Study of CP-690,550 Versus Placebo In Rheumatoid Arthritis Patients On Background Methotrexate With Inadequate Response To Tumor Necrosis Factor (TNF) Inhibitors

Study Overview
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Brief Summary
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This study will test if CP-690,550 is safe and effective in rheumatoid arthritis patients taking methotrexate who have an inadequate response to tumor necrosis factor inhibitor treatment.

Official Title
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Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Of The Safety And Efficacy Of 2 Doses Of CP-690,550 In Patients With Active Rheumatoid Arthritis On Background Methotrexate With Inadequate Response To TNF Inhibitors

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: CP-690,550
* Drug: CP-690,550
* Drug: Placebo
* Drug: CP-690,550
* Drug: Placebo
* Drug: CP-690,550


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults with moderate to severe rheumatoid arthritis on a stable dose of methotrexate who have inadequate response to Tumor Necrosis Factor (TNF) inhibitors. Exclusion Criteria: Pregnancy, severe acute or chronic medical conditions, including serious infections or clinically significant laboratory abnormalities.

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: Sequence 1<br> | Drug: CP-690,550<br>* Oral tablets administered at 5 mg BID daily for 6 months during the double-blind, placebo-controlled period.<br>|
| Experimental: Sequence 2<br> | Drug: CP-690,550<br>* Oral tablets administered at 10 mg BID daily for 6 months during the double-blind, placebo-controlled period.<br>|
| Placebo Comparator: Sequence 3<br> | Drug: Placebo<br>* Oral placebo tablets administered BID daily during the first 3 months of the double-blind, study period.<br>* Other names: double-blind, placebo-controlled phase;Drug: CP-690,550<br>* Oral tablets administered at 5 mg BID daily during the second 3 months of the double-blind, study period.<br>* Other names: double-blind, extension phase;|
| Placebo Comparator: Sequence 4<br> | Drug: Placebo<br>* Oral placebo tablets administered BID daily during the first 3 months of the double-blind, placebo-controlled period.<br>* Other names: double-blind, placebo-controlled phase;Drug: CP-690,550<br>* Oral tablets administered at 10 mg BID daily during the second 3 months of the double-blind, study period.<br>* Other names: double-blind, extension phase;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Month 3 | ACR20 response: greater than or equal to (>=) 20 percent (%) improvement in tender joints count (TJC); >= 20% improvement in swollen joints count (SJC); and >= 20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant 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). For comparison of CP-690,550 with placebo, placebo sequences were combined into single reporting group for Month 3 analysis. | Month 3 | 
| Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Month 3 | HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities:dress/groom;arise;eat; walk;reach;grip; hygiene;common activities over past week. Each item scored on 4-point scale from 0-3:0=no difficulty;1=some difficulty;2=much difficulty;3=unable to do. Overall score was computed as sum of domain scores and divided by number of domains answered. Total possible score range 0-3:0=least difficulty and 3=extreme difficulty. For comparison of CP-690,550 with placebo, placebo sequences were combined into single reporting group for Month 3 analysis. | Baseline, Month 3 | 
| Percentage of Participants With Disease Activity Score Based on 28-Joint Count and Erythrocyte Sedimentation Rate (4 Variables) (DAS28-4 [ESR]) Less Than 2.6 at Month 3 | DAS28-4 (ESR) was calculated from SJC and TJC using 28 joints count, erythrocyte sedimentation rate (ESR)(millimeter/hour [mm/hour]) and patient's global assessment (PtGA) of disease activity (participant rated arthritis activity assessment). Total score range:0-9.4, higher score=more disease activity. DAS28-4 (ESR) less than or equal to (<=)3.2 implied low disease activity, greater than (>)3.2 to 5.1 implied moderate to high disease activity, less than (<)2.6=remission. For comparison of CP-690,550 with placebo, placebo sequences were combined into single reporting group for Month 3 analysis. | Month 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 2 and Month 1 | ACR20 response: >=20% improvement in TJC; >=20% improvement in SJC; and >= 20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP. | Week 2, Month 1 | 
| Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Month 4.5 and 6 | ACR20 response: >=20% improvement in TJC; >=20% improvement in SJC; and >=20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP. | Month 4.5, 6 | 
| Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 2, Month 1 and 3 | ACR50 response: >= 50% improvement in TJC or SJC and 50% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP. | Week 2, Month 1, 3 | 
| Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Month 4.5 and 6 | ACR50 response: >= 50% improvement in TJC or SJC and 50% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP. | Month 4.5 and 6 | 
| Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 2, Month 1 and 3 | ACR70 response: >=70% improvement in TJC or SJC and 70% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP. | Week 2, Month 1, 3 | 
| Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Month 4.5 and 6 | ACR70 response: >=70% improvement in TJC or SJC and 70% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP. | Month 4.5, 6 | 
| Disease Activity Score Based on 28-Joints Count and C-Reactive Protein (3 Variables) (DAS28-3 [CRP]) at Baseline, Week 2, Month 1 and 3 | DAS28-3 (CRP) was calculated from the SJC and TJC 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) <=3.2 implied low disease activity and >3.2 to 5.1 implied moderate to high disease activity, and DAS28-3 (CRP) <2.6 = remission. | Baseline, Week 2, Month 1, 3 | 
| Disease Activity Score Based on 28-Joints Count and C-Reactive Protein (3 Variables) (DAS28-3 [CRP]) at Month 4.5 and 6 | DAS28-3 (CRP) was calculated from the SJC and TJC 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) <= 3.2 implied low disease activity and >3.2 to 5.1 implied moderate to high disease activity, and DAS28-3 (CRP) <2.6 = remission. | Month 4.5, 6 | 
| Disease Activity Score Based on 28-Joints Count and Erythrocyte Sedimentation Rate (4 Variables) (DAS28-4 [ESR]) at Baseline and Month 3 | DAS28-4 (ESR) was calculated from SJC and TJC using 28 joints count, ESR (mm/hour) and PtGA of disease activity (participant rated arthritis activity assessment). Total score range: 0-9.4, higher score=more disease activity. DAS28-4 (ESR) <= 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, Month 3 | 
| Disease Activity Score Based on 28-Joints Count and Erythrocyte Sedimentation Rate (4 Variables) (DAS28-4 [ESR]) at Month 6 | DAS28-4 (ESR) was calculated from SJC and TJC using 28 joints count, ESR (mm/hour) and PtGA of disease activity (participant rated arthritis activity assessment). Total score range: 0-9.4, higher score=more disease activity. DAS28-4 (ESR) <= 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. | Month 6 | 
| Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 2, Month 1 and 3 | HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; common activities over past week. Each item scored on 4-point scale from 0-3:0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as sum of domain scores and divided by number of domains answered. Total possible score range 0-3:0=least difficulty and 3=extreme difficulty. | Week 2, Month 1, 3 | 
| Health Assessment Questionnaire-Disability Index (HAQ-DI) at Month 4.5 and 6 | HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; common activities over past week. Each item scored on 4-point scale from 0-3:0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as sum of domain scores and divided by number of domains answered. Total possible score range 0-3:0=least difficulty and 3=extreme difficulty. | Month 4.5, 6 | 
| Patient Assessment of Arthritis Pain at Baseline, Week 2, Month 1 and 3 | Participants rated the severity of arthritis pain on a 0 to 100 millimeter (mm) Visual Analog Scale (VAS), where 0 mm = no pain and 100 mm = most severe pain. | Baseline, Week 2, Month 1, 3 | 
| Patient Assessment of Arthritis Pain at Month 4.5 and 6 | Participants rated the severity of arthritis pain on a 0 to 100 mm VAS, where 0 mm = no pain and 100 mm = most severe pain. | Month 4.5, 6 | 
| Patient Global Assessment (PtGA) of Arthritis Pain at Baseline, Week 2, Month 1 and 3 | Participants answered: Considering all the ways your arthritis affects you, how are you feeling today? Participants responded by using a 0 - 100 mm VAS, where 0 mm = very well and 100 mm = very poorly. | Baseline, Week 2, Month 1, 3 | 
| Patient Global Assessment (PtGA) of Arthritis Pain at Month 4.5 and 6 | Participants answered: Considering all the ways your arthritis affects you, how are you feeling today? Participants responded by using a 0 - 100 mm VAS, where 0 mm = very well and 100 mm = very poorly. | Month 4.5, 6 | 
| Physician Global Assessment of Arthritis at Baseline, Week 2, Month 1 and 3 | Physician Global Assessment of Arthritis was measured on a 0 to 100 mm VAS, where 0 mm = very good and 100 mm = very bad. | Baseline, Week 2, Month 1, 3 | 
| Physician Global Assessment of Arthritis at Month 4.5 and 6 | Physician Global Assessment of Arthritis was measured on a 0 to 100 mm VAS, where 0 mm = very good and 100 mm = very bad. | Month 4.5, 6 | 
| 36-Item Short-Form Health Survey (SF-36) at Baseline, Week 2, Month 1 and 3 | SF-36 is a standardized survey evaluating 8 domains (of 2 components; physical and mental) of functional health and well being: physical and social functioning, physical and emotional role (role-physical, role-emotional) limitations, bodily pain, general health, vitality, mental health. The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). | Baseline, Week 2, Month 1, 3 | 
