Efficacy and Safety of Everolimus in Recipients of Heart Transplants to Prevent Acute and Chronic Rejection
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
Studieoversigt
Status
Betingelser
Intervention / Behandling
Undersøgelsestype
Tilmelding (Faktiske)
Fase
- Fase 3
Kontakter og lokationer
Studiesteder
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Buenos Aires, Argentina
- Fundacion Favalaro
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Santa Fe
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Rosario, Santa Fe, Argentina
- Sanatorio Parque
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New South Wales
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Darlinghurst, New South Wales, Australien
- St Vincents Hospital
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Queensland
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Chermside, Queensland, Australien
- Prince Charles Hospital
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Western Australia
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Perth, Western Australia, Australien
- Royal Perth Hospital
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Bruxelles, Belgien
- Cliniques universitaires Saint-Luc
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Alberta
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Edmonton, Alberta, Canada
- University of Alberta Hospital
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British Columbia
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Vancouver, British Columbia, Canada
- St Paul's Hospital
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Nova Scotia
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Halifax, Nova Scotia, Canada
- New Halifax Infirmary
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Ontario
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Toronto, Ontario, Canada
- Toronto General Hospital
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Quebec
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Sainte-Foy, Quebec, Canada
- Institut Univ. de cardiologie et pneumologie de Quebec
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Birmingham, Det Forenede Kongerige
- Queen Elizabeth Hospital
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Cambridge, Det Forenede Kongerige
- Papworth Hospital
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Manchester, Det Forenede Kongerige
- Wythenshawe Hospital
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California
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Los Angeles, California, Forenede Stater
- UCLA Medical Center
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San Francisco, California, Forenede Stater
- California Pacific Medical Center
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Stanford, California, Forenede Stater
- Stanford U Sch, Falk Cardiovasular Research Ctr.
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Florida
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Gainesville, Florida, Forenede Stater
- University of Florida Shands Hospital
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Georgia
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Atlanta, Georgia, Forenede Stater
- Emory University Hospital
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Illinois
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Maywood, Illinois, Forenede Stater
- Loyola Univerisity Medical School
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Massachusetts
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Boston, Massachusetts, Forenede Stater
- Massachusetts General Hospital
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Boston, Massachusetts, Forenede Stater
- Tufts Medical Center
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Michigan
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Ann Arbor, Michigan, Forenede Stater
- University of Michigan Health System
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Missouri
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St. Louis, Missouri, Forenede Stater
- Washington University School of Medicine
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New York
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New York, New York, Forenede Stater
- Columbia University Medical Center
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New York, New York, Forenede Stater
- Recanati Miller Transplant Institute
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North Carolina
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Chapel Hill, North Carolina, Forenede Stater
- UNC Division of Cardiology
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Durham, North Carolina, Forenede Stater
- Duke University Heart Failure Research
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Ohio
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Cleveland, Ohio, Forenede Stater
- Cleveland Clinic Foundation
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Pennsylvania
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Hershey, Pennsylvania, Forenede Stater
- Penn State College of Medicine
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Philadelphia, Pennsylvania, Forenede Stater
- Temple University Hospital
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Philadelphia, Pennsylvania, Forenede Stater
- Thomas Jefferson University Hospital
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Philadelphia, Pennsylvania, Forenede Stater
- Hahnemann University Hospital
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South Carolina
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Charleston, South Carolina, Forenede Stater
- Medical University of South Carolina
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Texas
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Austin, Texas, Forenede Stater
- Texas Cardiovascular Consultants
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Galveston, Texas, Forenede Stater
- University of Texas Medical Branch, Div of Cardio Thoracic
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Houston, Texas, Forenede Stater, 77030
- Methodist Hospital/DeBakey Heart Failure Research Center
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Utah
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Murray, Utah, Forenede Stater
- Intermountain Medical Center
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Wisconsin
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Madison, Wisconsin, Forenede Stater, 53792
- University of Wisconsin - Madison Medical School
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Milwakee, Wisconsin, Forenede Stater
- St. Luke's Medical Center Cardiac Services
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Lyon, Frankrig
- Hopital Cardiologique de Lyon
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Paris, Frankrig
- Hôpital Pitie Salpétrière
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Paris, Frankrig
- Hopital Georges Pompidou
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Strasbourg, Frankrig
