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

Primary Purpose

Graft Rejection, Kidney Failure

Status
Completed
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
cyclosporine or tacrolimus
sirolimus
Sponsored by
Wyeth is now a wholly owned subsidiary of Pfizer
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Graft Rejection focused on measuring Heart Transplant, Kidney Failure

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site
  • Pfizer Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

1

2

Arm Description

Group 1: Continuation of CNI regimen

Group 2: (CNI-Free) Conversion to SRL-based regimen

Outcomes

Primary Outcome Measures

Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 52 Weeks Post-randomization
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
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
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
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
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
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
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)
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)
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
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
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 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
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

Full Information

First Posted
August 25, 2006
Last Updated
May 25, 2011
Sponsor
Wyeth is now a wholly owned subsidiary of Pfizer
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1. Study Identification

Unique Protocol Identification Number
NCT00369382
Brief Title
Study Of The Safety And Efficacy Of Conversion From A CNI To Sirolimus In Renally-Impaired Heart Transplant Recipients
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 Type
Interventional

2. Study Status

Record Verification Date
May 2011
Overall Recruitment Status
Completed
Study Start Date
September 2006 (undefined)
Primary Completion Date
April 2010 (Actual)
Study Completion Date
May 2010 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Wyeth is now a wholly owned subsidiary of Pfizer

4. Oversight

Data Monitoring Committee
Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft Rejection, Kidney Failure
Keywords
Heart Transplant, Kidney Failure

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
121 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Active Comparator
Arm Description
Group 1: Continuation of CNI regimen
Arm Title
2
Arm Type
Experimental
Arm Description
Group 2: (CNI-Free) Conversion to SRL-based regimen
Intervention Type
Drug
Intervention Name(s)
cyclosporine or tacrolimus
Other Intervention Name(s)
Brand names for cyclosporine are Neoral®, Sandimmune®, and Gengraf®; brand names for tacrolimus are Prograf® and Adagraf™.
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
sirolimus
Other Intervention Name(s)
Rapamune®
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 52 Weeks Post-randomization
Description
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.
Time Frame
Baseline and Week 52
Title
Calculated Creatinine Clearance (Cockcroft-Gault Equation) at Baseline
Description
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.
Time Frame
Baseline
Secondary Outcome Measure Information:
Title
Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization
Description
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.
Time Frame
Baseline and Weeks 4, 16, 24, 32, and 40
Title
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
Description
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.
Time Frame
Baseline and Weeks 4, 16, 24, 32, 40 and 52
Title
Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at Baseline
Description
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.
Time Frame
Baseline
Title
Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization
Description
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.
Time Frame
Baseline and Weeks 4, 16, 24, 32, 40, and 52
Title
Serum Creatinine Level at Baseline
Description
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.
Time Frame
Baseline
Title
Annual Change in Calculated Creatinine Clearance (Cockcroft-Gault Equation)
Description
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.
Time Frame
Baseline to discontinuation (up to Week 52)
Title
Overall Survival (OS)
Description
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.
Time Frame
Baseline until death (up to Week 56)
Title
Number of Participants With Acute Rejection
Description
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.
Time Frame
Baseline to Week 52
Title
Number of Participants With Biopsy-confirmed Acute Rejection by Severity
Description
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 Frame
Baseline to Week 52
Title
Time to First Acute Rejection
Description
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.
Time Frame
Baseline to Week 52
Title
Number of Participants Requiring Antibody Use in Treatment of Acute Rejection
Description
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.
Time Frame
Baseline to Week 52
Title
Number of Participants in Sirolimus Treatment Group Requiring Conversion Back to CNI Therapy
Time Frame
Baseline up to Week 52

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Pfizer CT.gov Call Center
Organizational Affiliation
Pfizer
Official's Role
Study Director
Facility Information:
Facility Name
Pfizer Investigational Site
City
Tampa
State/Province
Florida
ZIP/Postal Code
33606
Country
United States
Facility Name
Pfizer Investigational Site
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Pfizer Investigational Site
City
New York
State/Province
New York
ZIP/Postal Code
10027-6902
Country
United States
Facility Name
Pfizer Investigational Site
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19102
Country
United States
Facility Name
Pfizer Investigational Site
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Pfizer Investigational Site
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
Pfizer Investigational Site
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Pfizer Investigational Site
City
Norfolk
State/Province
Virginia
ZIP/Postal Code
23507
Country
United States
Facility Name
Pfizer Investigational Site
City
Darlinghurst
State/Province
New South Wales
ZIP/Postal Code
2010
Country
Australia
Facility Name
Pfizer Investigational Site
City
Vienna
ZIP/Postal Code
A-1090
Country
Austria
Facility Name
Pfizer Investigational Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H1T 1C8
Country
Canada
Facility Name
Pfizer Investigational Site
City
Sainte-Foy
State/Province
Quebec
ZIP/Postal Code
G1V 4G5
Country
Canada
Facility Name
Pfizer Investigational Site
City
Quebec
ZIP/Postal Code
G1V 4G5
Country
Canada
Facility Name
Pfizer Investigational Site
City
Epsom
State/Province
Auckland
ZIP/Postal Code
1003
Country
New Zealand
Facility Name
Pfizer Investigational Site
City
Auckland
Country
New Zealand
Facility Name
Pfizer Investigational Site
City
L'Hospitalet de Llobregat
State/Province
Barcelona
ZIP/Postal Code
08907
Country
Spain
Facility Name
Pfizer Investigational Site
City
Santander
State/Province
Cantabria
ZIP/Postal Code
39008
Country
Spain
Facility Name
Pfizer Investigational Site
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Pfizer Investigational Site
City
La Coru?a
ZIP/Postal Code
15001
Country
Spain
Facility Name
Pfizer Investigational Site
City
Madrid
ZIP/Postal Code
28035
Country
Spain
Facility Name
Pfizer Investigational Site
City
Sevilla
ZIP/Postal Code
41013
Country
Spain
Facility Name
Pfizer Investigational Site
City
Valencia
ZIP/Postal Code
46009
Country
Spain
Facility Name
Pfizer Investigational Site
City
Bern
ZIP/Postal Code
3010
Country
Switzerland

12. IPD Sharing Statement

Citations:
PubMed Identifier
22776430
Citation
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.
Results Reference
derived
Links:
URL
https://trialinfoemail.pfizer.com/pages/landing.aspx?StudyID=0468E7-408&StudyName=Study%20Of%20The%20Safety%20And%20Efficacy%20Of%20Conversion%20From%20A%20CNI%20To%20Sirolimus%20In%20Renally-Impaired%20Heart%20Transplant%20Recipients
Description
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Learn more about this trial

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

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