| 36-Item Short-Form Health Survey (SF-36) at Month 6 | SF-36 is a standardized survey evaluating 8 domains (of 2 components; physical and mental) of functional health and well being: physical and social functioning, physical and emotional role (role-physical, role-emotional) limitations, bodily pain, general health, vitality, mental health. The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). | Month 6 | 
| Medical Outcomes Study Sleep Scale (MOS-SS) at Baseline, Week 2, Month 1 and 3 | Participant-rated 12-item questionnaire to assess constructs of sleep over past week; 7 subscales:sleep disturbance,snoring,awakened short of breath,sleep adequacy,somnolence (range:0-100);sleep quantity (range:0-24),optimal sleep(yes/no), and 9 item index measures of sleep disturbance provide composite scores:sleep problem summary,overall sleep problem.Except adequacy,optimal sleep and quantity,higher scores=more impairment.Scores transformed(actual raw score[RS] minus lowest possible score divided by possible RS range*100);total score range:0-100;higher score=more intensity of attribute. | Baseline, Week 2, Month 1, 3 | 
| Medical Outcomes Study Sleep Scale (MOS-SS) at Month 6 | Participant-rated 12-item questionnaire to assess constructs of sleep over past week; 7 subscales:sleep disturbance,snoring,awakened short of breath,sleep adequacy,somnolence (range:0-100);sleep quantity (range:0-24),optimal sleep(yes/no), and 9 item index measures of sleep disturbance provide composite scores:sleep problem summary,overall sleep problem.Except adequacy,optimal sleep and quantity,higher scores=more impairment.Scores transformed(actual raw score[RS] minus lowest possible score divided by possible RS range*100);total score range:0-100;higher score=more intensity of attribute. | Month 6 | 
| Number of Participants With Optimal Sleep Assessed Using Medical Outcomes Study Sleep Scale (MOS-SS) at Baseline, Week 2, Month 1, and 3 | MOS-SS: participant-rated 12 item questionnaire to assess constructs of sleep over past week. It included 7 subscales: sleep disturbance, snoring, awakened short of breath, sleep adequacy, somnolence, sleep quantity and optimal sleep. Participants responded whether their sleep was optimal or not optimal by choosing yes or no. Number of participants with optimal sleep is reported. | Baseline, Week 2, Month 1, 3 | 
| Number of Participants With Optimal Sleep Assessed Using Medical Outcomes Study Sleep Scale (MOS-SS) at Month 6 | MOS-SS: participant-rated 12 item questionnaire to assess constructs of sleep over past week. It included 7 subscales: sleep disturbance, snoring, awakened short of breath, sleep adequacy, somnolence, sleep quantity and optimal sleep. Participants responded whether their sleep was optimal or not optimal by choosing yes or no. Number of participants with optimal sleep is reported. | Month 6 | 
| Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale at Baseline and Month 3 | FACIT-Fatigue Scale (FS):13-item questionnaire, participant scored each item on a 5-point scale: 0 (not at all) to 4 (very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as 4 minus the participant's response. The sum of all responses resulted in the FACIT-FS for a total possible score of 0 (worse score) to 52 (better score). A higher score reflected an improvement in the participant's health status. | Baseline, Month 3 | 
| Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale at Month 6 | FACIT-FS:13-item questionnaire, participant scored each item on a 5-point scale: 0 (not at all) to 4 (very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as 4 minus the participant's response. The sum of all responses resulted in the FACIT-FS for a total possible score of 0 (worse score) to 52 (better score). A higher score reflected an improvement in the participant's health status. | Month 6 | 
| Euro Quality of Life - 5 Dimensions (EQ-5D)- Health State Profile Utility Score at Baseline, Month 1 and 3 | EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state (confined to bed). Scoring formula developed by EuroQoL Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state. | Baseline, Month 1, 3 | 
| Euro Quality of Life - 5 Dimensions (EQ-5D) - Health State Profile Utility Score at Month 6 | EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state (confined to bed). Scoring formula developed by EuroQoL Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state. | Month 6 | 
| Work Productivity and Healthcare Resource Utilization (HCRU) at Baseline, Month 3 | Rheumatoid Arthritis (RA)-HCRU assessed healthcare usage during last 3 months for direct, indirect medical cost domains. Direct cost:visit to doctor,non-medical practitioner,nursing home,hospital,surgery,emergency room(ER) treatment,diagnostic tests, over-night stay,home healthcare services, aids/devices used. Indirect costs associated with functional disability:employment status,willingness to work,work disability due to RA,sick leave,part time work,ability to perform chores,chores done by family/friends/housekeeper. Assessment was based on 0 to 2-point scale;higher score=higher medical cost. | Baseline, Month 3 | 
