A Comparison of AlloMap Molecular Testing and Traditional Biopsy-based Surveillance for Heart Transplant Rejection Early Post-transplantation

Study Overview
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Brief Summary
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This study is designed to evaluate the safety and efficacy of a peripheral blood mononuclear cell gene expression profiling method (AlloMap) in monitoring asymptomatic heart transplant patients for acute rejection beginning 2-6 months(≥ 55-185 days) after transplantation.

Detailed Description
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Cardiac allograft rejection is experienced by 20-50% of patients at least once during the first year after cardiac transplantation under the present immunosuppression regimens. The standard for rejection surveillance has been the endomyocardial biopsy (EMB). However, EMB is invasive, causes morbidity, and is subject to sampling error and inter-observer variability. Gene expression profiling (GEP), with its high negative predictive value (NPV) for acute cellular rejection (ACR), appears to be well suited to identify low-risk patients who can be safely managed without routine invasive endomyocardial biopsy (EMB). The Invasive Monitoring Attenuation through Gene Expression (IMAGE) multicenter study was conducted between the years 2005-2009 and studied patients who were >6 months-5 years post transplant. The IMAGE study demonstrated that the clinical outcome of heart transplant patients managed with AlloMap® was noninferior to patients managed with EMB. The EIMAGE study expands the time window under study to include patients who are 2 months (≥ 55 days) post-transplant. This earlier time frame of study is the primary difference between the EIMAGE study and the IMAGE study.

Official Title
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Early Invasive Monitoring Attenuation Through Gene Expression (EIMAGE) Trial

Conditions
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Graft Rejection, Heart Diseases

Intervention / Treatment
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* Procedure: Endomyocardial biopsy
* Procedure: AlloMap Molecular Testing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Heart transplant recipients who are 2-6 months (≥55 days -185 days) post-transplant at the time of the first study surveillance visit Age ≥ 18 years Left ventricular ejection fraction ≥ 50% by Echocardiography, Multiple Gated Acquisition (MUGA) scan, or ventriculography at study entry (baseline / enrollment study) Exclusion Criteria: Any clinical signs of declining graft function: Symptoms of Congestive Heart Failure (CHF) at the first study surveillance visit Signs of decompensated heart failure, including the development of a new S3 gallop at the enrollment visit Elevated right heart pressures with diminished cardiac index < 2.2 L/min/m2 that is new compared to a previous measurement within 2 months Decrease in LVEF as measured by echocardiography: ≥ 25% compared to prior measurement within 2 months Rejection therapy for biopsy-proven ISHLT Grade 3A or higher during the preceding 2 months Prior or current evidence of antibody-mediated rejection (AMR). AMR is defined according to the ISHLT 2004 Guidelines as positive histology and immunopathology (either immunofluorescence or immunoperoxidase) staining for AMR Major changes in immunosuppression therapy within previous 30 days (e.g., discontinuation of calcineurin inhibitors, switch from mycophenolate mofetil to sirolimus or vice versa) Unable to give written informed consent Patient receiving hematopoietic growth factors (e.g., Neupogen, Epogen) currently or during the previous 30 days Patients receiving ≥ 20 mg/day of prednisone equivalent corticosteroids at the time of first study surveillance visit Patient enrolled in a trial requiring routine surveillance endomyocardial biopsies Patient received transfusion within preceding 4 weeks Patients with end-stage renal disease requiring some form of renal replacement therapy (hemodialysis or peritoneal dialysis) Pregnancy at the time of first study surveillance visit

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: AlloMap Molecular testing<br>Gene expression profiling in the monitoring of asymptomatic heart transplant patients for acute cellular rejection. | Procedure: AlloMap Molecular Testing<br>* Gene expression profiling in the monitoring of asymptomatic heart transplant patients for acute cellular rejection.<br>* Other names: GEP;|
| Active Comparator: Endomyocardial biopsy<br>Right ventricular endomyocardial biopsy in the monitoring of asymptomatic heart transplant patients for acute cellular rejection | Procedure: Endomyocardial biopsy<br>* Right ventricular endomyocardial biopsy in monitoring of asymptomatic heart transplant patients for acute cellular rejection<br>* Other names: EMB;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free Survival and intravascular ultrasound (IVUS) measures | Event-Free Survival (EFS) is a composite of: the development of hemodynamic compromise with rejection, allograft dysfunction (hemodynamic compromise without histologically confirmed rejection), death from any cause, or re-transplantation. IVUS co-primary endpoint: maximal intimal thickness of the coronary arteries from baseline (measured at 6 weeks ± 30 days) to month 12 of ≥0.5mm, as measured by IVUS. | 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time from enrollment to death from any cause, and cause of death. |  | 1.5 years | 
| Number of biopsies performed. |  | 1.5 years | 
| Time from study enrollment to biopsy-related complications, as well as the number and type of biopsy-related complications. |  | 1.5 years | 
| QOL responses as collected from the SF-12 form |  | Enrollment and one year post-transplant | 
| Biopsy-related patient preferences satisfaction using a non-validated survey |  | Enrollment and one year post transplant | 
| Objective measurements of cardiac function |  | 1.5 years | 
| Gene expression profiling scores and immunosuppressant doses |  | 1.5 years | 
| Number of rejection episodes. |  | 1.5 years | 
| Utilization of AlloMap or biopsy to manage corticosteroid weaning between month 6 and month 12 post-transplant. |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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molecular expression testing, right ventricular endomyocardial biopsy