Efficacy and Safety of Everolimus in Recipients of Heart Transplants to Prevent Acute and Chronic Rejection
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| ClinicalTrials.gov Identifier: NCT00300274 |
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Recruitment Status :
Completed
First Posted : March 8, 2006
Results First Posted : August 16, 2012
Last Update Posted : August 16, 2012
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Graft Rejection | Drug: everolimus Drug: mycophenolate mofetil Drug: cyclosporine Drug: corticosteroids | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 721 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | 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 |
| Study Start Date : | January 2006 |
| Actual Primary Completion Date : | July 2011 |
| Actual Study Completion Date : | July 2011 |
| Arm | Intervention/treatment |
|---|---|
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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.
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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:
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. |
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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. |
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:
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. |
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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.
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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. |
- Percentage of Participants With Composite Efficacy Failure at 12 Months [ Time Frame: 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.
- Percentage of Participants With Graft Loss/Re-transplant, Death or Loss to Follow-up at 12 Months [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
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| Ages Eligible for Study: | 18 Years to 70 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00300274
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| Study Director: | Novartis | Novartis |
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT00300274 |
| Other Study ID Numbers: |
CRAD001A2310 |
| First Posted: | March 8, 2006 Key Record Dates |
| Results First Posted: | August 16, 2012 |
| Last Update Posted: | August 16, 2012 |
| Last Verified: | July 2012 |
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Everolimus heart transplant heart disease transplantation |
heart IVUS assessment at 12 months rate of graft loss acute rejection episodes survival |
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Cyclosporine Mycophenolic Acid Everolimus Cyclosporins Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antifungal Agents |
Anti-Infective Agents Dermatologic Agents Antirheumatic Agents Calcineurin Inhibitors Antineoplastic Agents Antibiotics, Antineoplastic Antibiotics, Antitubercular Antitubercular Agents Anti-Bacterial Agents |