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

This study has been completed.
Sponsor:
Information provided by:
Wyeth is now a wholly owned subsidiary of Pfizer
ClinicalTrials.gov Identifier:
NCT00369382
First received: August 25, 2006
Last updated: May 25, 2011
Last verified: May 2011
  Purpose

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 Intervention Phase
Graft Rejection
Kidney Failure
Drug: cyclosporine or tacrolimus
Drug: sirolimus
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Wyeth is now a wholly owned subsidiary of Pfizer:

Primary Outcome Measures:
  • Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 52 Weeks Post-randomization [ Time Frame: Baseline and Week 52 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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:
  • 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 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and Weeks 4, 16, 24, 32, 40 and 52 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and Weeks 4, 16, 24, 32, 40, and 52 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline to discontinuation (up to Week 52) ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline until death (up to Week 56) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Baseline up to Week 52 ] [ Designated as safety issue: Yes ]

Enrollment: 121
Study Start Date: September 2006
Study Completion Date: May 2010
Primary Completion Date: April 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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®

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00369382

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:
No publications provided by Wyeth is now a wholly owned subsidiary of Pfizer

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Director, Clinical Trial Disclosure Group, Pfizer, Inc
ClinicalTrials.gov Identifier: NCT00369382     History of Changes
Other Study ID Numbers: 0468E7-408, B1741006
Study First Received: August 25, 2006
Results First Received: April 26, 2011
Last Updated: May 25, 2011
Health Authority: Australia: Human Research Ethics Committee
Austria: Federal Ministry for Health and Women
Canada: Health Canada
New Zealand: Health Research Council
Spain: Ministry of Health
Switzerland: Swissmedic
United States: Food and Drug Administration

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
Cyclosporins
Cyclosporine
Sirolimus
Everolimus
Tacrolimus
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on July 23, 2014