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

Study Overview
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Brief Summary
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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.

Official Title
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A 24-month, Multi-center, Randomized, Open-label, Non-inferiority Study of Efficacy and Safety Comparing Two Exposures of Concentration-controlled Everolimus With Reduced Cyclosporine Versus 3.0 g Mycophenolate Mofetil With Standard Dose Cyclosporine in de Novo Heart Transplant Recipients

Conditions
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Graft Rejection

Intervention / Treatment
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* Drug: everolimus
* Drug: mycophenolate mofetil
* Drug: cyclosporine
* Drug: corticosteroids


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: everolimus 1.5 mg<br>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. | Drug: everolimus<br>* Everolimus supplied as 0.75 mg tablets. Everolimus was also supplied in 0.25 mg and 0.5 mg tablets for dose adjustments.<br>* Other names: Certican®;Drug: cyclosporine<br>* Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm.<br>* Other names: Neoral®;Drug: corticosteroids<br>* Corticosteroids standard dose.<br>|
| Experimental: everolimus 3.0 mg<br>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. | Drug: everolimus<br>* Everolimus supplied as 0.75 mg tablets. Everolimus was also supplied in 0.25 mg and 0.5 mg tablets for dose adjustments.<br>* Other names: Certican®;Drug: cyclosporine<br>* Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm.<br>* Other names: Neoral®;Drug: corticosteroids<br>* Corticosteroids standard dose.<br>|
| Active Comparator: mycophenolate mofetil<br>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. | Drug: mycophenolate mofetil<br>* Mycophenolate mofetil supplied as 500 mg tablets.<br>* Other names: Cellcept®;Drug: cyclosporine<br>* Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm.<br>* Other names: Neoral®;Drug: corticosteroids<br>* Corticosteroids standard dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Composite Efficacy Failure at 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. | 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Graft Loss/Re-transplant, Death or Loss to Follow-up at 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). | 12 Months | 
| Renal Function Measured by Glomerular Filtration Rate (GFR) at 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 | 12 Months | 
| Change From Baseline in the Average Maximum Intimal Thickness at 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. | Baseline, Month 12 | 
| Percentage of Participants With Cardiac Allograft Vasculopathy (CAV) at Month 12 | 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. | 12 Months | 
| 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 | 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. | 12 Months | 
| Percentage of Participants With Composite Efficacy Failure at 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. | 24 Months | 
| Percentage of Participants With Graft Loss/Re-transplant, Death or Loss to Follow-up at 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). | 24 Months | 
| Renal Function Calculated by Glomerular Filtration Rate (GFR) at 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 | 24 Months | 
| 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 | 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. | 24 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Everolimus, heart transplant, heart disease, transplantation, heart IVUS assessment at 12 months, rate of graft loss, acute rejection episodes, survival