Extension Study Of Subjects From Study A3921030 For The Prevention Of Acute Rejection In Kidney Transplant Patients

Study Overview
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Brief Summary
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This is a study that will follow transplant patients from Study A3921030 to monitor for long term safety, tolerability and efficacy for 5 additional years, except in Portugal where the study will follow transplant patients through Month 36 posttransplant. Patients will continue their study medications that were previously assigned.

Official Title
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A Phase 2, Multicenter, Open-label, Active Comparator-controlled, Extension Trial To Evaluate The Long-term Safety And Efficacy Of Cp-690,550 In Renal Allograft Recipients

Conditions
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Kidney Transplantation

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who successfully completed Study A3921030 Exclusion Criteria: Subjects who are on the waiting list for a second kidney transplant or any non-renal organ transplants

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment Arm 1<br>Treatment Arm 1 will also receive standard of care medications | Drug: Cyclosporine<br>* Standard of care<br>|
| Experimental: Treatment Arm 2<br>Treatment Arm 2 will also receive standard of care medications | Drug: CP-690,550<br>* CP-690,550 tablets dosed BID Months 12-72<br>|
| Experimental: Treatment Arm 3<br>Treatment Arm 3 will also receive standard of care medications | Drug: CP-690,550<br>* CP-690,550 tablets dosed BID Months 12-72<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Analysis of Percentage of Participants With Clinically Significant Infection by Visit | Clinically significant infection was defined as the presence of documented infection confirmed by culture, biopsy, genomic, or serologic findings post-randomization and requiring hospitalization or parenteral anti-infective treatment, or otherwise deemed significant by the investigator. The 'Number' and 'Other Confidence Interval Level' columns represent cumulative proportions and 60% confidence intervals (CIs) as estimated from the fitted Kaplan-Meier curves for each treatment at scheduled visits. | Months 12, 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 | 
| Percentage of Participants With Malignancies | All treatment-emergent malignancies in Study A3921050 were included as collected on the Malignancy Case Report Form page. | Months 12 through 72. | 
| Least Squares Means of Measured Glomerular Filtration Rate (GFR) (Iohexol Serum Clearance in Milliliters Per Minute [mL/Min]) | Glomerular filtration rate (GFR): an index of kidney function. GFR described the flow rate of filtered fluid through the kidney. GFR was calculated using iohexol serum clearance. For determination of iohexol serum clearance, iohexol was administered as an intravenous (IV) bolus over 5 minutes immediately after morning dosing of Tofacitinib or CsA on day of GFR evaluation. Blood samples for iohexol (3 millilitres [mL] each to provide a minimum of 1 mL serum) were collected into appropriately labeled tubes containing no additives at 120, 180, 240, and 300 minutes after the end of the iohexol IV bolus. A normal GFR is greater than (>) 90 mL/min, although children and older people usually have a lower GFR. Lower values indicated poor kidney function. A GFR less than (<) 15 mL/min indicated kidney failure. | Month 36 | 
| Percentage of Participants With Progression of Chronic Allograft Lesions at Month 36 | Progression of chronic allograft lesions was defined as an increase in the Banff chronicity score (Banff-CS) in biopsy from the implantation (baseline) biopsy in a given participant. Banff-CS was the sum of the Banff scores for the 4 chronic basic lesions (allograft glomerulopathy [cg] + interstitial fibrosis [ci] + tubular atrophy [ct] + vascular intimal thickening [cv]). The Banff-CS ranged from 0-12, higher score indicated greater lesions and Month 36 Banff-CS greater than the implantation biopsy score indicated progression of lesions. | Month 36 | 
| Kaplan-Meier Analysis of Percentage of Participants With First Biopsy Proven Acute Rejection (BPAR) by Visit | BPAR was category acute rejection as interpreted by the central blinded pathologist according to the Banff 97 working classification. The 'Number' and 'Other Confidence Interval Level' columns represent cumulative proportions and 60% confidence intervals (CIs) as estimated from the fitted Kaplan-Meier curves for each treatment at scheduled visits. | Months 12, 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 | 
