Effects of Tofacitinib (CP-690,550) on Magnetic Resonance Imaging (MRI)- Assessed Joint Structure In Early Rheumatoid Arthritis (RA)

Study Overview
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Brief Summary
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Evaluation of efficacy and safety of tofacitinib (CP-690,550) for the treatment of early rheumatoid arthritis in adult patients with moderate to severe disease who are methotrexate naïve. The efficacy will be evaluated by exploring the effects on joint structure assessed by magnetic resonance imaging, x-rays and by standard clinical assessment.

Official Title
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An Exploratory Phase 2, Randomized, Double-blind, Multicenter Study To Assess The Effects Of Tofacitinib (Cp-690,550) On Magnetic Resonance Imaging Endpoints, In Methotrexate Naive Subjects With Early Active Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Tasocitinib plus Methotrexate
* Drug: Tofacitinib plus placebo methotrexate
* Drug: Placebo tofacitinib plus Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients with moderate to severe early rheumatoid arthritis (< 2 years) who are methotrexate and biologic disease modifying antirheumatic drug naive. Exclusion Criteria: Pregnant or lactating patients; Patients with renal or hepatic impairment or other severe or progressing disease; Patients with contraindication to magnetic resonance imaging with gadolinium contrast.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tofacitinib (CP 690,550) 10 mg BID plus MTX<br> | Drug: Tasocitinib plus Methotrexate<br>* Tofacitinib (CP 690,550) 10 mg BID, tablets + methotrexate (MTX) 10 mg/wk to 20 mg/wk, titrated over 2 months<br>|
| Experimental: Tofacitinib (CP-690,550) 10 mg BID, tablet plus placebo MTX<br> | Drug: Tofacitinib plus placebo methotrexate<br>* Tofacitinib (CP-90,550) 10 mg BID, tablets. Placebo to match methotrexate (MTX) capsules titrated as in Treatment Arm 1.<br>|
| Active Comparator: Placebo tofacitinib (CP-690,55) plus MTX 10 mg/wk to 20 mg/wk<br> | Drug: Placebo tofacitinib plus Methotrexate<br>* Methotrexate (MTX) 10 mg/wk to 20 mg/wk, capsules, titrated over 2 months. Placebo in tablets to match tofacitinib<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Month 3 in Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) Wrist and Metacarpophalangeal (MCP) Synovitis | Synovitis is defined as an area in the synovial compartment that shows above normal postgadolinium enhancement of a thickness greater than the width of the normal synovium. T1-weighted images were acquired before and after the administration of intravenous contrast agent containing gadolinium. Intravenous contrast was required to demonstrate enhancing synovitis. Synovitis was scored 0 to 3 in 3 wrist regions and in each of the first through fifth MCP joints. A score of 0 is normal, with no enhancement or enhancement up to the thickness of normal synovium, while scores of 1 to 3 (mild, moderate, severe) refer to increments of one-third of the presumed maximum volume of enhancing tissue in the synovial compartment. Total synovitis score ranges from a minimum of 0 to a maximum of 24. A negative value in synovitis change from Baseline score indicates an improvement. | Month 3 | 
| Change From Baseline to Month 6 in OMERACT RAMRIS Wrist and MCP Bone Marrow Edema | Bone edema was assessed at 25 anatomic locations: 15 in 1 wrist and 10 in attached hand. Bone edema was defined as a lesion within the trabecular bone, with ill-defined margins and signal characteristics consistent with increased water content. Each bone was scored separately; the scale was 0-3 based on the proportion of bone with edema, as follows 0: no edema; 1: 1-33% of bone edematous; 2: 34-66% of bone edematous; 3: 67-100%. OMERACT RAMRIS total bone edema score for hands/wrists was sum of the individual scores for each location. Thus the maximum score per hand/wrist was 75 (range 0-75). Increasing score=greater severity. | Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Months 1, 6, and 12 in OMERACT RAMRIS Wrist and MCP Synovitis | Synovitis is defined as an area in the synovial compartment that shows above normal postgadolinium enhancement of a thickness greater than the width of the normal synovium. T1-weighted images were acquired before and after the administration of intravenous contrast agent containing gadolinium. Intravenous contrast was required to demonstrate enhancing synovitis. Synovitis was scored 0 to 3 in 3 wrist regions and in each of the first through fifth MCP joints. A score of 0 is normal, with no enhancement or enhancement up to the thickness of normal synovium, while scores of 1 to 3 (mild, moderate, severe) refer to increments of one-third of the presumed maximum volume of enhancing tissue in the synovial compartment. Total synovitis score ranges from a minimum of 0 to a maximum of 24. A negative value in synovitis change from Baseline score indicates an improvement. | Months 1, 6, and 12 | 
