Long-Term Effectiveness And Safety Of CP-690,550 For The Treatment Of Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of this study is to determine the long-term effectiveness and safety of CP-690,550 for the treatment of rheumatoid arthritis. Subjects are eligible for this study only after participating in another qualifying study of CP-690,550 A sub-study will be conducted within the A3921024 study, this study will evaluate the immune response to pneumococcal and influenza vaccines in patients receiving CP-690,550

Official Title
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A Long-term, Open-label Follow-up Study Of Tofacitinib (Cp-690,550) For Treatment Of Rheumatoid Arthritis

Conditions
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Arthritis, Rheumatoid

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who have participated in a randomized qualifying study of CP-690,550 for the treatment of rheumatoid arthritis Vaccine sub-study visit Subjects actively participating in Study A3921024 must have completed at least 3 months of continuous 10 mg BID CP-690,550 treatment in A3921024 as defined by >80% compliance with prescribed dose consumption of CP-690,550 over the previous 3 months. Exclusion Criteria: Serious medical conditions that would make treatment with CP-690,550 potentially unsafe Vaccine sub-study visit Any documented influenza or pneumococcal infection within the last 3 months prior to randomization in this study Received any vaccine within 1 month prior to randomization in this study Received an influenza vaccine within 6 months or a pneumococcal vaccine within 5 years of randomization in this study.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-Label Active Treatment Enrolled from Phase 2<br>Patients enrolling from Phase 2 studies | Drug: CP-690,550<br>* 5 mg PO BID open label; may increase to 10 mg PO BID to provide greater control of RA if no related AEs are present. May be off study drug temporarily for up to 28 days for mild to moderate AEs.<br>|
| Experimental: Open-Label Active Treatment Enrolled from Phase 3<br>Patients enrolling from Phase 3 studies | Drug: CP-690,550<br>* 10 mg PO BID open label; may decrease to 5 mg PO BID for mild to moderate AEs. May be off study drug temporarily for up to 28 days for mild to moderate AEs.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Initial Period: Primary Endpoints Were Standard Laboratory Safety Data (Chemistry, Hematology, Etc.) and Adverse Event (AE) Reports | Treatment-emergent non serious AEs by System Organ Class (SOC) (all causalities) and Laboratory Test Abnormalities (without regard to baseline) The stated number of participants analyzed was the total number of participants in each group (AEs). The actual number of participants analyzed for each laboratory parameter varied, and is provided for each. Abs=absolute; ALT=alanine aminotransferase; AST=aspartate aminotransferase; ESR=erythrocyte sedimentation rate; GGT=gamma glutamyl transferase; hgb=hemoglobin; HDL=high density lipids; LDL=low density lipids; LLN=lower limit of normal; qual=qualitative; Tot=total; ULN=upper limit of normal; WBC=white blood cell | Includes laboratory test abnormality data for all visits and adverse event data up to 999 days after last dose of study drug | 
| Extension Period: Number of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both serious and non-serious adverse events. | Baseline (Day 1 at Entry of Extension Period) up to 28 days after last study drug dose in Extension Period (13 Months) | 
| Extension Period: Number of Participants With Laboratory Test Abnormalities | Criteria for laboratory abnormalities: hemoglobin (Hg), hematocrit, red blood cell (RBC), high density lipoprotein (HDL) cholesterol:<0.8*lower limit of normal (LLN), platelet<0.5*LLN/>1.75*upper limit of normal (ULN), white blood cell (WBC)<0.6*LLN/>1.5*ULN, lymphocyte, neutrophil, protein, albumin <0.8*LLN/>1.2*ULN, basophil, eosinophil, monocyte, low density lipoprotein (LDL) cholesterol: >1.2*ULN; bilirubin>1.5*ULN, aspartate amino transferase(AT), alanine AT, gammaglutamyl transferase, alkaline phosphatase:>3.0*ULN; blood urea nitrogen, creatinine, cholesterol, triglyceride:>1.3*ULN; sodium <0.95*LLN/>1.05*ULN, potassium, chloride, calcium, bicarbonate: <0.9*LLN/>1.1*ULN; glucose<0.6*LLN/>1.5*ULN; Urine (specific gravity<1.003/>1.030, pH<4.5/>8, glucose, ketone, protein, blood/Hg(>=1; RBC, WBC>=20; creatinine kinase>2*ULN). | Baseline (Day 1 at Entry of Extension Period) up to 28 days after last study drug dose in Extension Period (13 Months) | 