| Kaplan-Meier Analysis of Percentage of Participants With Treated Clinical Acute Rejection by Visit | Treated clinical acute rejection was defined as an acute rejection episode that was diagnosed based on local biopsy readout and received anti-rejection treatment. The 'Number' and 'Other Confidence Interval Level' columns represent cumulative proportions and 60% confidence intervals (CIs) as estimated from the fitted Kaplan-Meier curves for each treatment at scheduled visits. | Months 12, 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan-Meier Analysis of Percentage of Participants With Efficacy Failure by Visit | Efficacy failure was the first occurrence of BPAR diagnosed by the central pathologist or graft loss including participant death. BPAR (category acute rejection) was interpreted by the central blinded pathologist according to the Banff 97 working classification. The 'Number' and 'Other Confidence Interval Level' columns represent cumulative proportions and 60% confidence intervals (CIs) as estimated from the fitted Kaplan-Meier curves for each treatment at scheduled visits. | Months 12, 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 | 
| Kaplan-Meier Analysis of Percentage of Participants With Combined Banff Rejection by Visit | Banff 97: standard classification for scoring and classifying rejection of kidney transplant biopsies in 6 diagnostic categories: normal, antibody-mediated rejection, borderline changes: 'suspicious' for acute cellular rejection, acute/active cellular rejection, chronic/sclerosing allograft nephropathy, and other. Combined Banff rejection was calculated from categories of antibody-mediated rejection (Category 2) plus borderline changes (Category 3) plus acute rejection (Category 4), as interpreted by the central pathologist. The 'Number' and 'Other Confidence Interval Level' columns represent cumulative proportions and 60% confidence intervals (CIs) as estimated from the fitted Kaplan-Meier curves for each treatment at scheduled visits. | Months 12, 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 | 
| Kaplan-Meier Analysis of Percent of Participants With Graft Survival With Death Censored by Visit | Graft loss was defined as graft nephrectomy, subject death, retransplantation, or return to dialysis for at least 6 consecutive weeks. The 'Number' and 'Other Confidence Interval Level' columns represent cumulative proportions and 60% confidence intervals (CIs) as estimated from the fitted Kaplan-Meier curves for each treatment at scheduled visits. Included data up to 2 months postdose in the clinical Follow-up visit. | Months 12, 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 | 
| Kaplan-Meier Analysis of Percentage of Participants Surviving by Visit | The 'Number' and 'Other Confidence Interval Level' columns represent cumulative proportions and 60% confidence intervals (CIs) as estimated from the fitted Kaplan-Meier curves for each treatment at scheduled visits. Included data up to 2 months postdose in the clinical Follow-up visit. | Months 12, 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 | 
| Percentage of Participants Discontinuing From the Study | Discontinuations were due to any reason including those occurring as a result of protocol Amendments 3 and 4. | Months 12 through 72. | 
| Least Squares Means of Total Serum Cholesterol Levels (Milligrams Per Deciliter [mg/dL]) by Visit | Model contained treatment, visit and treatment by visit interaction as fixed effects and Baseline (predose in Study A3921030) as a covariate. A first-order autoregressive variance-covariance structure was used. | Months 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 | 
| Least Squares Means of Total Serum Low Density Lipoprotein (LDL) Cholesterol Levels (mg/dL) by Visit | Model contained treatment, visit and treatment by visit interaction as fixed effects and Baseline (predose in Study A3921030) as a covariate. A first-order autoregressive variance-covariance structure was used. | Months 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 | 
| Least Squares Means of Total Serum High Density Lipoprotein (HDL) Cholesterol Levels (mg/dL) by Visit | Model contained treatment, visit and treatment by visit interaction as fixed effects and Baseline (predose in Study A3921030) as a covariate. A first-order autoregressive variance-covariance structure was used. | Months 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 | 
