A 6-Month Study Of CP-690,550 Versus Tacrolimus In Kidney Transplant Patients

Study Overview
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Brief Summary
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This Phase 2 study was designed to evaluate the safety and efficacy of 2 dose levels of CP-690,550 (15 mg twice daily and 30 mg twice) against tacrolimus, in combination with basiliximab induction, mycophenolate mofetil and corticosteroids, in kidney transplant patients. Stage 1 was to randomize approximately 54 subjects. After all Stage 1 subjects had completed 6 months of treatment, Stage 2 was to randomize an additional 195 subjects to the same treatment groups.

Official Title
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A 6-Month, Phase 2, Multicenter, Randomized, Open-Label, Comparative Study Of 2 Dose Levels Of CP-690,550 Administered Concomitantly With IL-2 Receptor Antagonist Induction Therapy, Mycophenolate Mofetil And Corticosteroids Versus A Tacrolimus-Based Immunosuppressive Regimen For The Prevention Of Allograft Rejection In De Novo Renal Allograft Recipients

Conditions
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Kidney Transplantation

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recipient of a first-time kidney transplant Between the ages of 18 and 70 years, inclusive Exclusion Criteria: Recipient of any non-kidney transplant

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 |
| --- | --- |
| Experimental: CP-690,550 15 mg BID<br> | Drug: CP-690,550<br>* 15 mg twice daily<br>|
| Experimental: CP-690,550 30 mg BID<br> | Drug: CP-690,550<br>* 30 mg twice daily<br>|
| Active Comparator: tacrolimus<br> | Drug: tacrolimus<br>* dose adjusted according to level<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With First Biopsy Proven Acute Rejection (BPAR) at Month 6 | BPAR categorized as acute rejection as interpreted by the central blinded pathologist according to the Banff 97 working classification. | Baseline up to Month 6 | 
| Glomerular Filtration Rate (GFR) by Nankivell Equation at Month 6 | GFR: index of kidney function described the flow rate of filtered fluid through the kidney. GFR was measured directly or estimated using established formulas. GFR was calculated by creatinine clearance (CLcr) using Nankivell equation. CLcr by Nankivell equation= (6.7 per serum creatinine) plus (0.25*body weight) minus (0.5*serum urea) minus (100 per square height) plus (35 for male/25 for female). A normal GFR is >90 milliliter/minute (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. | Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Failure | Treatment failure was defined as the first occurrence of BPAR, graft loss, participant's death or premature discontinuation of study medication for any reason. | Month 3, 6 | 
| Number of Participants With First Biopsy Proven Acute Rejection (BPAR) at Month 3 | BPAR categorized as acute rejection as interpreted by the central blinded pathologist according to the Banff 97 working classification. | Baseline up to Month 3 | 
| Number of Participants With First Biopsy Proven Chronic Allograft Nephropathy (BPCAN) | BPCAN categorized as chronic allograft nephropathy as interpreted by the central blinded pathologist according to the Banff 97 working classification. | Month 3, 6 | 
| Number of Participants With Ordered Categorical Severity of First Biopsy Proven Acute Rejection (BPAR) | Ordered categorical severity of first BPAR was classified according to the Banff Classification. Grade IA: moderate tubulitis, grade IB: severe tubulitis, grade IIA: mild to moderate intimal arteritis, grade IIB: severe intimal arteritis, grade III: transmural arteritis. (Racusen et al: The Banff classification, 1999). | Month 3, 6 | 
| Number of Participants With Ordered Categorical Severity of First Biopsy Proven Chronic Allograft Nephropathy (BPCAN) | Ordered categorical severity of first BPCAN was classified according to the Banff Classification. Grade I: mild, grade II: moderate and grade III: severe interstitial fibrosis and tubular atrophy/loss. (Racusen et al: The Banff classification, 1999). | Month 3, 6 | 
