Prevention of Transplant Atherosclerosis With Everolimus and Anti-cytomegalovirus Therapy - Full Text View

Purpose

Cardiac allograft vasculopathy (CAV) is the major cause of long-term graft failure in heart transplant recipients. Although several immune-mediated and metabolic risk factors have been implicated in the pathogenesis of CAV, no effective therapy is currently available to treat established CAV and prevent its adverse outcomes. Therefore, the main clinical strategy is based on prevention and treatment of factors known to trigger its development. Although the mechanism is vague, cytomegalovirus (CMV) infection is believed to play a key role in CAV progression.

Two strategies involving administration of specific anti-CMV agents are recommended for prevention of CMV infection/disease: universal prophylaxis and preemptive therapy. The pros and cons of the two strategies are still debated, in the absence of randomized studies addressing graft-related outcomes and viral mechanisms of graft damage, and without any clear evidence of superiority of either approach.

The investigators conceived this randomized prospective project to compare the effect of preemptive anti-CMV strategy with universal anti-CMV prophylaxis on CMV infection and on one-year increase in coronary intimal thickening. Patients will be additionally randomized to receive either mycophenolate mofetil or everolimus, in light of the possible anti-CMV properties of everolimus.

Condition	Intervention	Phase
Heart Transplantation Cardiac Allograft Vasculopathy Cytomegalovirus Infection	Drug: Pre-emptive strategy with valganciclovir plus everolimus Drug: Prophylaxis with valganciclovir plus mycophenolate Drug: Prophylaxis with valganciclovir plus everolimus Drug: Pre-emptive mycophenolate	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Prevention
Official Title:	Efficacy and Safety of Anti-cytomegalovirus Prophylaxis Versus Pre-emptive Approaches With Valganciclovir in Heart Transplant Recipients Treated With Everolimus or Mycophenolate. A Randomized Open-label Study for Prevention of Cardiaca Allograft Vasculopathy

Resource links provided by NLM:

MedlinePlus related topics: Atherosclerosis Cytomegalovirus Infections Heart Transplantation

Drug Information available for: Mycophenolic acid Mycophenolate sodium Sirolimus Mycophenolate mofetil hydrochloride Mycophenolate mofetil Everolimus Temsirolimus Valganciclovir hydrochloride

U.S. FDA Resources

Further study details as provided by University of Bologna:

Primary Outcome Measures:

Change in maximal intimal thickness [ Time Frame: one year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

CMV infection [ Time Frame: one year ] [ Designated as safety issue: No ]

Estimated Enrollment:	100
Study Start Date:	April 2009
Estimated Primary Completion Date:	April 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Pre-emptive everolimus	Drug: Pre-emptive strategy with valganciclovir plus everolimus Patients will be monitored for CMV infection and receive valganciclovir only for positive PCR or antigenemia. Everolimus plus cyclosporine and prednisone will be used for maintenance immunosuppression
Experimental: Prophylaxis mycophenolate	Drug: Prophylaxis with valganciclovir plus mycophenolate Patients will receive 3 months of oral valganciclovir with mycophenolate and standard cyclosporine and prednisone for maintenance immunosuppression
Experimental: Prophylaxis Everolimus	Drug: Prophylaxis with valganciclovir plus everolimus Patients will receive valganciclovir for 3 months after transplant. Everolimus plus reduced cyclosporine and prednisone will be used for maintenance immunosuppression
Active Comparator: Pre-emptive mycophenolate	Drug: Pre-emptive mycophenolate Patients will be monitored for CMV infection and receive valganciclovir only for positive PCR or antigenemia. Mycophenolate plus standard cyclosporine and prednisone will be used for maintenance immunosuppression

Eligibility

Ages Eligible for Study:	18 Years to 70 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Age ≥ 18y
Heart or heart-kidney combined transplant
Positive CMV serology at the time of transplant
Glomerular filtration rate ≥ 20 ml/min/1.73m2 with MDRD at randomization.
Written informed consent

Exclusion Criteria:

Panel Reactive Antibody ≥50%
Less than 1000/mmc neutrophils at the time of randomization
Less than 30,000/mmc platelets at the time of randomization
Clinical significant infection in the 2 weeks prior to transplant
Glomerular filtration rate < 20 ml/min/1.73m2 estimated with MDRD formula at the time of randomization or hemodialysis treatment
Intolerance towards valganciclovir, everolimus, mycophenolate or cyc-losporine
Known contraindication to statin use
Negative CMV serology at the time of transplant
HIV positive testing
Severe comorbidities that, based on investigator's judgment, contraindicate study drugs or procedures
Potentially childbearing women who refuse to use contraceptives
Participation to an interventional study in the 2 preceding weeks
Unwillingness or inability to follow study procedure and to sign written in-formed consent

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00966836

Contacts

Contact: Luciano Potena, MD PhD	+390516364526	luciano.potena2@unibo.it
Contact: Francesco Grigioni, MD PhD	+390516364526	francesco.grigioni@unibo.it

Locations

Italy
Azienda Ospedaliero-Universitaria S Orsola Malpighi	Recruiting
Bologna, Italy
Sub-Investigator: Luciano Potena, MD PhD

Sponsors and Collaborators

University of Bologna

More Information

Publications:

Potena L, Grigioni F, Magnani G, Lazzarotto T, Musuraca AC, Ortolani P, Coccolo F, Fallani F, Russo A, Branzi A. Prophylaxis versus preemptive anti-cytomegalovirus approach for prevention of allograft vasculopathy in heart transplant recipients. J Heart Lung Transplant. 2009 May;28(5):461-7.

Potena L, Valantine HA. Cytomegalovirus-associated allograft rejection in heart transplant patients. Curr Opin Infect Dis. 2007 Aug;20(4):425-31. Review.

Hill JA, Hummel M, Starling RC, Kobashigawa JA, Perrone SV, Arizón JM, Simonsen S, Abeywickrama KH, Bara C. A lower incidence of cytomegalovirus infection in de novo heart transplant recipients randomized to everolimus. Transplantation. 2007 Dec 15;84(11):1436-42.

Responsible Party:	Angelo Branzi, University of Bologna
ClinicalTrials.gov Identifier:	NCT00966836 History of Changes
Other Study ID Numbers:	PROTECT 2008-006980-35
Study First Received:	August 26, 2009
Last Updated:	August 26, 2009
Health Authority:	Italy: Agenzia Italiana del Farmaco (AIFA)

Keywords provided by University of Bologna:

Heart Transplantation
Cardiac Allograft Vasculopathy
Cytomegalovirus Infection

Everolimus
Valganciclovir
Mycophenolate

Additional relevant MeSH terms:

Cytomegalovirus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Mycophenolic Acid
Sirolimus
Mycophenolate mofetil
Everolimus
Valganciclovir
Ganciclovir
Antibiotics, Antineoplastic
Antineoplastic Agents

Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents
Antiviral Agents

ClinicalTrials.gov processed this record on May 16, 2013

Prevention of Transplant Atherosclerosis With Everolimus and Anti-cytomegalovirus Therapy (PROTECT)