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

July 10, 2012 updated by: Novartis Pharmaceuticals

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

721

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Argentina
      • Buenos Aires, Argentina
        • Fundacion Favalaro
    • Santa Fe
      • Rosario, Santa Fe, Argentina
        • Sanatorio Parque
  • Australia
    • New South Wales
      • Darlinghurst, New South Wales, Australia
        • St Vincents Hospital
    • Queensland
      • Chermside, Queensland, Australia
        • Prince Charles Hospital
    • Western Australia
      • Perth, Western Australia, Australia
        • Royal Perth Hospital
  • Austria
      • Vienna, Austria
        • Universitaet Wien
  • Belgium
      • Bruxelles, Belgium
        • Cliniques universitaires Saint-Luc
  • Canada
    • Alberta
      • Edmonton, Alberta, Canada
        • University of Alberta Hospital
    • British Columbia
      • Vancouver, British Columbia, Canada
        • St Paul's Hospital
    • Nova Scotia
      • Halifax, Nova Scotia, Canada
        • New Halifax Infirmary
    • Ontario
      • Toronto, Ontario, Canada
        • Toronto General Hospital
    • Quebec
      • Sainte-Foy, Quebec, Canada
        • Institut Univ. de cardiologie et pneumologie de Quebec
  • France
      • Lyon, France
        • Hopital Cardiologique de Lyon
      • Paris, France
        • Hôpital Pitie Salpétrière
      • Paris, France
        • Hopital Georges Pompidou
      • Strasbourg, France
        • CHU de Strasbourg Hopital Civil Medicale B
      • Vandoeuvre les Nancy, France
        • CHU Hopital de Brabois
  • Germany
      • Bad Oeynhausen, Germany
        • Herz- u. Diabeteszentrum NRW/Ruhr-Univ. Bochum
      • Berlin, Germany
        • Deutsches Herzzentrum Berlin
      • Hamburg, Germany
        • Universitaetsklinikum Hamburg-Eppendorf
      • Hannover, Germany
        • Kliniken der Med. Hochschule
      • Kiel, Germany
        • Universitaetsklinikum Kiel
      • Regensburg, Germany
        • Universitaetsklinik Regensburg
  • Italy
      • Bologna, Italy
        • Az. Osp. di Bologna Policl. S. Orsola-Malpighi Univ. degli Studi
      • Cagliari, Italy
        • Azienda Ospedaliera G. Brotzu
      • Padova, Italy
        • A.O.-Universita di Padova-Universita degli Studi
      • Pavio, Italy
        • Fodazione IRCCS Policlinico S. Matteo
      • Roma, Italy
        • Azienda Ospedaliera S. Camillo-Forlanini
      • Torino, Italy
        • Az. Ospedaliero-Universitaria S. Giovanni Battista di Torino
  • New Zealand
      • Auckland, New Zealand
        • Auckland Hospital
  • Norway
      • Oslo, Norway
        • Rikshospitalet, Hjertemedisinskavdeling
  • Puerto Rico
      • San Juan, Puerto Rico
        • Cardiovascular Center of Puerto Rico and the Caribbean
  • Spain
      • Cordoba, Spain
        • Hospital Universitario Reina Sofia
      • Madrid, Spain
        • Hospital Puerta de Hierro Majadahonda
  • Taiwan
      • Taipei, Taiwan
        • National Taiwan University Hospital
  • United Kingdom
      • Birmingham, United Kingdom
        • Queen Elizabeth Hospital
      • Cambridge, United Kingdom
        • Papworth Hospital
      • Manchester, United Kingdom
        • Wythenshawe Hospital
  • United States
    • California
      • Los Angeles, California, United States
        • UCLA Medical Center
      • San Francisco, California, United States
        • California Pacific Medical Center
      • Stanford, California, United States
        • Stanford U Sch, Falk Cardiovasular Research Ctr.
    • Florida
      • Gainesville, Florida, United States
        • University of Florida Shands Hospital
    • Georgia
      • Atlanta, Georgia, United States
        • Emory University Hospital
    • Illinois
      • Maywood, Illinois, United States
        • Loyola Univerisity Medical School
    • Massachusetts
      • Boston, Massachusetts, United States
        • Massachusetts General Hospital
      • Boston, Massachusetts, United States
        • Tufts Medical Center
    • Michigan
      • Ann Arbor, Michigan, United States
        • University of Michigan Health System
    • Missouri
      • St. Louis, Missouri, United States
        • Washington University School of Medicine
    • New York
      • New York, New York, United States
        • Columbia University Medical Center
      • New York, New York, United States
        • Recanati Miller Transplant Institute
    • North Carolina
      • Chapel Hill, North Carolina, United States
        • UNC Division of Cardiology
      • Durham, North Carolina, United States
        • Duke University Heart Failure Research
    • Ohio
      • Cleveland, Ohio, United States
        • Cleveland Clinic Foundation
    • Pennsylvania
      • Hershey, Pennsylvania, United States
        • Penn State College of Medicine
      • Philadelphia, Pennsylvania, United States
        • Temple University Hospital
      • Philadelphia, Pennsylvania, United States
        • Thomas Jefferson University Hospital
      • Philadelphia, Pennsylvania, United States
        • Hahnemann University Hospital
    • South Carolina
      • Charleston, South Carolina, United States
        • Medical University of South Carolina
    • Texas
      • Austin, Texas, United States
        • Texas Cardiovascular Consultants
      • Galveston, Texas, United States
        • University of Texas Medical Branch, Div of Cardio Thoracic
      • Houston, Texas, United States, 77030
        • Methodist Hospital/DeBakey Heart Failure Research Center
    • Utah
      • Murray, Utah, United States
        • Intermountain Medical Center
    • Wisconsin
      • Madison, Wisconsin, United States, 53792
        • University of Wisconsin - Madison Medical School
      • Milwakee, Wisconsin, United States
        • St. Luke's Medical Center Cardiac Services

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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
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).
12 Months
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
12 Months
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.
Baseline, Month 12
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.
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
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.
12 Months
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.
24 Months
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).
24 Months
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
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
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.
24 Months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Novartis Pharmaceuticals

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2006

Primary Completion (Actual)

July 1, 2011

Study Completion (Actual)

July 1, 2011

Study Registration Dates

First Submitted

March 6, 2006

First Submitted That Met QC Criteria

March 6, 2006

First Posted (Estimate)

March 8, 2006

Study Record Updates

Last Update Posted (Estimate)

August 16, 2012

Last Update Submitted That Met QC Criteria

July 10, 2012

Last Verified

July 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CRAD001A2310

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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