| Number of Participants With Efficacy Failure | Efficacy failure was the first occurrence of BPAR, graft loss or participant's death. | Month 3, 6 | 
| Number of Participants With Graft Loss | Graft loss was defined as graft nephrectomy, participant's death due to graft loss, re-transplantation, or return to dialysis for greater than or equal to (>=) 6 consecutive weeks. | Month 6 | 
| Number of Participants Who Died |  | Month 6 | 
| Number of Participants With Rejection | Rejection was defined as first occurrence of BPAR, antibody mediated rejection, or suspicious for acute rejection. | Month 3, 6 | 
| Population Pharmacokinetics (PK) | Data for this Outcome Measure are not reported here because the analysis population includes participants who were not enrolled in this study. ClinicalTrials.gov is designed for reporting results from only those participants who were enrolled in the study and described in the Participant Flow and Baseline Characteristics modules. | Pre-dose on Day 1, 3, 7, 14, Month 1, 3, 6, between 1 to 2 hours post-dose at Month 3 and between 3 to 4 hours post-dose at Month 6 | 
| Fluorescence-Activated Cell Sorting (FACS) of Lymphocyte Subsets | The absolute cell counts of cluster of differentiation 8 (CD8): Cytotoxic T-lymphocytes reactive with major histocompatibility complex-1 (MHC-I), CD19: B- Lymphocytes, CD56: natural killer cells were determined using FACS, a specialized type of flow cytometry which sorts a heterogeneous mixture based upon the specific light scattering and fluorescent characteristics of each cell. | Baseline, Day 14, Month 1, 3, 6 | 
| Reticulocyte Count | Reticulocytes are slightly immature red blood cells in the blood. Reticulocyte counts are reported as cells*10^3 per cubic millimeter (cells*10^3/mm^3). | Baseline, Day 14, Month 1, 3, 6 | 
| Trough Levels of Tacrolimus (TAC) |  | Pre-dose on Day 14, Month 1, 3, 6 | 
| 36-Item Short-Form Health Survey (SF-36) Version 2.0 (V2) | SF-36 is a standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. These 8 aspects can also be summarized as physical and mental component scores (CS). Total of 11 variables were analyzed (8 subscales, 2 composite subscales and Question 2 how would you rate your health in general now? (range 1= better, 5= worst). The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). | Baseline, Month 6 | 
| End-Stage Renal Disease Symptom Checklist-Transplantation Module (ESRD-SCL) | ESRD-SCL:43-item disease specific self-administered questionnaire. Participants' rated questionAt the moment,how much do you suffer?for each item on 5 point scale,ranged (Ra) 0(not at all)to 4(extremely).Consisted of 6 subscales:cardiac and renal dysfunction;Ra 0-28,increased(In) growth of gum and hair;Ra 0-20,limited cognitive capacity;Ra 0-32,limited physical capacity;Ra 0-40,side effects (SEs) of corticosteroids;Ra 0-20,transplantation associated psychological distress(TAPD);Ra 0-32(higher scores=greater dysfunction for each subscale).Total score:0-172,higher scores=greater dysfunction. | Baseline, Month 6 | 
| Healthcare Resource Utilization Questionnaire (HCRUQ) | Healthcare Resource Utilization Questionnaire (HCRUQ) was used to assess healthcare resources which included number of events such as physician and other health professional visits, number of treatments or diagnostic tests, number of hospitalizations, and number of emergency room visits. | Baseline, Month 6 | 
| Healthcare Resource Utilization Questionnaire (HCRUQ) - 5th Question | Fifth question in the HCRUQ was Upon discharge from the hospital, did you return to your previous place of residence? and number of participants who responded yes or no to the question was reported. | Month 6 | 
| Glomerular Filtration Rate (GFR) by Cockcroft-Gault | GFR: index of kidney function described the flow rate of filtered fluid through the kidney. GFR was measured directly or estimated using established formulas. GFR was calculated using Cockcroft-Gault equation. GFR by Cockcroft-Gault equation= body weight*(140 minus age in years) divided by (72*serum creatinine). 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. | Day 14, Month 1, 3, 6 | 
