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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT00300274
Registration number
NCT00300274
Ethics application status
Date submitted
6/03/2006
Date registered
8/03/2006
Date last updated
16/08/2012
Titles & IDs
Public title
Efficacy and Safety of Everolimus in Recipients of Heart Transplants to Prevent Acute and Chronic Rejection
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Scientific 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
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Secondary ID [1]
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CRAD001A2310
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Graft Rejection
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Condition category
Condition code
Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - everolimus
Treatment: Drugs - mycophenolate mofetil
Treatment: Drugs - cyclosporine
Treatment: Drugs - corticosteroids
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.
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.
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.
Treatment: Drugs: everolimus
Everolimus supplied as 0.75 mg tablets. Everolimus was also supplied in 0.25 mg and 0.5 mg tablets for dose adjustments.
Treatment: Drugs: mycophenolate mofetil
Mycophenolate mofetil supplied as 500 mg tablets.
Treatment: Drugs: cyclosporine
Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm.
Treatment: Drugs: corticosteroids
Corticosteroids standard dose.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Percentage of Participants With Composite Efficacy Failure at 12 Months
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Assessment method [1]
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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.
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Timepoint [1]
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12 Months
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Secondary outcome [1]
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Percentage of Participants With Graft Loss/Re-transplant, Death or Loss to Follow-up at 12 Months
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Assessment method [1]
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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).
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Timepoint [1]
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12 Months
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Secondary outcome [2]
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Renal Function Measured by Glomerular Filtration Rate (GFR) at 12 Months
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Assessment method [2]
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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
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Timepoint [2]
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12 Months
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Secondary outcome [3]
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Change From Baseline in the Average Maximum Intimal Thickness at Month 12
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Assessment method [3]
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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.
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Timepoint [3]
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Baseline, Month 12
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Secondary outcome [4]
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Percentage of Participants With Cardiac Allograft Vasculopathy (CAV) at Month 12
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Assessment method [4]
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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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Timepoint [4]
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12 Months
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Secondary outcome [5]
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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
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Assessment method [5]
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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.
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Timepoint [5]
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12 Months
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Secondary outcome [6]
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Percentage of Participants With Composite Efficacy Failure at 24 Months
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Assessment method [6]
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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.
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Timepoint [6]
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24 Months
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Secondary outcome [7]
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Percentage of Participants With Graft Loss/Re-transplant, Death or Loss to Follow-up at 24 Months
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Assessment method [7]
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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 631 (start day of 24 Month visit window).
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Timepoint [7]
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24 Months
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Secondary outcome [8]
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Renal Function Calculated by Glomerular Filtration Rate (GFR) at 24 Months
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Assessment method [8]
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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
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
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Timepoint [8]
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24 Months
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Secondary outcome [9]
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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
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Assessment method [9]
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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.
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Timepoint [9]
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24 Months
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Eligibility
Key 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.
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Minimum age
18
Years
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Maximum age
70
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/01/2006
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
1/07/2011
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Sample size
Target
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Accrual to date
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Final
721
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Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA
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Recruitment hospital [1]
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St Vincents Hospital - Darlinghurst
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Recruitment hospital [2]
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Prince Charles Hospital - Chermside
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Recruitment hospital [3]
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Royal Perth Hospital - Perth
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Recruitment postcode(s) [1]
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- Darlinghurst
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Recruitment postcode(s) [2]
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- Chermside
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Recruitment postcode(s) [3]
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- Perth
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Recruitment outside Australia
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United States of America
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California
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United States of America
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Florida
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United States of America
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Georgia
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Illinois
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Massachusetts
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Michigan
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Missouri
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Argentina
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Santa Fe
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Vienna
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Bruxelles
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France
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Vandoeuvre les Nancy
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Bad Oeynhausen
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Kiel
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Italy
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Roma
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Italy
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Torino
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Auckland
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Oslo
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Cordoba
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Madrid
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Taipei
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Birmingham
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Cambridge
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United Kingdom
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Manchester
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Novartis Pharmaceuticals
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Address
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Ethics approval
Ethics application status
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Summary
Brief 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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT00300274
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Novartis
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Address
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Novartis
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT00300274
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