| Initial Period: The Long Term Safety and Tolerability of CP-690,550 5 Milligrams (mg) Twice Daily (BID) and 10 mg BID for the Treatment of Rheumatoid Arthritis | Treatment-emergent AEs by SOC (all causalities) - all participants, by time. Data presented for Post Month 96 includes data up to and including Month 114. | Includes AEs for every visit and up to 999 days after last dose of study drug | 
| Extension Period: Percentage of Participants With Adverse Events and Who Discontinued Treatment Due to Adverse Events to Assess Long-term Safety and Tolerability of Tofacitinib | Long term safety and tolerability of Tofacitinib was measured as following: percentage (%) of participants with AEs, percentage of participants who discontinued due to AEs. An AE is any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. | Baseline (Day 1 at Entry of Extension Period) up to Month 6 of Extension Period; Month 6 of Extension Period to Month 12 of Extension Period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Initial Period: Percentage of Patients With American College of Rheumatology (ACR) 20, 50, and 70 Responses | The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed on each occasion varied, and is provided for each visit presented. ACR20 is defined as a 20% improvement from baseline in tender/painful joint count and swollen joint count, and at least 3 of the following 5 variables: Subject's Global Assessment of Arthritis, Physician's Global Assessment of Arthritis, Subject's Assessment of Arthritis Pain, Health Assessment Questionnaire - Disability Index, C-Reactive Protein (CRP). ACR50 is a 50% improvement and ACR70 a 70% improvement in these variables. | Every visit until study completion | 
| Extension Period: Percentage of Participants With American College of Rheumatology (ACR) 20, 50, and 70 Responses | ACR20=20 percent (%) improvement from baseline (Month 0 at entry of Initial Period) in tender/painful joint count and swollen joint count, and in at least 3 of 5 variables: participant's global assessment of arthritis (PtGA), physician's global assessment of arthritis (PGA), participant's assessment of arthritis pain (PtA), HAQ-DI, C-reactive protein. ACR50 is a 50% improvement and ACR70 is a 70% improvement in these variables. PtGA: participant assessed overall disease activity, score: 0 (no arthritis) to 10 (extreme arthritis), higher score=more arthritis. PGA: physician judged participant's overall disease activity, score: 0 (no arthritis) to 10 (extreme arthritis), higher score=more arthritis. PtA: participant assessed arthritis pain by 100 millimeter (mm) visual analogue scale, score: 0 mm (no pain) to 100 mm (extreme pain), higher score=more pain. HAQ-DI: functional disability evaluation, score: 0 (no difficulty) to 3 (extreme difficulty), higher score=more disability. | Month 3, 6, 9 and 12 of Extension Period | 
| Initial Period: Area Under American College of Rheumatology (ACR) n Curve | No data were collected for this endpoint because it was removed from the protocol in a previous amendment. | Not applicable as no data were collected for this endpoint. | 
| Initial Period: Disease Activity Score (DAS)28 (C-reactive Protein [CRP]) and DAS28 (Erythrocyte Sedimentation Rate [ESR]) | Descriptive statistics for DAS28-3 (CRP) and DAS28-4 (ESR). The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed on each occasion varied, and is provided for each visit presented. DAS28 is a composite score, calculated using a mathematical formula, and is derived from the number of tender/painful joints (out of 28), number of swollen joints (out of 28), and a blood marker of inflammation (ESR or CRP). DAS28-4 also includes a score of general health in the formula. The score range is from 0 to 9.4, with a higher score indicating more disease activity. A score of >5.1 indicates active disease, a score of ≤3.2 indicates low disease activity, and a score of <2.6 indicates disease remission. | Every visit until study completion | 
