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

10 juli 2012 uppdaterad av: 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.

Studieöversikt

Status

Avslutad

Betingelser

Intervention / Behandling

Studietyp

Interventionell

Inskrivning (Faktisk)

721

Fas

  • Fas 3

Kontakter och platser

Det här avsnittet innehåller kontaktuppgifter för dem som genomför studien och information om var denna studie genomförs.

Studieorter

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

Deltagandekriterier

Forskare letar efter personer som passar en viss beskrivning, så kallade behörighetskriterier. Några exempel på dessa kriterier är en persons allmänna hälsotillstånd eller tidigare behandlingar.

Urvalskriterier

Åldrar som är berättigade till studier

18 år till 70 år (Vuxen, Äldre vuxen)

Tar emot friska volontärer

Nej

Kön som är behöriga för studier

Allt

Beskrivning

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.

Studieplan

Det här avsnittet ger detaljer om studieplanen, inklusive hur studien är utformad och vad studien mäter.

Hur är studien utformad?

Designdetaljer

  • Primärt syfte: Behandling
  • Tilldelning: Randomiserad
  • Interventionsmodell: Parallellt uppdrag
  • Maskning: Ingen (Open Label)

Vapen och interventioner

Deltagargrupp / Arm
Intervention / Behandling
Experimentell: 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.
Läkemedel: everolimus
Everolimus supplied as 0.75 mg tablets. Everolimus was also supplied in 0.25 mg and 0.5 mg tablets for dose adjustments.
Andra namn:
  • Certican®
  • Zortress®
Läkemedel: cyclosporine
Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm.
Andra namn:
  • Neoral®
Läkemedel: corticosteroids
Corticosteroids standard dose.
Experimentell: 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.
Läkemedel: everolimus
Everolimus supplied as 0.75 mg tablets. Everolimus was also supplied in 0.25 mg and 0.5 mg tablets for dose adjustments.
Andra namn:
  • Certican®
  • Zortress®
Läkemedel: cyclosporine
Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm.
Andra namn:
  • Neoral®
Läkemedel: corticosteroids
Corticosteroids standard dose.
Aktiv komparator: 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.
Läkemedel: cyclosporine
Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm.
Andra namn:
  • Neoral®
Läkemedel: corticosteroids
Corticosteroids standard dose.
Läkemedel: mycophenolate mofetil
Mycophenolate mofetil supplied as 500 mg tablets.
Andra namn:
  • Cellcept®

Vad mäter studien?

Primära resultatmått

Resultatmått
Åtgärdsbeskrivning
Tidsram
Percentage of Participants With Composite Efficacy Failure at 12 Months
Tidsram: 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

Sekundära resultatmått

Resultatmått
Åtgärdsbeskrivning
Tidsram
Percentage of Participants With Graft Loss/Re-transplant, Death or Loss to Follow-up at 12 Months
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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

Samarbetspartners och utredare

Det är här du hittar personer och organisationer som är involverade i denna studie.

Sponsor

Novartis Pharmaceuticals

Studieavstämningsdatum

Dessa datum spårar framstegen för inlämningar av studieposter och sammanfattande resultat till ClinicalTrials.gov. Studieposter och rapporterade resultat granskas av National Library of Medicine (NLM) för att säkerställa att de uppfyller specifika kvalitetskontrollstandarder innan de publiceras på den offentliga webbplatsen.

Studera stora datum

Studiestart

1 januari 2006

Primärt slutförande (Faktisk)

1 juli 2011

Avslutad studie (Faktisk)

1 juli 2011

Studieregistreringsdatum

Först inskickad

6 mars 2006

Först inskickad som uppfyllde QC-kriterierna

6 mars 2006

Första postat (Uppskatta)

8 mars 2006

Uppdateringar av studier

Senaste uppdatering publicerad (Uppskatta)

16 augusti 2012

Senaste inskickade uppdateringen som uppfyllde QC-kriterierna

10 juli 2012

Senast verifierad

1 juli 2012

Mer information

Termer relaterade till denna studie

Nyckelord

Ytterligare relevanta MeSH-villkor

Andra studie-ID-nummer

  • CRAD001A2310

Denna information hämtades direkt från webbplatsen clinicaltrials.gov utan några ändringar. Om du har några önskemål om att ändra, ta bort eller uppdatera dina studieuppgifter, vänligen kontakta register@clinicaltrials.gov. Så snart en ändring har implementerats på clinicaltrials.gov, kommer denna att uppdateras automatiskt även på vår webbplats .

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