Study Of The Safety And Efficacy Of Conversion From A CNI To Sirolimus In Renally-Impaired Heart Transplant Recipients

Phase 4

Completed

Conditions: Graft Rejection
Kidney Failure

Interventions: Drug: cyclosporine or tacrolimus
Drug: sirolimus

Registration Number: NCT00369382

Lead Sponsor: Wyeth is now a wholly owned subsidiary of Pfizer

Brief Summary: The primary purpose of this study is to determine whether converting from calcineurin inhibitor (CNI) therapy to sirolimus therapy will be more effective than continuing calcineurin inhibitor therapy with respect to renal function in cardiac transplant recipients with mild to moderate renal dysfunction.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 121

Inclusion Criteria

Cardiac transplant recipients age 18 years or older receiving cyclosporine or tacrolimus since the time of transplant.
12 months after cardiac transplantation but less than 96 months post-transplantation.

Exclusion Criteria

Multiple-organ transplant recipients (such as heart-lung, heart-kidney, or heart after kidney transplant recipients).
Prior or current use of sirolimus or everolimus unless administration was part of a "CNI holiday" lasting no more than 10 days.
History of acute rejection within the last 3 months, malignancy within the last 5 years (except for adequately treated basal cell or squamous cell carcinoma of the skin), and human immunodeficiency virus (HIV) patients.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1	cyclosporine or tacrolimus	Group 1: Continuation of CNI regimen
2	sirolimus	Group 2: (CNI-Free) Conversion to SRL-based regimen

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 52 Weeks Post-randomization	Baseline and Week 52	Creatinine Clearance (CC) calculated using Cockcroft-Gault equation, adjusted for body surface area. Calculated CC: method to approximate kidney function. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is greater than or equal to (≥) 90 milliliters per minute per 1.73 meters squared (mL/min/1.73m\^2). Change from baseline=CC at Week 52 minus CC at baseline where higher scores represented improved renal function; Least squares mean adjusted for baseline calculated creatinine clearance and center.
Calculated Creatinine Clearance (Cockcroft-Gault Equation) at Baseline	Baseline	Creatinine clearance at baseline calculated using Cockcroft-Gault equation and adjusted for body surface area. Calculated CC: method to approximate kidney function. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is ≥ 90 mL/min/1.73m\^2.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization	Baseline and Weeks 4, 16, 24, 32, and 40	Creatinine Clearance (CC) calculated using Cockcroft-Gault equation, adjusted for body surface area. Calculated CC: method to approximate kidney function. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is ≥ 90 mL/min/1.73m\^2. Change from baseline=CC at Week X minus CC at baseline where higher scores represented improved renal function; Least squares mean adjusted for baseline calculated creatinine clearance and center.
Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization	Baseline and Weeks 4, 16, 24, 32, 40 and 52	Creatinine clearance calculated using MDRD equation. Normal adult creatinine clearance is ≥ 90 mL/min/1.73m\^2. Change from baseline=CC at Week X minus CC at baseline where higher scores represented improved renal function. Least squares mean adjusted for baseline calculated creatinine clearance (MDRD) and center.
Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at Baseline	Baseline	Creatinine clearance calculated using MDRD equation. Calculated CC: method to approximate kidney function. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is ≥ 90 mL/min/1.73m\^2.
Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization	Baseline and Weeks 4, 16, 24, 32, 40, and 52	Serum creatinine is an indicator of kidney function. Creatinine is a substance formed from the metabolism of creatine, commonly found in blood, urine, and muscle tissue. It is removed from the blood by the kidneys and excreted in urine. Normal adult blood levels of creatinine=45 to 90 micromoles per liter (mcmol/L) for females, 60 to 110 mcmol/L for males, however normal values are age-dependent. Change from baseline=creatinine level at Week x minus baseline level where higher scores represented decreased kidney function. Least squares mean adjusted for treatment group and center.
Serum Creatinine Level at Baseline	Baseline	Serum creatinine is an indicator of kidney function. Creatinine is a substance formed from the metabolism of creatine, commonly found in blood, urine, and muscle tissue. It is removed from the blood by the kidneys and excreted in urine.
Annual Change in Calculated Creatinine Clearance (Cockcroft-Gault Equation)	Baseline to discontinuation (up to Week 52)	The change in creatinine clearance over time assessed using the random coefficient slope of the regression line with creatinine clearance as the dependent variable and study day as the independent variable. Time points calculated as study days, relative to time of randomization of study medication. Observed data multiplied by a scale factor of 365 to express an annual change.
Overall Survival (OS)	Baseline until death (up to Week 56)	Survival time from the start of study treatment to date of death due to any cause, censored at the last visit if no death. Death was determined from the Death report. The distribution of time to death was to be estimated using Kaplan-Meier method and compared between treatment groups with a proportional hazard model. The number and percent of survival at 6 and 12 months were to be reported.
Number of Participants With Acute Rejection	Baseline to Week 52	Based on International Society for Heart and Lung Transplantation \[ISHLT\] 1990 criteria: rejections Grade 3A or higher, rejection accompanied by hemodynamic compromise or requiring treatment. Grade 3A or higher included: multifocal aggressive infiltrates and/or myocyte damage, diffuse inflammatory process with necrosis, diffuse aggressive polymorphus with necrosis, increased infiltrates, and changes in edema, hemorrhage, or vasculitis. Biopsies performed for clinically suspected rejection (for cause), site's standard of care (site protocol biopsy), or protocol mandated.
Number of Participants With Biopsy-confirmed Acute Rejection by Severity	Baseline to Week 52	Severity of acute rejection summarized using revised 2005 ISHLT criteria. Grade 0R: no rejection, Grade 1R: Focal (perivascular or interstitial) infiltrate without necrosis, diffuse but sparse infiltrate without necrosis, or one focus only with aggressive infiltration and/or focal myocyte damage, Grade 2R:Multifocal aggressive infiltrates and/or myocyte damage, and Grade 3R:Diffuse inflammatory process with necrosis, or diffuse aggressive polymorphous with necrosis, increased infiltrate, changes in edema, hemorrhage and vasculitis.
Time to First Acute Rejection	Baseline to Week 52	Time from baseline to first biopsy-confirmed acute rejection defined as any of the following (based on ISHLT 1990 criteria): all rejections Grade 3A or higher, any rejection accompanied by hemodynamic compromise, or any rejection requiring treatment. ISHLT Grade 3A or higher included: Multifocal aggressive infiltrates and/or myocyte damage, diffuse inflammatory process with necrosis, diffuse aggressive polymorphus with necrosis, increased infiltrates, and changes in edema, hemorrhage, or vasculitis.
Number of Participants Requiring Antibody Use in Treatment of Acute Rejection	Baseline to Week 52	Number of participants requiring antilymphocyte antibody therapy with suspected or biopsy-proven, steroid-resistant, acute rejection with or without hemodynamic compromise. Acute rejection based on ISHLT 1990 criteria: all rejections Grade 3A or higher, any rejection accompanied by hemodynamic compromise, or any rejection requiring treatment. ISHLT Grade 3A or higher included: Multifocal aggressive infiltrates and/or myocyte damage, diffuse inflammatory process with necrosis, diffuse aggressive polymorphus with necrosis, increased infiltrates, and changes in edema, hemorrhage, or vasculitis.
Number of Participants in Sirolimus Treatment Group Requiring Conversion Back to CNI Therapy	Baseline up to Week 52