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

• Percentage of Participants With Graft Loss/Re-transplant, Death or Loss to Follow-up at 12 Months [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
  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 [ Time Frame: 12 Months ] [ Designated as safety issue: Yes ]

  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 [ Time Frame: Baseline, Month 12 ] [ Designated as safety issue: No ]
  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 [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
  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 [ Time Frame: 12 Months ] [ Designated as safety issue: No ]

  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 [ Time Frame: 24 Months ] [ Designated as safety issue: No ]

  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 [ Time Frame: 24 Months ] [ Designated as safety issue: No ]
  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 [ Time Frame: 24 Months ] [ Designated as safety issue: Yes ]

  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 [ Time Frame: 24 Months ] [ Designated as safety issue: No ]

  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.

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.

• Drug: everolimus
  Everolimus supplied as 0.75 mg tablets. Everolimus was also supplied in 0.25 mg and 0.5 mg tablets for dose adjustments.
  Other Names:

  • Zortress®
  • Certican®
• Drug: mycophenolate mofetil
  Mycophenolate mofetil supplied as 500 mg tablets.
  Other Name: Cellcept®
• Drug: cyclosporine
  Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm.
  Other Name: Neoral®
• Drug: corticosteroids
  Corticosteroids standard dose.

• Experimental: everolimus 1.5 mg
  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.
  Interventions:

  • Drug: everolimus
  • Drug: cyclosporine
  • Drug: corticosteroids
• Experimental: everolimus 3.0 mg

  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.

  Interventions:

  • Drug: everolimus
  • Drug: cyclosporine
  • Drug: corticosteroids
• Active Comparator: 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.
  Interventions:

  • Drug: mycophenolate mofetil
  • Drug: cyclosporine
  • Drug: corticosteroids

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.