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

Kidney Transplantation Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00658359
• Other study ID #: A3921050
• Secondary ID: 2008-002345-23
• Status: Completed
• Phase: Phase 2
• First received: April 9, 2008
• Last updated: February 20, 2018
• Start date: August 2008
• Est. completion date: June 2015

Study information

• Verified date: February 2018
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 178
• Est. completion date: June 2015
• Est. primary completion date: March 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Kidney Transplantation

Intervention

Drug:
• Cyclosporine
Standard of care
• CP-690,550
CP-690,550 tablets dosed BID Months 12-72
• CP-690,550
CP-690,550 tablets dosed BID Months 12-72

Locations

Country	Name	City	State
Australia	Central Northern Adelaide Renal and Transplantation Service	Adelaide	South Australia
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Westmead Hospital, Department of Renal Medicine	Westmead	New South Wales
Australia	The Queen Elizabeth Hospital	Woodville	South Australia
Belgium	Hopital Erasme	Anderlecht	Brussels
Belgium	Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg	Leuven
Brazil	Irmandade Santa Casa de Misericordia de Porto Alegre	Porto Alegre	RS
Brazil	Ambulatorio Pos Transplante do Hospital do Rim a Hipertensao	Sao Paulo	SP
Brazil	Hospital do Rim e Hipertensao	Sao Paulo
Brazil	Hospital do Rim e Hipertensao	Sao Paulo	SP
Canada	University of Alberta Hospital	Edmonton	Alberta
Czechia	Institut Klinicke a Experimentalni Mediciny	Praha 4 Krc
France	Hopital Necker	Paris Cedex 15
France	CHRU de Nancy-Brabois - Service de Nephrologie	Vandoeuvre Les Nancy
Germany	Charite - Universitatsmedizin Berlin	Berlin
Italy	Azienda Ospedaliero Universitaria di Bologna Policlinico Sant'Orsola Malpighi	Bologna
Italy	Istituto di Clinica Chirurgica, Universita Cattolica del Sacro Cuore	Roma	RM
Korea, Republic of	Asan Medical Center, Department of Surgery	Seoul
Korea, Republic of	Department of Surgery, Yonsei University College of Medicine Severance Hospital	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Netherlands	Erasmus Medisch Centrum	Rotterdam
Norway	Oslo universitetssykehus HF- Rikshospitalet	Oslo
Poland	Akademicki Szpital Kliniczny im. J. Mikulicza - Radeckiego we Wroclawiu	Wroclaw
Portugal	Hospitais da Universidade de Coimbra, EPE	Coimbra
Portugal	Hospital Curry Cabral	Lisboa
Spain	Hospital Clinic i Provincial de Barcelona	Barcelona
Spain	Hospital Universitari de Bellvitge	Hospitalet de Llobregat	Barcelona
United States	University of Michigan Health System	Ann Arbor	Michigan
United States	University of Colorado Denver	Aurora	Colorado
United States	Division of Pharmacotherapy, School of Pharmacy, University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Investigational Drug Services (IDS) / UNC Healthcare	Chapel Hill	North Carolina
United States	Transplant Clinic/UNC Heathcare	Chapel Hill	North Carolina
United States	UNC Department of Surgery, Clinical Trials Consortium	Chapel Hill	North Carolina
United States	UNC Department of Surgery/Abdominal Transplant Division	Chapel Hill	North Carolina
United States	University of North Carolina, Department of Medicine/Nephrology	Chapel Hill	North Carolina
United States	Medical University of South Carolina, Department of Transplantation Surgery	Charleston	South Carolina
United States	Nephrology Clinic	Charleston	South Carolina
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	NUCATS's Clinical Research Unit	Chicago	Illinois
United States	Annette C. and Harold C. Simmons Transplant Institute at Baylor University Medical Center	Dallas	Texas
United States	Baylor University Medical Center	Dallas	Texas
United States	Dallas Transplant Institute	Dallas	Texas
United States	Henry Ford Hospital	Detroit	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	University Of Florida	Gainesville	Florida
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Cedars-Sinai MedicalCenter	Los Angeles	California
United States	Ronald Reagan UCLA Medical Center	Los Angeles	California
United States	UCLA Medical Center	Los Angeles	California
United States	Yale Physicians Building	New Haven	Connecticut
United States	Yale-New Haven Hospital	New Haven	Connecticut
United States	Stanford School of Medicine	Palo Alto	California
United States	Stanford University Medical Center	Palo Alto	California
United States	Drexel University College of Medicine - Hahnemann University Hospital	Philadelphia	Pennsylvania
United States	Hahnemann University Hospital	Philadelphia	Pennsylvania
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Balboa Institute of Transplantation	San Diego	California
United States	California Institute of Renal Research	San Diego	California
United States	Sharp Memorial Hospital	San Diego	California
United States	California Pacific Medical Center	San Francisco	California
United States	California Pacific Medical Center - Pacific Campus	San Francisco	California
United States	UCSF Medical Center - Long Hospital	San Francisco	California
United States	USCF Medical Center - Connie Frank Transplant Center	San Francisco	California
United States	Tampa General Hospital	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  Czechia,  France,  Germany,  Italy,  Korea, Republic of,  Netherlands,  Norway,  Poland,  Portugal,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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.
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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

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