Efficacy and Safety of Everolimus in Recipients of Heart Transplants to Prevent Acute and Chronic Rejection

Phase 3

Completed

Conditions: Graft Rejection

Interventions: Drug: mycophenolate mofetil
Drug: everolimus
Drug: cyclosporine
Drug: corticosteroids

Registration Number: NCT00300274

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: This trial was to examine the impact of everolimus and reduced dose of cyclosporine on efficacy and safety compared to mycophenolate mofetil and a standard dose of cyclosporine in heart transplant recipients.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 721

Inclusion Criteria

Male or female cardiac recipients 18-70 years of age undergoing primary heart transplantation.
The graft must be functional at time of randomization.

Exclusion Criteria

Patients who are recipients of multiple solid organ transplants or tissue transplants or have previously received organ transplants.
Patients who are recipients of ABO incompatible transplants.

Other protocol-defined inclusion/exclusion criteria may apply.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
everolimus 1.5 mg	corticosteroids	Within 72 hours after transplantation participants received 0.75 mg everolimus tablets twice a day 12 hours apart for a total 1.5 mg daily dose in combination with reduced cyclosporine and standard dose corticosteroids for 24 months. The everolimus dose could be adjusted to maintain a target everolimus trough level of 3-8 ng/mL.
everolimus 3.0 mg	cyclosporine	Within 72 hours after transplantation participants received 1.5 mg everolimus tablets twice a day 12 hours apart for a total 3.0 mg daily dose in combination with reduced cyclosporine and standard dose corticosteroids for 24 months. The everolimus dose could be adjusted to maintain a target everolimus trough level of 6-12 ng/mL. Randomization of new patients in this arm was prematurely stopped as of 27 March 2008 due to high mortality rate, as per Data Monitoring Committee.
everolimus 3.0 mg	corticosteroids	Within 72 hours after transplantation participants received 1.5 mg everolimus tablets twice a day 12 hours apart for a total 3.0 mg daily dose in combination with reduced cyclosporine and standard dose corticosteroids for 24 months. The everolimus dose could be adjusted to maintain a target everolimus trough level of 6-12 ng/mL. Randomization of new patients in this arm was prematurely stopped as of 27 March 2008 due to high mortality rate, as per Data Monitoring Committee.
mycophenolate mofetil	mycophenolate mofetil	Within 72 hours after transplantation participants received 3 tablets 500 mg mycophenolate mofetil twice a day 12 hours apart for a total daily dose of 3000 mg in combination with a standard cyclosporine dose and standard dose corticosteroids for 24 months.
everolimus 3.0 mg	everolimus	Within 72 hours after transplantation participants received 1.5 mg everolimus tablets twice a day 12 hours apart for a total 3.0 mg daily dose in combination with reduced cyclosporine and standard dose corticosteroids for 24 months. The everolimus dose could be adjusted to maintain a target everolimus trough level of 6-12 ng/mL. Randomization of new patients in this arm was prematurely stopped as of 27 March 2008 due to high mortality rate, as per Data Monitoring Committee.
mycophenolate mofetil	corticosteroids	Within 72 hours after transplantation participants received 3 tablets 500 mg mycophenolate mofetil twice a day 12 hours apart for a total daily dose of 3000 mg in combination with a standard cyclosporine dose and standard dose corticosteroids for 24 months.
everolimus 1.5 mg	everolimus	Within 72 hours after transplantation participants received 0.75 mg everolimus tablets twice a day 12 hours apart for a total 1.5 mg daily dose in combination with reduced cyclosporine and standard dose corticosteroids for 24 months. The everolimus dose could be adjusted to maintain a target everolimus trough level of 3-8 ng/mL.
everolimus 1.5 mg	cyclosporine	Within 72 hours after transplantation participants received 0.75 mg everolimus tablets twice a day 12 hours apart for a total 1.5 mg daily dose in combination with reduced cyclosporine and standard dose corticosteroids for 24 months. The everolimus dose could be adjusted to maintain a target everolimus trough level of 3-8 ng/mL.
mycophenolate mofetil	cyclosporine	Within 72 hours after transplantation participants received 3 tablets 500 mg mycophenolate mofetil twice a day 12 hours apart for a total daily dose of 3000 mg in combination with a standard cyclosporine dose and standard dose corticosteroids for 24 months.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Composite Efficacy Failure at 12 Months	12 Months	Composite efficacy failure was defined as Biopsy Proven Acute Rejection(BPAR) of International Society for Heart and Lung Transplantation(ISHLT) grade ≥3A, Acute Rejection associated with Hemodynamic Compromise, Graft loss/Retransplant, Death or Loss to follow-up. Identification of acute rejection was based on the local pathologist's evaluation of endomyocardial biopsy slides. Hemodynamic compromise was present if 1 or more of the following were met: Ejection fraction ≤30% or 25% lower than Baseline or Fractional shortening ≤20% or 25% lower than Baseline and/or use of inotropic treatment.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Graft Loss/Re-transplant, Death or Loss to Follow-up at 12 Months	12 Months	Loss to follow-up for this composite endpoint included participants who did not experience graft loss/re-transplant or death and whose last day of contact was prior to Day 316 (start day of the Month 12 visit window).