| Extension Period: Change From Baseline in Disease Activity Score (DAS) 28-3 C-Reactive Protein (CRP)(DAS28-3 CRP) and DAS28-4 Erythrocyte Sedimentation Rate (ESR)(DAS28-4 ESR) at Month 3, 6, 9 and 12 | DAS28 is composite score, calculated using mathematical formula, derived from: 1) tender/painful joints count, out of 28 joints (TJC28), 2) swollen joints count, out of 28 joints (SJC28), 3) blood marker of inflammation (ESR [millimeter per hour] or CRP [milligram per liter]). DAS28-4 also include score of general health (GH). GH is general health or participants' global assessment of disease activity on 100 mm visual analog scale (GH score: 0 mm [very well] to 100 mm [extremely bad], higher scores = worse health condition). DAS28-3(CRP) = (0.56*sqrt[TJC28] + 0.28*sqrt[SJC28] + 0.36*ln[CRP+1]) *1.10 + 1.15) and DAS28-4(ESR) = (0.56*sqrt[TJC28] + 0.28*sqrt[SJC28] + 0.70*ln[ESR] + 0.014*GH), where sqrt = square root, ln = natural logarithm. DAS28-4 ESR and DAS28-3 CRP: score ranges from 0 (none) to 9.4 (extreme disease activity), with a higher score indicating more disease activity. Score of <=3.2 indicate low disease activity and score of <2.6 indicate disease remission. | Baseline (Month 0 at the entry of Initial period); Month 3, 6, 9 and 12 of Extension Period | 
| Initial Period: Number (%) of Participants With DAS28-4 (ESR) and DAS28-3 (CRP) <2.6 and ≤3.2 | Percent participants with DAS28-4 (ESR) <2.6 and ≤3.2 and percent participants with DAS28-3 (CRP) <2.6 and ≤3.2. The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed on each occasion varied, and is provided for each visit presented. DAS28 is a composite score, calculated using a mathematical formula, and is derived from the number of tender/painful joints (out of 28), number of swollen joints (out of 28), and a blood marker of inflammation (ESR or CRP). DAS28-4 also includes a score of general health in the formula. The score range is from 0 to 9.4, with a higher score indicating more disease activity. A score of >5.1 indicates active disease, a score of ≤3.2 indicates low disease activity, and a score of <2.6 indicates disease remission. | Every visit until study completion | 
| Extension Period: Percentage of Participants With DAS28-4 (ESR) and DAS28-3 (CRP) Less Than (<) 2.6 and Less Than or (<=) 3.2 | DAS28 is composite score, calculated using mathematical formula, derived from: 1) tender/painful joints count, out of 28 joints (TJC28), 2) swollen joints count, out of 28 joints (SJC28), 3) blood marker of inflammation (ESR [millimeter per hour] or CRP [milligram per liter]). DAS28-4 also include score of GH. GH is general health or participants' global assessment of disease activity on 100 mm visual analog scale (GH score: 0 mm [very well] to 100 mm [extremely bad], higher scores = worse health condition). DAS28-3(CRP) = (0.56*sqrt[TJC28] + 0.28*sqrt[SJC28] + 0.36*ln[CRP+1]) *1.10 + 1.15) and DAS28-4(ESR) = (0.56*sqrt[TJC28] + 0.28*sqrt[SJC28] + 0.70*ln[ESR] + 0.014*GH), where sqrt = square root, ln = natural logarithm. DAS28-4 ESR and DAS28-3 CRP: score range is from 0 (none) to 9.4 (extreme disease activity), with a higher score indicating more disease activity. Score of <=3.2 indicate low disease activity and score of <2.6 indicate disease remission. | Baseline (Day 1 at the entry of Extension period); Month 3, 6, 9 and 12 of Extension Period | 
| Initial Period: Health Assessment Questionnaire - Disability Index (HAQ-DI) Score | Change from baseline by visit. HAQ-DI scores range from 0 to 3, where lower score implies less disease. A reduction from baseline in score indicates an improvement in condition. A clinically meaningful decrease from baseline is defined as a decrease of at least 0.22 units. The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed on each occasion varied, and is provided for each visit presented. | Every visit until study completion | 
| Extension Period: Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Month 3, 6, 9 and 12 | HAQ-DI assesses the degree of difficulty a participant has experienced during the past week in 8 categories of daily living activities: dressing/grooming; arising; eating; walking; reach; grip; hygiene; and other activities. Each activity category consisted of 2-3 questionnaire. Each questionnaire was scored on a 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Any activity that required assistance from another individual or required the use of an assistive device was adjusted to a score of 2 to represent a more limited functional status. Overall score was computed as the sum of total scores divided by the number of questionnaire answered. Total possible HAQ-DI score range: 0 (least difficulty) and 3 (extreme difficulty), where higher scores indicate more difficulty while performing daily living activities. | Baseline (Month 0 at the entry of Initial Period); Month 3, 6, 9, and 12 of Extension Period | 