| Change From Baseline to Months 1, 3, and 12 in OMERACT RAMRIS Bone Marrow Edema in Wrist and MCP | Bone edema was assessed at 25 anatomic locations: 15 in 1 wrist and 10 in attached hand. Bone edema was defined as a lesion within the trabecular bone, with ill-defined margins and signal characteristics consistent with increased water content. Each bone was scored separately; the scale was 0â€3 based on the proportion of bone with edema, as follows 0: no edema; 1: 1â€33% of bone edematous; 2: 34â€66% of bone edematous; 3: 67â€100%. OMERACT RAMRIS total bone edema score for hands/wrists was sum of the individual scores for each location. Thus the maximum score per hand/wrist was 75 (range 0-75). Increasing score=greater severity. | Months 1, 3, and 12 | 
| Change From Baseline to Months 1, 3, 6, and 12 in OMERACT RAMRIS Wrist and MCP Erosions | Bone erosion assessed at 25 anatomic locations: 15 in 1 wrist and 10 in attached hand. Each site was scored in 1.0 increments from 0 (no damage) to 10 (severe damage), indicating erosion (each unit=10% bone loss) of original articular bone. OMERACT RAMRIS total erosion score for hands/wrists was sum of the individual scores for each location. Thus the maximum score per hand/wrist is 250 (range 0-250). Increasing score=greater severity. | Months 1, 3, 6, and 12 | 
| Modified Total Sharp Score (mTSS) at Months 6 and 12 | Modified TSS is a measure of change in joint health. TSS is defined as joint space narrowing score (range 0 [no narrowing] to 168 [high narrowing]) plus (+) erosion score (range is from 0 [no erosion] to 280 [high erosion]). The modified TSS range is from 0 (no damage) to 448 (bad joint status). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement. | Months 6 and 12 | 
| Change From Baseline to Months 6 and 12 in mTSS | Modified TSS is a measure of change in joint health. TSS is defined as joint space narrowing score (range 0 [no narrowing] to 168 [high narrowing]) + erosion score (range is from 0 [no erosion] to 280 [high erosion]). The modified TSS range is from 0 (no damage) to 448 (bad joint status). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement. | Months 6 and 12 | 
| Joint Space Narrowing (JSN) Scores at Months 6 and 12 | JSN score (a component of the modified TSS) is a measure of change in joint health. JSN score range is 0 (no narrowing) to 168 (high narrowing). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement. | Months 6 and 12 | 
| Change From Baseline to Months 6 and 12 in JSN Scores | JSN score (a component of the modified TSS) is a measure of change in joint health. JSN score range is 0 (no narrowing) to 168 (high narrowing). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement. | Months 6 and 12 | 
| Erosion Scores at Months 6 and 12 | Erosion score (a component of the modified TSS) is a measure of change in joint health. Erosion score range is from 0 (no erosion) to 280 (high erosion). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement. | Months 6 and 12 | 
| Change From Baseline to Months 6 and 12 in Erosion Score | Erosion score (a component of the modified TSS) is a measure of change in joint health. Erosion score range is from 0 (no erosion) to 280 (high erosion). Increase from baseline represents disease progression and / or joint worsening; no change represents halting of disease progression; a decrease represents improvement. | Months 6 and 12 | 
| Percentage of Participants With an American College of Rheumatology (ACR) 20 Percent (%) Improvement (ACR20) Response | ACR20 response: greater than or equal to (â‰¥)20% improvement in tender joint count; â‰¥20% improvement in swollen joint count; and â‰¥20% improvement in at least 3 of 5 remaining ACR core measures: Participant's Assessment of Pain; Participant's Global Assessment of Disease Activity; Physician Global Assessment of Disease Activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP). | Months 1, 2, 3, 6, 9, and 12 | 
| Percentage of Participants With an ACR 50% Improvement (ACR50) Response | ACR50 response: â‰¥ 50% improvement in tender or swollen joint counts and 50% improvement in 3 of the following 5 criteria: 1) Physician's Global Assessment of Disease Activity, 2) Participant's Assessment of disease activity, 3) Paricipant's Assessment of Pain, 4) Participant's assessment of functional disability via a HAQ, and 5) CRP at each visit. | Months 1, 2, 3, 6, 9, and 12 | 
