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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

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

ClinicalTrials.gov processed this record on September 16, 2014