| Initial Period: Short-Form-36 Health Survey (SF-36) Score | Change from Baseline for Physical Component and Mental Component Scores by visit. SF-36 is a health status measure of 8 general health domains, each scored on a 0 to 100 scale: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. These domains can be summarized as physical and mental component scores. The domain scores were normed and the resulting component scores treated as Z-scores with a scale of negative to positive infinity. A higher score implies less disease. The greater the change from baseline, the greater the improvement. The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed on each occasion varied, and is provided for each visit presented. | Every visit until study completion | 
| Initial Period: FACIT Fatigue Scale, EuroQol EQ 5D, Work Limitations Questionnaire, and RA Healthcare Resource Utilization Questionnaire (RA-HCRU) | Change from Baseline Scores for each: FACIT Fatigue Scale (score range 0 to 52, higher score indicates higher quality of life and an increase from baseline score indicates improvement), EuroQol EQ 5D (index values derived from a measure of central tendency and a measure of dispersion, an increase from baseline indicates improvement, score range 0 to 1), Work Limitations (WL) Physical Demands (covers ability to perform job tasks that involve bodily strength, a decrease from baseline indicates improvement, score range 0 to 100, higher scores indicating greater limitation), and RA Healthcare Resource Utilization Work Performance in Past 3 Months on Days Bothered by RA (assesses healthcare use over previous 3 months, a decrease from baseline indicates improvement, score range 0 to 10). The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed on each occasion varied, and is provided for each visit presented. | Every visit until study completion | 
| Initial Period: Preservation of Joint Structure in Participants Who Had Baseline Radiographs Obtained in Their Qualifying Index Study | Modified Total Sharp Score per visit. Baseline score was the last available assessment from the index study. The Modified Total Sharp Score measures disease progression; increased scores indicate disease progression. Score range 0 (normal) to 448 (worst possible total score). The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed on each occasion varied, and is provided for each visit presented. TSS=Total Sharp Score | Every 6 months until study completion | 
| Vaccine Sub-study. Percent Achieving a Satisfactory Humoral Response to the Pneumococcal Vaccine as Defined by ≥ 2-fold Increase in Antibody Concentrations | Number (%) of participants achieving a satisfactory humoral response to the pneumococcal vaccine as defined by ≥2-fold increase in antibody concentration from vaccine sub-study visit 2 (vaccination baseline) in ≥6 of 12 anti-pneumococcal antigens (serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) The number of participants was the number with a determinate antibody titer to the given vaccine antigen within the population. 95% CI is based on Clopper-Pearson exact method for response rate. | From vaccine sub-study visit 2 (baseline) to sub-study visit 4 | 
| Vaccine Sub-study. Percent Achieving a Satisfactory Humoral Response to the Seasonal Influenza Vaccine as Defined by ≥ 4-fold Increase in Antibody Titers | Number of participants achieving a satisfactory humoral response to the seasonal influenza vaccine as defined by ≥4-fold increase in antibody titers from visit 2 (vaccination baseline) in ≥2 of 3 influenza antigens (HAI B, HAI H1N1, and HAI H3N2) The number of participants was the number with a determinate antibody titer to the given vaccine antigen within the population. 95% CI is based on Clopper-Pearson exact method for response rate. | From vaccine sub-study visit 2 (baseline) to sub-study visit 4 | 