| Percentage of Participants With an ACR 70% Improvement (ACR70) Response | ACR70 response: â‰¥70% improvement in tender or swollen joint counts and 70% improvement in 3 of the following 5 criteria: 1) Physician's Global Assessment of Disease Activity, 2) Participant's Assessment of Disease Activity, 3) Participant's Assessment of Pain, 4) Participant's Assessment of Functional Disability via a HAQ, and 5) CRP at each visit. | Months 1, 2, 3, 6, 9, and 12 | 
| Disease Activity Score Based on 28-Joint Count and CRP (DAS28-3 [CRP]) | DAS28-3 (CRP) was calculated from the swollen joint count and tender joint count using the 28 joints count and CRP (mg/L). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-3 (CRP) less than or equal to (â‰¤)3.2 implied low disease activity and greater than (>)3.2 to 5.1 implied moderate to high disease activity, and DAS28-3 (CRP) less than (<)2.6 = remission. | Baseline and Months 1, 2, 3, 6, 9, and 12 | 
| Change From Baseline in DAS28-3 (CRP) | DAS28-3 (CRP) was calculated from the swollen joint count and tender joint count using the 28 joints count and CRP (mg/L). Total score range: 0 to 9.4, higher score indicated more disease activity. | Months 1, 2, 3, 6, 9, and 12 | 
| Disease Activity Score Based on 28-Joint Count and Erythrocyte Sedimentation Rate (DAS28-4 [ESR]) | DAS28-4 (ESR) was calculated from swollen joint count and tender joint count using 28 joints count, ESR (millimeters per hour [mm/hour]) and Participant Global Assessment of disease activity (participant rated arthritis activity assessment). Total score range: 0 to 9.4; higher score=more disease activity. DAS28-4 (ESR) â‰¤3.2 implied low disease activity and >3.2 to 5.1 implied moderate to high disease activity, and DAS28-4 (ESR) <2.6 = remission. | Baseline and Months 1, 2, 3, 6, 9, and 12 | 
| Change From Baseline in DAS28-4 (ESR) | DAS28-4 (ESR) was calculated from swollen joint count and tender joint count using 28 joints count, ESR (millimeters per hour [mm/hour]) and Participant Global Assessment of disease activity (participant rated arthritis activity assessment). Total score range: 0 to 9.4; higher score=more disease activity. | Months 1, 2, 3, 6, 9, and 12 | 
| Percentage of Participants With DAS28-3 (CRP) Response (Good or Moderate Improvement) | DAS28-3(CRP) was calculated from the swollen joint count and tender joint count using 28-joints count and CRP (mg/L). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28 categorical responses define a good (absolute: <3.2 or >1.2 improvement from baseline [BL]), moderate (absolute: 3.2-5.1 or 0.6-1.2 change from BL), or no response (absolute: >5.1 or <0.6 change from BL). | Months 1, 2, 3, 6, 9, and 12 | 
| Percentage of Participants With DAS28-3 (CRP) Score â‰¤3.2 | DAS28-3(CRP) was calculated from the swollen joint count and tender joint count using 28-joints count and CRP (mg/L). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-3(CRP) â‰¤3.2 implied low disease activity. | Months 1, 2, 3, 6, 9, and 12 | 
| Percentage of Participants With DAS28-3 (CRP) Score <2.6 | DAS28-3(CRP) was calculated from the swollen joint count and tender joint count using 28-joints count and CRP (mg/L). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-3(CRP) <2.6 implied remission. | Months 1, 2, 3, 6, 9, and 12 | 
| Percentage of Participants With DAS28-4 (ESR) Response (Good or Moderate Improvement) | DAS28-4(ESR) was calculated from swollen joint count and tender joint count using 28 joints count, ESR (mm/hour) and Participant's Global Assessment of Disease Activity (participant rated arthritis activity assessment). Total score range: 0 to 9.4, higher score=more disease activity. DAS28 categorical responses define a good (absolute: <3.2 or >1.2 improvement from BL), moderate (absolute: 3.2-5.1 or 0.6-1.2 change from BL), or no response (absolute: >5.1 or <0.6 change from BL). | Months 1, 2, 3, 6, 9, and 12 | 
| Percentage of Participants With DAS28-4 (ESR) â‰¤3.2 | DAS28-4(ESR) was calculated from swollen joint count and tender joint count using 28 joints count, ESR (mm/hour) and Participant's Global Assessment of Disease Activity (participant rated arthritis activity assessment). Total score range: 0 to 9.4, higher score=more disease activity. DAS28-4(ESR) â‰¤3.2 implied low disease activity. | Months 1, 2, 3, 6, 9, and 12 | 
| Percentage of Participants With DAS28-4 (ESR) <2.6 | DAS28-4(ESR) was calculated from swollen joint count and tender joint count using 28 joints count, ESR (mm/hour) and Participant's Global Assessment of Disease Activity (participant rated arthritis activity assessment). Total score range: 0 to 9.4, higher score=more disease activity. DAS28-4(ESR) <2.6 implied remission. | Months 1, 2, 3, 6, 9, and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Early Rheumatoid Arthritis, Joint Structure, Magnetic Resonance Imaging, Janus Kinase (JAK) Inhibitor, Tasocitinib, Tofacitinib