Renal Function Measured by Glomerular Filtration Rate (GFR) at 12 Months	12 Months	GFR was calculated using the Modification of Diet and Renal Disease (MDRD) formula: GFR \[mL/min/1.73m\^2\] = 186.3\(C\^-1.154)\(A\^-0.203)\G\R where C is the serum concentration of creatinine \[mg/dL\] A is age \[years\] G=0.742 when gender is female, otherwise G=1 R=1.21 when race is black, otherwise R=1
Change From Baseline in the Average Maximum Intimal Thickness at Month 12	Baseline, Month 12	Maximum intimal thickness was assessed using Intravascular Ultrasound (IVUS). IVUS is a technique for taking ultrasound pictures of the wall of an artery from inside the artery itself. It shows the thickness of the artery wall and any narrowing of the artery.
Percentage of Participants With Cardiac Allograft Vasculopathy (CAV) at Month 12	12 Months	Cardiac allograft vasculopathy is defined as a 0.5 mm increase in maximum intimal thickness as measured by Intravascular Ultrasound (IVUS) in at least one matched slice between baseline and Month 12.
Percentage of Participants With Biopsy-proven Acute Rejection (BPAR of ISHLT Grade ≥ 3A), Acute Rejection Associated With Hemodynamic Compromise (HDC), Graft Loss/Re-transplant and Death at Month 12	12 Months	Identification of acute rejections was based on the local pathologist's evaluation of endomyocardial biopsy slides. Hemodynamic compromise was present if 1 or more of the following were met: Ejection fraction ≤ 30% or 25% lower than Baseline or Fractional shortening ≤ 20% or 25% lower than Baseline, and/or use of inotropic treatment.
Percentage of Participants With Composite Efficacy Failure at 24 Months	24 Months	Composite efficacy failure was defined as Biopsy Proven Acute Rejection (BPAR) of International Society for Heart and Lung Transplantation grade ≥ 3A, Acute Rejection associated with Hemodynamic Compromise, Graft loss/Retransplant, Death or Loss to follow-up. Identification of acute rejections was based on the local pathologist's evaluation of endomyocardial biopsy slides. Hemodynamic compromise was present if 1 or more of the following were met: Ejection fraction ≤ 30% or 25% lower than Baseline or Fractional shortening ≤ 20% or 25% lower than Baseline and/or use of inotropic treatment.
Percentage of Participants With Graft Loss/Re-transplant, Death or Loss to Follow-up at 24 Months	24 Months	Loss to follow-up for this composite endpoint included participants who did not experience graft loss/re-transplant or death and whose last day of contact was prior to Day 631 (start day of 24 Month visit window).
Renal Function Calculated by Glomerular Filtration Rate (GFR) at 24 Months	24 Months	GFR was calculated using the Modification of Diet and Renal Disease (MDRD) formula: GFR \[mL/min/1.73m\^2\] = 186.3\(C\^-1.154)\(A\^-0.203)\G\R C is the serum concentration of creatinine \[mg/dL\] A is age \[years\] G=0.742 when gender is female, otherwise G=1 R=1.21 when race is black, otherwise R=1
Percentage of Participants With Biopsy-proven Acute Rejection (BPAR of ISHLT Grade ≥ 3A), Acute Rejection (AR) Associated With Hemodynamic Compromise (HDC), Graft Loss/Re-transplant and Death at Month 24	24 Months	Identification of acute rejections was based on the local pathologist's evaluation of endomyocardial biopsy slides. Hemodynamic compromise was present if 1 or more of the following were met: Ejection fraction ≤ 30% or 25% lower than Baseline or Fractional shortening ≤ 20% or 25% lower than Baseline, and/ or use of inotropic treatment.

Trial Locations

Locations (64): UCLA Medical Center
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Los Angeles, California, United States
California Pacific Medical Center
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San Francisco, California, United States
Stanford U Sch, Falk Cardiovasular Research Ctr.
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Stanford, California, United States
University of Florida Shands Hospital
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Gainesville, Florida, United States
Emory University Hospital
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Atlanta, Georgia, United States
Loyola Univerisity Medical School
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Maywood, Illinois, United States
Massachusetts General Hospital
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Boston, Massachusetts, United States
Tufts Medical Center
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Boston, Massachusetts, United States
University of Michigan Health System
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Ann Arbor, Michigan, United States
Washington University School of Medicine
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St. Louis, Missouri, United States
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UCLA Medical Center
🇺🇸Los Angeles, California, United States