Graft RejectionPhase 3NCT00300274
Efficacy and Safety of Everolimus in Recipients of Heart Transplants to Prevent Acute and Chronic Rejection
A Phase 3 study testing everolimus, mycophenolate mofetil and cyclosporine in people with Graft Rejection, run by Novartis Pharmaceuticals at 64 sites in 15 countries.
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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Graft Rejection
- What is being tested?
- everolimus, mycophenolate mofetil and cyclosporine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 721 participants
- Where
- 64 sitesin 15 countries
- Study dates
- Jan 2006to Jul 2011
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male or female cardiac recipients 18-70 years of age undergoing primary heart transplantation.
- The graft must be functional at time of randomization.
Who cannot join
- 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.
Trial locations and contacts
64 sites in 15 countries.
64 sites in 15 countries
United States26 sites
University of Michigan Health System
Ann Arbor, Michigan
Emory University Hospital
Atlanta, Georgia
Texas Cardiovascular Consultants
Austin, Texas
Massachusetts General Hospital
Boston, Massachusetts
Tufts Medical Center
Boston, Massachusetts
UNC Division of Cardiology
Chapel Hill, North Carolina
Medical University of South Carolina
Charleston, South Carolina
Cleveland Clinic Foundation
Cleveland, Ohio
Duke University Heart Failure Research
Durham, North Carolina
University of Florida Shands Hospital
Gainesville, Florida
University of Texas Medical Branch, Div of Cardio Thoracic
Galveston, Texas
Penn State College of Medicine
Hershey, Pennsylvania
Methodist Hospital/DeBakey Heart Failure Research Center
Houston, Texas, 77030
UCLA Medical Center
Los Angeles, California
University of Wisconsin - Madison Medical School
Madison, Wisconsin, 53792
Loyola Univerisity Medical School
Maywood, Illinois
St. Luke's Medical Center Cardiac Services
Milwakee, Wisconsin
Intermountain Medical Center
Murray, Utah
Columbia University Medical Center
New York, New York
Recanati Miller Transplant Institute
New York, New York
Hahnemann University Hospital
Philadelphia, Pennsylvania
Temple University Hospital
Philadelphia, Pennsylvania
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
California Pacific Medical Center
San Francisco, California
Washington University School of Medicine
St Louis, Missouri
Stanford U Sch, Falk Cardiovasular Research Ctr.
Stanford, California
Germany6 sites
Herz- u. Diabeteszentrum NRW/Ruhr-Univ. Bochum
Bad Oeynhausen
Deutsches Herzzentrum Berlin
Berlin
Universitaetsklinikum Hamburg-Eppendorf
Hamburg
Kliniken der Med. Hochschule
Hanover
Universitaetsklinikum Kiel
Kiel
Universitaetsklinik Regensburg
Regensburg
Italy6 sites
Az. Osp. di Bologna Policl. S. Orsola-Malpighi Univ. degli Studi
Bologna
Azienda Ospedaliera G. Brotzu
Cagliari
A.O.-Universita di Padova-Universita degli Studi
Padova
Fodazione IRCCS Policlinico S. Matteo
Pavia
Azienda Ospedaliera S. Camillo-Forlanini
Roma
Az. Ospedaliero-Universitaria S. Giovanni Battista di Torino
Torino
Canada5 sites
University of Alberta Hospital
Edmonton, Alberta
New Halifax Infirmary
Halifax, Nova Scotia
Institut Univ. de cardiologie et pneumologie de Quebec
Sainte-Foy, Quebec
Toronto General Hospital
Toronto, Ontario
St Paul's Hospital
Vancouver, British Columbia
France5 sites
Hopital Cardiologique de Lyon
Lyon
Hopital Georges Pompidou
Paris
Hopital Pitie Salpetriere
Paris
CHU de Strasbourg Hopital Civil Medicale B
Strasbourg
CHU Hopital de Brabois
Vandœuvre-lès-Nancy
Australia3 sites
Prince Charles Hospital
Chermside, Queensland
St Vincents Hospital
Darlinghurst, New South Wales
Royal Perth Hospital
Perth, Western Australia
United Kingdom3 sites
Queen Elizabeth Hospital
Birmingham
Papworth Hospital
Cambridge
Wythenshawe Hospital
Manchester
Argentina2 sites
Fundacion Favalaro
Buenos Aires
Sanatorio Parque
Rosario, Santa Fe Province
Spain2 sites
Hospital Universitario Reina Sofia
Córdoba
Hospital Puerta de Hierro Majadahonda
Madrid
Puerto Rico1 site
Cardiovascular Center of Puerto Rico and the Caribbean
San Juan
About this study
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
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.
- Conditions
- Graft Rejection
- Being tested
- everolimus, mycophenolate mofetil, cyclosporine, corticosteroids
- Keywords
- Everolimus, heart transplant, heart disease, transplantation, heart IVUS assessment at 12 months, rate of graft loss, acute rejection episodes, survival
- Medical subject headings
- Heart Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
everolimusDrug
Also called Zortress®, Certican®
Everolimus supplied as 0.75 mg tablets. Everolimus was also supplied in 0.25 mg and 0.5 mg tablets for dose adjustments.
Also called Cellcept®
Mycophenolate mofetil supplied as 500 mg tablets.
cyclosporineDrug
Also called Neoral®
Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm.
corticosteroidsDrug
Corticosteroids standard dose.
| Study group | Role | What they receive |
|---|---|---|
| everolimus 1.5 mg | Experimental | 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. Receives: Drug: everolimus; Drug: cyclosporine; Drug: corticosteroids |
| everolimus 3.0 mg | Experimental | 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. Receives: Drug: everolimus; Drug: cyclosporine; Drug: corticosteroids |
| mycophenolate mofetil | Active comparator | 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. Receives: Drug: mycophenolate mofetil; Drug: cyclosporine; Drug: corticosteroids |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 12 Months
Secondary outcomes (9)
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).