| Glomerular Filtration Rate (GFR) by Modification of Diet in Renal Disease (MDRD) Equation | GFR: index of kidney function described the flow rate of filtered fluid through the kidney. GFR was measured directly or estimated using established formulas. GFR was calculated using MDRD equation. GFR by MDRD equation= 170 * (serum creatinine) ^ (-0.999)*(age in years)^(-0.176)*(0.762 if female) * (1.18 if black)*(blood urea nitrogen concentration)^(-0.170)*(serum albumin concentration)^(0.318). Normal GFR is >90 mL/min/1.73 square meter (m^2), although children and older people usually have a lower GFR. Lower values indicated poor kidney function. A GFR <15 mL/min indicated kidney failure. | Day 14, Month 1, 3, 6 | 
| Glomerular Filtration Rate (GFR) by Reciprocal of Serum Creatinine (1/sCr) | GFR is a measure of renal function. The reciprocal of serum creatinine is an estimate of GFR. | Day 14, Month 1, 3, 6 | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) or 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. An 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. Treatment-emergent are events between first dose of study drug and up to 2 months after last dose that were absent before treatment or that worsened relative to pretreatment state. | Baseline up to Month 8 (2 months follow-up) | 
| Number of Participants With First Clinically Significant Infection | Clinically significant (Viral, Bacterial and Fungal) infection was defined as the presence of presumed or documented infection confirmed by culture, biopsy, genomic or serologic findings post-randomization and required hospitalization or anti-infective treatment, or otherwise deemed significant by the Investigator. | Month 3, 6 | 
| Number of Participants With New Onset Diabetes Mellitus (NODM) |  | Month 3, 6 | 
| Fasting Serum Glucose Levels |  | Baseline, Day 14, Month 1, 3, 6 | 
| Number of Participants With Hypercholesterolemia | Hypercholesterolemia is a condition characterized by very high levels of cholesterol in the blood. Hypercholesterolemia was defined as a value of total serum cholesterol greater than 240 mg/dL. | Baseline, Day 14, Month 1, 3, 6 | 
| Total Serum Cholesterol, Low Density Lipoprotein (LDL) and High Density Lipoprotein (HDL) Levels |  | Baseline, Day 14, Month 1, 3, 6 | 
| Number of Participants With Hypertriglyceridemia | Hypertriglyceridemia was defined as a value of triglycerides greater than 200 mg/dL. | Baseline, Day 14, Month 1, 3, 6 | 
| Supine Systolic and Diastolic Blood Pressure (BP) |  | Baseline, Day 2, 3, 14, Month 1, 3, 6 | 
| Number of Participants With Drug Usage | Lipid lowering agents, antihypertensive agents, oral hypoglycemic agents (OHA) , anti-diabetic agents (ADA) and insulin drug usage was collected. | Baseline, Day 14, Month 1, 3, 6 | 
| Epstein Barr Virus (EBV) and Cytomegalovirus (CMV) Deoxyribonucleic Acid (DNA) Load |  | Baseline, Month 1, 3, 6 for CMV; Baseline, Day 14, Month 1, 3, 6 for EBV | 
| BK Virus (BKV) Deoxyribonucleic Acid (DNA) Load |  | Baseline, Month 1, 3, 6 | 
| Number of Participants With Cytomegalovirus (CMV) Disease |  | Month 3, 6 | 
| Total White Blood Cells (WBC), Absolute Basophil, Absolute Eosinophil, Absolute Lymphocyte, Absolute Monocyte, Absolute Neutrophil |  | Baseline, Day 14, Month 1, 3, 6 | 
| Absolute Platelet Levels |  | Baseline, Day 14, Month 1, 3, 6 | 
| Hemoglobin Level | Hemoglobin is the protein molecule in red blood cells that carries oxygen from the lungs to the body's tissues and returns carbon dioxide from the tissues back to the lungs. | Baseline, Day 14, Month 1, 3, 6 | 
| Hematocrit Level | The hematocrit is recorded as the percentage of volume of red blood cells (RBCs) in a blood sample. | Baseline, Day 14, Month 1, 3, 6 | 
| Alanine Aminotransferase (ALT) Level | ALT is the enzyme found in the liver and it is measured to see if the liver is damaged or diseased. | Baseline, Day 14, Month 1, 3, 6 | 
| Electrocardiogram (ECG) Parameters | ECG parameters included PR interval, QT interval, corrected QT using Bazett's formula (QTcB) and QTc using Fridericia's formula (QTcF) interval, and QRS width. | Baseline, Month 3, 6 | 
| Number of Participants With Discontinuation |  | Month 1, 2, 3, 4, 5, 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tofacitinib, CP-690550, kidney transplant