| Least Squares Means of Total Serum Triglycerides (mg/dL) by Visit | Model contained treatment, visit and treatment by visit interaction as fixed effects and Baseline (predose in Study A3921030) as a covariate. A first-order autoregressive variance-covariance structure was used. | Month 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 | 
| Mean Absolute Neutrophil Counts (ANC) (Kelvin Per Millimeter Cubed [K/mm^3]) by Visit | Follow-up visit included Month 74 visit for completers and 2-month postdose visit for early withdrawals. | Months 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 and Follow-up | 
| Mean Hemoglobin (Hgb) (Grams Per Deciliter [g/dL]) by Visit | Follow-up visit included Month 74 visit for completers and 2-month postdose visit for early withdrawals. | Months 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 and Follow-up | 
| Mean Glycosylated Hemoglobin (HBA1c) (Percent [%]) by Visit | HbA1c is a form of hemoglobin which is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. The normal range for the HbA1c test is between 4% and 5.6%. HbA1c levels between 5.7% and 6.4% indicate increased risk of diabetes and levels of 6.5% or higher indicate diabetes. | Months 24, 36, 48, 60, 72 | 
| Least Squares Means of Fasting Serum Glucose Levels (mg/dL) by Visit | Model contained treatment, visit and treatment by visit interaction as fixed effects and Baseline (predose in Study A3921030) as a covariate. A compund symmetry variance-covariance structure was used. | Months 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 | 
| Percentage of Participants by Proteinuria Category by Visit | Proteinuria was defined as the presence of an excess of serum proteins in the urine. Normal value of proteinuria is below 0.15 grams per 24 hours (g/24 hr). Follow-up visit included Month 74 visit for completers and 2-month postdose visit for early withdrawals. | Months 24, 36, 48, 60, 72 and Follow-up | 
| Least Square Means of Estimated GFR Calculated Using the Nankivell Equation by Visit | GFR: an index of kidney function. GFR described the flow rate of filtered fluid through the kidney. GFR was measured directly or estimated using established formulas. GFR was calculated using Nankivell formula, where: Creatinine clearance (mL/min) = 6.7/serum creatinine (millimols per litre [mmol/L]) - serum urea (mmol/dL)/2 + actual body weight (kilograms [kg])/4 - 100/Height (metres [m])^2 + (35 for male or 25 for female). A normal GFR for adults is > 90 mL/min. Lower values indicate poor kidney function. A GFR <15 is consistent with kidney failure. Model contained treatment, visit and treatment by visit interaction as fixed effects. An unstructured variance-covariance structure was used. | Month 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 | 
| Least Squares Means of Estimated GFR Calculated Using the Cockcroft-Gault Equation by Visit | GFR: an index of kidney function. GFR described the flow rate of filtered fluid through the kidney. GFR was measured directly or estimated using established formulas. GFR (mL/min) was calculated using Cockcroft-Gault equation. GFR by Cockcroft-Gault equation= body weight (kg)*(140 minus age in years) divided by (72*serum creatinine [mg/dL]). For females value obtained was multiplied by 0.85. A normal GFR is >90 mL/min, although children and older people usually have a lower GFR. Lower values indicated poor kidney function. A GFR <15 mL/min indicated kidney failure. Model contained treatment, visit and treatment by visit interaction as fixed effects. An unstructured variance-covariance structure was used. | Months 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 | 
| Least Squares Means of Estimated GFR (eGFR) (mL/Min/1.73 Square Meter [m^2]) Calculated by the Modification of Diet in Renal Disease (MDRD) Equation With Last Observation Carried Forward (LOCF) Plus Imputation (eGFR=0 for Graft Loss/Death) by Visit | GFR: an index of kidney function. GFR described the flow rate of filtered fluid through the kidney. GFR was calculated using MDRD equation. GFR (mL/min/1.73 m^2) by MDRD equation = 170 * (serum creatinine [mg/dL])^(-0.999) * (age in years)^(-0.176) * (0.762 if female) * (1.18 if black) * (blood urea nitrogen concentration [mg/dL])^(-0.170) * (serum albumin concentration [g/dL])^(0.318). A normal GFR is >90 mL/min/1.73 m^2, although children and older people usually have a lower GFR. Lower values indicated poor kidney function. A GFR <15 mL/min/1.73 m^2 indicated kidney failure. Model contained treatment, visit and treatment by visit interaction as fixed effects. An unstructured variance-covariance structure was used. | Months 15, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72 | 