Measured: 12 Months
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
Measured: 12 Months
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.
Measured: Baseline, Month 12
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.
Measured: 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
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.
Measured: 12 Months
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.
Measured: 24 Months
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).
Measured: 24 Months
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
Measured: 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
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.
Measured: 24 Months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Mar 2006 (estimated)
- Study startJan 2006
- Primary completionJul 2011
- Study completionJul 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Graft RejectionStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 721 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis, Study director, Novartis
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00300274
- Sponsor's protocol ID
- CRAD001A2310
- Status last verified
- Jul 2012
- First submitted
- 6 Mar 2006
- Last updated
- 16 Aug 2012
- Results posted
- Yes, on ClinicalTrials.gov
Study at a glance
From the registry record, last updated by the sponsor on 16 Aug 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00300274
- Acronym / sponsor ID
- CRAD001A2310
- Conditions
- Graft Rejection
- Keywords
- Everolimus, heart transplant, heart disease, transplantation, heart IVUS assessment at 12 months, rate of graft loss, acute rejection episodes, survival
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 721 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- Jan 2006
- Primary completion
- Jul 2011 (actual)
- Study completion
- Jul 2011 (actual)
- First posted
- 8 Mar 2006 (estimated)
- Results
- Posted 16 Aug 2012
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| everolimus 1.5 mg | Experimental | Drug: everolimus, Drug: cyclosporine, Drug: corticosteroidsWithin 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 3.0 mg | Experimental | Drug: everolimus, Drug: cyclosporine, Drug: corticosteroidsWithin 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. |
| mycophenolate mofetil | Active comparator | Drug: mycophenolate mofetil, Drug: cyclosporine, Drug: corticosteroidsWithin 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. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Male or female cardiac recipients 18-70 years of age undergoing primary heart transplantation.
- The graft must be functional at time of randomization.
Key exclusion criteria (3 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| everolimusAlso: Zortress®, Certican®Everolimus supplied as 0.75 mg tablets. Everolimus was also supplied in 0.25 mg and 0.5 mg tablets for dose adjustments. | Drug | everolimus 1.5 mg, everolimus 3.0 mg |
| mycophenolate mofetilAlso: Cellcept®Mycophenolate mofetil supplied as 500 mg tablets. | Drug | mycophenolate mofetil |
| cyclosporineAlso: Neoral®Cyclosporine reduced dose in the everolimus arms (approximately half of the standard dose) and standard dose in the mycophenolate mofetil arm. | Drug | everolimus 1.5 mg, everolimus 3.0 mg, mycophenolate mofetil |
| corticosteroidsCorticosteroids standard dose. | Drug | everolimus 1.5 mg, everolimus 3.0 mg, mycophenolate mofetil |
Primary outcome
Percentage of Participants With Composite Efficacy Failure at 12 Months
Time frame: 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.
9 secondary outcomes
Percentage of Participants With Graft Loss/Re-transplant, Death or Loss to Follow-up at 12 Months
Time frame: 12 Months
Renal Function Measured by Glomerular Filtration Rate (GFR) at 12 Months
Time frame: 12 Months
Change From Baseline in the Average Maximum Intimal Thickness at Month 12
Time frame: Baseline, Month 12
Percentage of Participants With Cardiac Allograft Vasculopathy (CAV) at Month 12
Time frame: 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
Time frame: 12 Months
Percentage of Participants With Composite Efficacy Failure at 24 Months
Time frame: 24 Months
Percentage of Participants With Graft Loss/Re-transplant, Death or Loss to Follow-up at 24 Months
Time frame: 24 Months
Renal Function Calculated by Glomerular Filtration Rate (GFR) at 24 Months
Time frame: 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
Time frame: 24 Months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Aug 2012.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Related trials for Graft Rejection
RecruitingObservational study
Long-term Evaluation and Follow-up Care of Patients Treated With Stem Cell Transplants
Graft-versus-leukemia, Graft vs Host Disease
RecruitingPhase 2
A Study to Learn About the Effects of Felzartamab Infusions in Adults With Kidney Transplants Who Have Late Isolated Microvascular Inflammation
Microvascular Inflammation
RecruitingPhase 1
A Study of LBP-MARCO and Ruxolitinib in People With Graft-Versus-Host Disease (GVHD)
Transplant Failure or Rejection of Bone Marrow (Graft vs Host Disease, GVHD)
Enrolling by invitationPhase 3
A Study to Learn More About the Long-Term Safety and Effects of Felzartamab Infusions in Adults With Kidney Transplants Who Have Antibody-Mediated Rejection (AMR) or Microvascular Inflammation (MVI) (TRANSCEND/TRANSPIRE LTE)
Antibody-mediated Rejection, Microvascular Inflammation
Not yet recruiting
Molecular Evidence of Rejection Intervention Trial
Heart Transplant Rejection
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis study director
Novartis
64 sites in 15 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing everolimus, mycophenolate mofetil and cyclosporine in people with Graft Rejection, run by Novartis Pharmaceuticals at 64 sites in 15 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Aug 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 64 sites in United States, Germany, Italy, Canada, France and 10 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 16 Aug 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Participants With Composite Efficacy Failure at 12 Months (time frame: 12 Months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Aug 2012.