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

• ClinicalTrials.gov Identifier: NCT00369382
• Recruitment Status: Completed
• First Posted: August 29, 2006
• Results First Posted: May 23, 2011
• Last Update Posted: May 30, 2011
• Sponsor: Wyeth is now a wholly owned subsidiary of Pfizer
• Information provided by: Wyeth is now a wholly owned subsidiary of Pfizer

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Graft Rejection; Kidney Failure	Drug: cyclosporine or tacrolimus; Drug: sirolimus	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 121 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Randomized Open-Label Study To Compare The Safety And Efficacy Of Conversion From A Calcineurin Inhibitor To Sirolimus Vs Continued Use Of A Calcineurin Inhibitor In Heart Transplant Recipients With Mild-Moderate Impaired Renal Function
• Study Start Date: September 2006
• Actual Primary Completion Date: April 2010
• Actual Study Completion Date: May 2010

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: 1; Group 1: Continuation of CNI regimen	Drug: cyclosporine or tacrolimus; Cyclosporine and tacrolimus are provided by the sites and dosed to achieve a target trough level determined by the investigator; therefore, form, dosage, and frequency are site and patient specific. Duration should be 52 weeks on-therapy.; Other Name: Brand names for cyclosporine are Neoral®, Sandimmune®, and Gengraf®; brand names for tacrolimus are Prograf® and Adagraf™.
Experimental: 2; Group 2: (CNI-Free) Conversion to SRL-based regimen	Drug: sirolimus; Oral (1 and 2 mg) tablets, dosing should be once daily to achieve a target trough level of 7- 15 ng/mL. Duration should be 52 weeks on-therapy.; Other Name: Rapamune®

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 52 Weeks Post-randomization [ Time Frame: 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.
2. Calculated Creatinine Clearance (Cockcroft-Gault Equation) at Baseline [ Time Frame: 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 :

1. Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization [ Time Frame: 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.
2. 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 [ Time Frame: 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.
3. Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at Baseline [ Time Frame: 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.
4. Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization [ Time Frame: 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.
5. Serum Creatinine Level at Baseline [ Time Frame: 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.
6. Annual Change in Calculated Creatinine Clearance (Cockcroft-Gault Equation) [ Time Frame: 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.
7. Overall Survival (OS) [ Time Frame: 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.
8. Number of Participants With Acute Rejection [ Time Frame: 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.
9. Number of Participants With Biopsy-confirmed Acute Rejection by Severity [ Time Frame: 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.
10. Time to First Acute Rejection [ Time Frame: 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.
11. Number of Participants Requiring Antibody Use in Treatment of Acute Rejection [ Time Frame: 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.
12. Number of Participants in Sirolimus Treatment Group Requiring Conversion Back to CNI Therapy [ Time Frame: Baseline up to Week 52 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Florida

Pfizer Investigational Site

Tampa, Florida, United States, 33606

United States, Minnesota

Pfizer Investigational Site

Rochester, Minnesota, United States, 55905

United States, New York

Pfizer Investigational Site

New York, New York, United States, 10027-6902

United States, Pennsylvania

Pfizer Investigational Site

Philadelphia, Pennsylvania, United States, 19102

Pfizer Investigational Site

Philadelphia, Pennsylvania, United States, 19104

Pfizer Investigational Site

Pittsburgh, Pennsylvania, United States, 15213

United States, Texas

Pfizer Investigational Site

Houston, Texas, United States, 77030

United States, Virginia

Pfizer Investigational Site

Norfolk, Virginia, United States, 23507

Australia, New South Wales

Pfizer Investigational Site

Darlinghurst, New South Wales, Australia, 2010

Austria

Pfizer Investigational Site

Vienna, Austria, A-1090

Canada, Quebec

Pfizer Investigational Site

Montreal, Quebec, Canada, H1T 1C8

Pfizer Investigational Site

Sainte-Foy, Quebec, Canada, G1V 4G5

Canada

Pfizer Investigational Site

Quebec, Canada, G1V 4G5

New Zealand

Pfizer Investigational Site

Epsom, Auckland, New Zealand, 1003

Pfizer Investigational Site

Auckland, New Zealand

Spain

Pfizer Investigational Site

L'Hospitalet de Llobregat, Barcelona, Spain, 08907

Pfizer Investigational Site

Santander, Cantabria, Spain, 39008

Pfizer Investigational Site

Barcelona, Spain, 08036

Pfizer Investigational Site

La Coru?a, Spain, 15001

Pfizer Investigational Site

Madrid, Spain, 28035

Pfizer Investigational Site

Sevilla, Spain, 41013

Pfizer Investigational Site

Valencia, Spain, 46009

Switzerland

Pfizer Investigational Site

Bern, Switzerland, 3010

Sponsors and Collaborators

Wyeth is now a wholly owned subsidiary of Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Zuckermann A, Keogh A, Crespo-Leiro MG, Mancini D, Vilchez FG, Almenar L, Brozena S, Eisen H, Tai SS, Kushwaha S. Randomized controlled trial of sirolimus conversion in cardiac transplant recipients with renal insufficiency. Am J Transplant. 2012 Sep;12(9):2487-97. doi: 10.1111/j.1600-6143.2012.04131.x. Epub 2012 Jul 9.

• Responsible Party: Director, Clinical Trial Disclosure Group, Pfizer, Inc
• ClinicalTrials.gov Identifier: NCT00369382
• Other Study ID Numbers: 0468E7-408; B1741006 ( Other Identifier: Pfizer )
• First Posted: August 29, 2006
• Results First Posted: May 23, 2011
• Last Update Posted: May 30, 2011
• Last Verified: May 2011

Keywords provided by Wyeth is now a wholly owned subsidiary of Pfizer:

Heart Transplant; Kidney Failure

Additional relevant MeSH terms:

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Cyclosporine; Sirolimus; Tacrolimus; Cyclosporins; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Calcineurin Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antifungal Agents; Anti-Infective Agents; Dermatologic Agents; Antirheumatic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antineoplastic Agents