| Vaccine Sub-study. Percentage of Participants Achieving Protective Antibody Titers to the Seasonal Influenza Vaccine as Measured by a Hemagglutination Inhibition (HI) Assay Titer of ≥ 1:40 in ≥ 2 of 3 Influenza Antigens at Vaccine Sub-study Visit 3 and 4 | Number (%) of participants achieving protective antibody titers to the seasonal influenza vaccine as measured by an HAI assay titer of ≥1:40 in ≥2 of 3 influenza antigens measured at vaccine sub-study visits 3 and 4. The number of participants was the number with a determinate antibody titer to the given vaccine antigen within the population. 95% CI is based on Clopper-Pearson exact method for response rate. | From vaccine sub-study visit 2 (baseline) to sub-study visit 4 | 
| Vaccine Sub-study. Percentage of Participants Who Respond to Each of the 12 Pneumococcal Antigens as Defined by ≥ 2-fold Increase in Antibody Concentrations From Vaccine Sub-study Visit 2 (Vaccination Baseline) Measured at Vaccine Sub-study Visit 4 | Number (%) of participants achieving a satisfactory humoral response to the pneumococcal vaccine as defined by ≥2-fold increase in antibody concentration from vaccine sub-study visit 2 (vaccination baseline) in ≥6 of 12 anti-pneumococcal antigens (serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) The number of participants was the number with a determinate antibody titer to the given vaccine antigen within the population. 95% CI is based on Clopper-Pearson exact method for response rate. | From vaccine sub-study visit 2 (baseline) to sub-study visit 4 | 
| Vaccine Sub-study. Percentage of Participants Who Respond to Each of the 3 Influenza Antigens as Defined by ≥ 4-fold Increase in Antibody Titers From Vaccine Sub-study Visit 2 (Vaccination Baseline) Measured at Vaccine Sub-study Visit 4 | Number (%) of participants achieving a satisfactory humoral response to the seasonal influenza vaccine defined as ≥4-fold increase in antibody titers from visit 2 (vaccination baseline) in ≥2 of 3 influenza antigens (HAI B, HAI H1N1, and HAI H3N2). The number of participants was the number with a determinate antibody titer to the given vaccine antigen within the population. 95% CI is based on Clopper-Pearson exact method for response rate. | From vaccine sub-study visit 2 (baseline) to sub-study visit 4 | 
| Vaccine Sub-study. Fold Increase of Anti-pneumococcal Antibody Levels to Each of the 12 Pneumococcal Antigens Above Vaccination Baseline Values (Vaccine Sub-study Visit 2) at Vaccine Sub-study Visit 4 | Geometric Mean Fold Increase From Baseline of Pneumococcal Antigens Measured at Visit 4. n was the number of participants with valid and determinate assay results for the specified serotype at the given visit. The stated number of participants analyzed was the total number of participants. The actual number of participants analyzed for some serotypes varied, and is provided where it differed from the total number of participants. Confidence Intervals (CIs) were back transformations of a CI based on the Student t distribution for the mean logarithm of the concentrations. | From vaccine sub-study visit 2 (baseline) to sub-study visit 4 | 
| Vaccine Sub-study. Fold Increase of Anti-influenza Antibody Levels to Each of the 3 Influenza Antigens Above Vaccination Baseline Values (Vaccine Sub-study Visit 2) at Vaccine Sub-study Visit 4 | Geometric Mean Fold Increase From Baseline of Influenza Antigens Measured at Visit 4. n was the number of participants with valid and determinate assay results for the specified HAI strain at the given visit. Confidence Intervals (CIs) were back transformations of a CI based on the Student t distribution for the mean logarithm of the titers. | From vaccine sub-study visit 2 (baseline) to sub-study visit 4 | 
| Vaccine Sub-study. Concentrations of Anti-pneumococcal Antibodies at Vaccine Sub-study Visit 3 and 4 | Mean pneumococcal concentrations (ug/mL) at vaccine baseline (visit 2) and post-vaccination visits (visits 3 and 4) by serotype. The stated number of participants analyzed was the total number of participants in each group. The actual number of participants analyzed for each serotype varied, and is provided for each individually. ug/mL=micrograms per milliliter | From vaccine sub-study visit 2 (baseline) to sub-study visit 4 | 
| Vaccine Sub-study. Titers of Anti-influenza Antibodies at Vaccine Sub-study Visit 3 and 4 | Mean influenza antibody titers at visits 3 and 4. | From vaccine sub-study visit 2 (baseline) to sub-study visit 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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long-term, open-label, safety