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

10 de julio de 2012 actualizado por: 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.

Descripción general del estudio

Estado

Terminado

Condiciones

Intervención / Tratamiento

Tipo de estudio

Intervencionista

Inscripción (Actual)

721

Fase

  • Fase 3

Contactos y Ubicaciones

Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.

Ubicaciones de estudio

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

Criterios de participación

Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.

Criterio de elegibilidad

Edades elegibles para estudiar

18 años a 70 años (Adulto, Adulto Mayor)

Acepta Voluntarios Saludables

No

Géneros elegibles para el estudio

Todos

Descripción

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.

Plan de estudios

Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.

¿Cómo está diseñado el estudio?

Detalles de diseño

  • Propósito principal: Tratamiento
  • Asignación: Aleatorizado
  • Modelo Intervencionista: Asignación paralela
  • Enmascaramiento: Ninguno (etiqueta abierta)

Armas e Intervenciones

Grupo de participantes/brazo
Intervención / Tratamiento
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.
Droga: everolimus
Everolimus supplied as 0.75 mg tablets. Everolimus was also supplied in 0.25 mg and 0.5 mg tablets for dose adjustments.
Otros nombres:
  • Certican®
  • Zortress®
Droga: cyclosporine
Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm.
Otros nombres:
  • Neoral®
Droga: 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.
Droga: everolimus
Everolimus supplied as 0.75 mg tablets. Everolimus was also supplied in 0.25 mg and 0.5 mg tablets for dose adjustments.
Otros nombres:
  • Certican®
  • Zortress®
Droga: cyclosporine
Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm.
Otros nombres:
  • Neoral®
Droga: corticosteroids
Corticosteroids standard dose.
Comparador activo: 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.
Droga: cyclosporine
Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm.
Otros nombres:
  • Neoral®
Droga: corticosteroids
Corticosteroids standard dose.
Droga: mycophenolate mofetil
Mycophenolate mofetil supplied as 500 mg tablets.
Otros nombres:
  • Cellcept®

¿Qué mide el estudio?

Medidas de resultado primarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Percentage of Participants With Composite Efficacy Failure at 12 Months
Periodo de tiempo: 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

Medidas de resultado secundarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Percentage of Participants With Graft Loss/Re-transplant, Death or Loss to Follow-up at 12 Months
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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

Colaboradores e Investigadores

Aquí es donde encontrará personas y organizaciones involucradas en este estudio.

Patrocinador

Novartis Pharmaceuticals

Fechas de registro del estudio

Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados ​​por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.

Fechas importantes del estudio

Inicio del estudio

1 de enero de 2006

Finalización primaria (Actual)

1 de julio de 2011

Finalización del estudio (Actual)

1 de julio de 2011

Fechas de registro del estudio

Enviado por primera vez

6 de marzo de 2006

Primero enviado que cumplió con los criterios de control de calidad

6 de marzo de 2006

Publicado por primera vez (Estimar)

8 de marzo de 2006

Actualizaciones de registros de estudio

Última actualización publicada (Estimar)

16 de agosto de 2012

Última actualización enviada que cumplió con los criterios de control de calidad

10 de julio de 2012

Última verificación

1 de julio de 2012

Más información

Términos relacionados con este estudio

Palabras clave

Términos MeSH relevantes adicionales

Otros números de identificación del estudio

  • CRAD001A2310

Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .

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