- CHU de Strasbourg Hopital Civil Medicale B
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Vandoeuvre les Nancy, Frankrig
- CHU Hopital de Brabois
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Bologna, Italien
- Az. Osp. di Bologna Policl. S. Orsola-Malpighi Univ. degli Studi
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Cagliari, Italien
- Azienda Ospedaliera G. Brotzu
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Padova, Italien
- A.O.-Universita di Padova-Universita degli Studi
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Pavio, Italien
- Fodazione IRCCS Policlinico S. Matteo
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Roma, Italien
- Azienda Ospedaliera S. Camillo-Forlanini
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Torino, Italien
- Az. Ospedaliero-Universitaria S. Giovanni Battista di Torino
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Auckland, New Zealand
- Auckland Hospital
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Oslo, Norge
- Rikshospitalet, Hjertemedisinskavdeling
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San Juan, Puerto Rico
- Cardiovascular Center of Puerto Rico and the Caribbean
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Cordoba, Spanien
- Hospital Universitario Reina Sofia
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Madrid, Spanien
- Hospital Puerta de Hierro Majadahonda
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Taipei, Taiwan
- National Taiwan University Hospital
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Bad Oeynhausen, Tyskland
- Herz- u. Diabeteszentrum NRW/Ruhr-Univ. Bochum
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Berlin, Tyskland
- Deutsches Herzzentrum Berlin
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Hamburg, Tyskland
- Universitaetsklinikum Hamburg-Eppendorf
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Hannover, Tyskland
- Kliniken der Med. Hochschule
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Kiel, Tyskland
- Universitaetsklinikum Kiel
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Regensburg, Tyskland
- Universitaetsklinik Regensburg
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Vienna, Østrig
- Universitaet Wien
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Deltagelseskriterier
Berettigelseskriterier
Aldre berettiget til at studere
Tager imod sunde frivillige
Køn, der er berettiget til at studere
Beskrivelse
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
Hvordan er undersøgelsen tilrettelagt?
Design detaljer
- Primært formål: Behandling
- Tildeling: Randomiseret
- Interventionel model: Parallel tildeling
- Maskning: Ingen (Åben etiket)
Våben og indgreb
Deltagergruppe / Arm |
Intervention / Behandling |
|---|---|
|
Eksperimentel: 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.
|
Everolimus supplied as 0.75 mg tablets.
Everolimus was also supplied in 0.25 mg and 0.5 mg tablets for dose adjustments.
Andre navne:
Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm.
Andre navne:
Corticosteroids standard dose.
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Eksperimentel: 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. |
Everolimus supplied as 0.75 mg tablets.
Everolimus was also supplied in 0.25 mg and 0.5 mg tablets for dose adjustments.
Andre navne:
Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm.
Andre navne:
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.
|
Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm.
Andre navne:
Corticosteroids standard dose.
Mycophenolate mofetil supplied as 500 mg tablets.
Andre navne:
|
Hvad måler undersøgelsen?
Primære resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
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Percentage of Participants With Composite Efficacy Failure at 12 Months
Tidsramme: 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
|
Sekundære resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
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Percentage of Participants With Graft Loss/Re-transplant, Death or Loss to Follow-up at 12 Months
Tidsramme: 12 Months
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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
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Renal Function Measured by Glomerular Filtration Rate (GFR) at 12 Months
Tidsramme: 12 Months
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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
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Change From Baseline in the Average Maximum Intimal Thickness at Month 12
Tidsramme: Baseline, Month 12
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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
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Percentage of Participants With Cardiac Allograft Vasculopathy (CAV) at Month 12
Tidsramme: 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.
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12 Months
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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
Tidsramme: 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
|
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Percentage of Participants With Composite Efficacy Failure at 24 Months
Tidsramme: 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
|
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Percentage of Participants With Graft Loss/Re-transplant, Death or Loss to Follow-up at 24 Months
Tidsramme: 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
|
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Renal Function Calculated by Glomerular Filtration Rate (GFR) at 24 Months
Tidsramme: 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
|
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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
Tidsramme: 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
|
Samarbejdspartnere og efterforskere
Sponsor
Datoer for undersøgelser
Studer store datoer
Studiestart
Primær færdiggørelse (Faktiske)
Studieafslutning (Faktiske)
Datoer for studieregistrering
Først indsendt
Først indsendt, der opfyldte QC-kriterier
Først opslået (Skøn)
Opdateringer af undersøgelsesjournaler
Sidste opdatering sendt (Skøn)
Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier
Sidst verificeret
Mere information
Begreber relateret til denne undersøgelse
Nøgleord
Yderligere relevante MeSH-vilkår
- Lægemidlers fysiologiske virkninger
- Molekylære mekanismer for farmakologisk virkning
- Anti-infektionsmidler
- Enzymhæmmere
- Antirheumatiske midler
- Antineoplastiske midler
- Immunsuppressive midler
- Immunologiske faktorer
- Dermatologiske midler
- Antibakterielle midler
- Antibiotika, antineoplastisk
- Antifungale midler
- Antituberkulære midler
- Antibiotika, Antituberkulær
- Calcineurin-hæmmere
- Mycophenolsyre
- Everolimus
- Cyclosporin
- Cyclosporiner
Andre undersøgelses-id-numre
- CRAD001A2310
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