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

Graft Rejection Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00300274
• Other study ID #: CRAD001A2310
• Status: Completed
• Phase: Phase 3
• First received: March 6, 2006
• Last updated: July 10, 2012
• Start date: January 2006
• Est. completion date: July 2011

Study information

• Verified date: July 2012
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 721
• Est. completion date: July 2011
• Est. primary completion date: July 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Graft Rejection

Intervention

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.
• mycophenolate mofetil
Mycophenolate mofetil supplied as 500 mg tablets.
• cyclosporine
Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm.
• corticosteroids
Corticosteroids standard dose.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Canada,  France,  Germany,  Italy,  New Zealand,  Norway,  Puerto Rico,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Composite Efficacy Failure at 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	No
Secondary	Percentage of Participants With Graft Loss/Re-transplant, Death or Loss to Follow-up at 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	No
Secondary	Renal Function Measured by Glomerular Filtration Rate (GFR) at 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	Yes
Secondary	Change From Baseline in the Average Maximum Intimal Thickness at 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	No
Secondary	Percentage of Participants With Cardiac Allograft Vasculopathy (CAV) at Month 12	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	No
Secondary	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	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	No
Secondary	Percentage of Participants With Composite Efficacy Failure at 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	No
Secondary	Percentage of Participants With Graft Loss/Re-transplant, Death or Loss to Follow-up at 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	No
Secondary	Renal Function Calculated by Glomerular Filtration Rate (GFR) at 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	Yes
Secondary	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	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	No