 or 12 or 24 months) minus baseline value; a lower value signifies improvement. | Baseline, 6 Months, 12 months, 24 months | 
| Number of Participants With Anti-CCP2 Positive and/or Rheumatoid Factor (RF) Positive Over Time | To assess the pharmacodynamic effect of abatacept on serum levels of autoantibodies, number of participants with Anti-CCP2 Positive of Rheumatoid Factor (RF) positive | Day 1, 6 months, 12 months, 24 months | 
| Frequency of Human Leukocyte Antigen (HLA) Typing | To assess the pharmacodynamic effect of abatacept on serum levels of autoantibodies, a blood sample was obtained for HLA typing to determine the presence or absence of alleles associated with RA susceptibility and severity (shared epitope alleles HLA-DRB10401 and HLA-DRB10404). | Day 1 | 
| DAS 28 C Reactive Protein (CRP) Score - Mean Change From Baseline | The DAS 28 (CRP) is a composite of 4 variables: 28 tender joint count, 28 swollen joint count, CRP, and subject assessment of disease activity measure on a VAS of 100 mm. Change from Baseline=postbaseline score-baseline score; a lower value signifies improvement. | 6 months, 12 months, 24 months | 
| Number of Participants With a DAS 28 (CRP) Score of ≤3.2 (Low Disease Activity) or <2.6 (in Remission) | The DAS 28 (CRP) is a composite of 4 variables: tender joint count, swollen joint count, CRP, and subject assessment of disease activity measure on a VAS of 100 mm. Scores for disease activity are defined as low (≤ 3.2) and in remission (< 2.6). | 6 months, 12 months, 24 months | 
| Number of Subjects With Health Assessment Questionnaire (HAQ) Disability Index Response | This questionnaire includes 20 questions assessing physical function in 8 domains. 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 indicate greater dysfunction. HAQ response =improvement of at least 0.3 units from baseline. | 6 months, 12 months, 24 months | 
| Overall Safety - Adverse Events (AEs), Serious AEs, and Deaths | AEs were monitored at all scheduled visits of the study drug treatment and observation periods and at the follow-up visits performed 28, 56, and 85 days after the last infusion of study medication for participants who were withdrawn prematurely | Throughout the treatment period (6 months) | 
| Number of Participants With Positive Responses for Serum Levels of Abatacept-specific Antibodies | Immunogenicity, as measured by the number of positive repsonses for serum levels of abatacept-specific antibodies measured by enzyme-linked immunosorbent assays (ELISA). Postive response for whole molecule assessment was a value of > 400 and for tip assessment was ≥25. | Up to 12 months |