| Work Productivity and Healthcare Resource Utilization (HCRU) at Month 6 | RA-HCRU assessed healthcare usage during last 3 months for direct, indirect medical cost domains. Direct cost: visit to doctor, non-medical practitioner, nursing home, hospital, surgery, emergency room(ER) treatment, diagnostic tests, over-night stay, home healthcare services, aids/devices used. Indirect costs associated with functional disability: employment status, willingness to work, work disability due to RA, sick leave, part time work, ability to perform chores, chores done by family/friends/housekeeper. Assessment was based on 0 to 2-point scale; higher score=higher medical cost. | Month 6 | 
| Number of Events Including Visits, Surgeries, Tests or Devices as Assessed Using RA-HCRU at Baseline and Month 3 | RA-HCRU assessed healthcare usage during previous 3 months for direct or indirect medical cost domains. Any RA/non-RA related number of events including visits to doctor, non-medical practitioner, hospital ER treatment, hospitalizations, number of surgeries, diagnostic tests, and devices/aids used were reported. | Baseline, Month 3 | 
| Number of Events Including Visits, Surgeries, Tests or Devices as Assessed Using RA-HCRU at Month 6 | RA-HCRU assessed healthcare usage during previous 3 months for direct or indirect medical cost domains. Any RA/non-RA related number of events including visits to doctor, non-medical practitioner, hospital ER treatment, hospitalizations, number of surgeries, diagnostic tests, and devices/aids used were reported. | Month 6 | 
| Number of Days as Assessed Using RA-HCRU at Baseline and Month 3 | RA-HCRU assessed healthcare usage during previous 3 months for direct or indirect medical cost domains. Any RA or non-RA related number of days spent in hospital, nursing home, aids/devices used, on sick leave, work per week, performed part time work, performed paid work, chores done by housekeeper and chores done by family/friends were reported. | Baseline, Month 3 | 
| Number of Days as Assessed Using RA-HCRU at Month 6 | RA-HCRU assessed healthcare usage during previous 3 months for direct or indirect medical cost domains. Any RA or non-RA related number of days spent in hospital, nursing home, aids/devices used, on sick leave, work per week, performed part time work, performed paid work, chores done by housekeeper and chores done by family/friends were reported. | Month 6 | 
| Number of Hours Per Day as Assessed RA-HCRU at Baseline and Month 3 | RA-HCRU assessed healthcare usage during previous 3 months for direct or indirect medical cost domains. Any RA or non-RA related number of hours spent per day for home healthcare services, chores done by housekeeper, chores done by family or friends, hours affected per day and average number of hours missed work per day were reported. | Baseline, Month 3 | 
| Number of Hours Per Day as Assessed RA-HCRU at Month 6 | RA-HCRU assessed healthcare usage during previous 3 months for direct or indirect medical cost domains. Any RA or non-RA related number of hours spent per day for home healthcare services, chores done by housekeeper, chores done by family or friends, hours affected per day and average number of hours missed work per day were reported. | Month 6 | 
| Work Performance in Past 3 Months on Days Bothered as Assessed Using RA-HCRU at Baseline and Month 3 | Work performance of participants on number of days bothered was based on 10-point scale, where higher score indicated lower work performance. | Baseline, Month 3 | 
| Work Performance in Past 3 Months on Days Bothered as Assessed Using RA-HCRU at Month 6 | Work performance of participants on number of days bothered was based on 10-point scale, where higher score indicated lower work performance. | Month 6 | 
| Work Limitations Questionnaire (WLQ) Score at Baseline and Month 3 | WLQ: participant-reported 25-item scale to evaluate degree to which health problems interfere with an ability to perform job roles along 4 dimensions: Time Management scale (TMS)(5-items); Physical Demands scale (PDS) (6-item); Mental-Interpersonal Demands Scale (MIDS) (9-items); Output Demands Scale (ODS) (5-items). All the scales ranged from 0 (limited none of the time) to 100 (limited all of the time). Work Loss Index (WLI), which represented percentage of lost work over time period relative to a normative population, was derived (total score: 0 [no loss] to 100 [complete loss of work]). | Baseline, Month 3 | 
| Work Limitations Questionnaire (WLQ) Score at Month 6 | WLQ: participant-reported 25-item scale to evaluate degree to which health problems interfere with an ability to perform job roles along 4 dimensions: Time Management scale (TMS)(5-items); Physical Demands scale (PDS) (6-item); Mental-Interpersonal Demands Scale (MIDS) (9-items); Output Demands Scale (ODS) (5-items). All the scales ranged from 0 (limited none of the time) to 100 (limited all of the time). Work Loss Index (WLI), which represented percentage of lost work over time period relative to a normative population, was derived (total score: 0 [no loss] to 100 [complete loss of work]). | Month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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randomized double-blind placebo-controlled investigational drug oral therapy safety and efficacy