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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00300274
First received: March 6, 2006
Last updated: July 10, 2012
Last verified: July 2012
  Purpose

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.


Condition Intervention Phase
Graft Rejection
Drug: everolimus
Drug: mycophenolate mofetil
Drug: cyclosporine
Drug: corticosteroids
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Percentage of Participants With Composite Efficacy Failure at 12 Months [ Time Frame: 12 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(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:
  • 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.



Enrollment: 721
Study Start Date: January 2006
Study Completion Date: July 2011
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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: 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 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:
  • Zortress®
  • Certican®
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.
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.
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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00300274

  Show 64 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Novartis
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00300274     History of Changes
Other Study ID Numbers: CRAD001A2310
Study First Received: March 6, 2006
Results First Received: July 6, 2012
Last Updated: July 10, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
Everolimus
heart transplant
heart disease
transplantation
heart IVUS assessment at 12 months
rate of graft loss
acute rejection episodes
survival

Additional relevant MeSH terms:
Cyclosporins
Cyclosporine
Mycophenolic Acid
Mycophenolate mofetil
Everolimus
Sirolimus
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on April 17, 2014