| Least Squares Means of Short Form 36 Version 2 (SF-36 V2) Component and Domain Scores at Months 24 and 36 | SF-36 v2 is a self-administered 36-item generic health status measure with 8 general health concepts which are the weighted sums of the questions in their section: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health. Each scale is transformed into a 0 (minimum) to 100 (maximum) scale on the assumption each question carries equal weight. These concepts were also summarized into 2 summary scores; Physical Component Summary and Mental Component Summary (both a 0-100 scale). The 8 subscales, 2 summary scores and transition Question 2 (TR Scale, measured on a scale of 1 [minimum] to 5 [maximum]) were subjected to analysis. Higher domain, summary scores, and TR scale scores indicate better health status. Model contained treatment, visit and treatment by visit interaction as fixed effects and Baseline (predose in Study A3921030) as a covariate. First-order autoregressive variance-covariance structure was used. | Months 24, 36 | 
| Least Squares Means of End-Stage Renal Disease (ESRD) Symptom Checklist (SCL) -Transplantation Modules at Months 24 and 36 | ESRD-SCL: a 43-item disease specific self-administered questionnaire. Participants' rated the question At the moment,how much do you suffer? for each item on a 5 point scale, range (Ra) from 0 (not at all) to 4 (extremely). Consisted of 6 subscales: Cardiac and Renal (CR) dysfunction; Ra 0 to 28, Increased(In) Growth of Gum and Hair (IGGH); Ra 0 to 20, Limited Cognitive Capacity (LCC); Ra 0 to 32, Limited Physical Capacity (LPC); Ra 0 to 40, Side Effects (SEs) of Corticosteroids; Ra 0 to 20, Transplantation Associated Psychological Distress (TAPD); Ra 0 to 32. Total Score: 0 to 172, higher scores indicate greater dysfunction. Model contained treatment, visit and treatment by visit interaction as fixed effects and Baseline (predose in Study A3921030) as a covariate. A first-order autoregressive variance-covariance structure was used. | Months 24, 36 | 
| Least Squares Means of Severity of Dyspepsia Assessment (SODA) Subscales at Months 24 & 36 | SODA:17-item health scale, assessed participant-reported perceptions of dyspepsia; consists of 3 subscales: Pain Intensity (PI, 6-items to assess pain and intensity of abdominal discomfort; Range: 2 to 47, higher score indicates greater pain and abdominal discomfort), Non-Pain Symptoms (NPS, 7-items to assess severity and impact of non-pain symptoms: burping/belching, heartburn, bloating, flatulence, sour taste, nausea, and bad breath; Range: 7 to 35, higher scores indicate increased symptom severity and influence), and Satisfaction (4-items to assess degree of satisfaction with abdominal discomfort; Range: 2 to 23, higher scores indicate more satisfaction). Model contained treatment, visit and treatment by visit interaction as fixed effects and Baseline (predose in Study A3921030) as a covariate. A first-order autoregressive variance-covariance structure was used. | Months 24, 36 | 
| Mean Trough Levels of Tofacitinib by Visit | The dates and times were recorded for the 6 doses of tofacitinib administered before each scheduled pharmacokinetic (PK) sampling. The participant was instructed to follow a 12 hourly schedule for these 6 doses of tofacitinib, with each dose administered within 1 hour of the scheduled time. Trough samples were collected 0 to 10 minutes prior to the morning dose. 1 hour postdose samples were required within 10 minutes of the nominal time point. Samples taken at -2 hours predose and at time points >1 hour post dose were required within 30 minutes of the nominal time point. | Months 18 and 24 (-2 hours, predose, 1 hour, 2 hours), Month 30 (predose, 1 hour and 2 hours), Month 36 (predose, 1, 2, and 4 hours), Months 42, 48, 54, 60, 66, 72 (predose and 2 hours) | 
| Mean Trough Levels of Cyclosporine by Visit | All CsA samples were taken predose (collected 0 to 10 minutes prior to the morning dose). | Predose: Months 18, 24, 36, 48, 60, 72 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunosuppression, JAK inhibitor, kidney transplantation