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

Early Invasive Monitoring Attenuation Through Gene Expression (EIMAGE) Trial

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.

Study Overview

• Status: Unknown
• Conditions: Heart Diseases; Graft Rejection
• Intervention / Treatment: Procedure: AlloMap Molecular Testing; Procedure: Endomyocardial biopsy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Beverly Hills, California, United States, 90211
      • Cedars-Sinai Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Heart transplant recipients who are 2-6 months (≥55 days -185 days) post-transplant at the time of the first study surveillance visit
2. Age ≥ 18 years
3. Left ventricular ejection fraction ≥ 50% by Echocardiography, Multiple Gated Acquisition (MUGA) scan, or ventriculography at study entry (baseline / enrollment study)

Exclusion Criteria:

1. 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
2. Rejection therapy for biopsy-proven ISHLT Grade 3A or higher during the preceding 2 months
3. 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
4. Major changes in immunosuppression therapy within previous 30 days (e.g., discontinuation of calcineurin inhibitors, switch from mycophenolate mofetil to sirolimus or vice versa)
5. Unable to give written informed consent
6. Patient receiving hematopoietic growth factors (e.g., Neupogen, Epogen) currently or during the previous 30 days
7. Patients receiving ≥ 20 mg/day of prednisone equivalent corticosteroids at the time of first study surveillance visit
8. Patient enrolled in a trial requiring routine surveillance endomyocardial biopsies
9. Patient received transfusion within preceding 4 weeks
10. Patients with end-stage renal disease requiring some form of renal replacement therapy (hemodialysis or peritoneal dialysis)
11. Pregnancy at the time of first study surveillance visit

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: XDx
• Investigators: Study Director: Upen Patil, MD, XDx, Inc.

Publications and helpful links

General Publications

• Starling RC, Pham M, Valantine H, Miller L, Eisen H, Rodriguez ER, Taylor DO, Yamani MH, Kobashigawa J, McCurry K, Marboe C, Mehra MR, Zuckerman A, Deng MC; Working Group on Molecular Testing in Cardiac Transplantation. Molecular testing in the management of cardiac transplant recipients: initial clinical experience. J Heart Lung Transplant. 2006 Dec;25(12):1389-95. doi: 10.1016/j.healun.2006.10.002. No abstract available. Erratum In: J Heart Lung Transplant. 2007 Feb;26(2):204.
• Pham MX, Teuteberg JJ, Kfoury AG, Starling RC, Deng MC, Cappola TP, Kao A, Anderson AS, Cotts WG, Ewald GA, Baran DA, Bogaev RC, Elashoff B, Baron H, Yee J, Valantine HA; IMAGE Study Group. Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med. 2010 May 20;362(20):1890-900. doi: 10.1056/NEJMoa0912965. Epub 2010 Apr 22.
• Deng MC, Eisen HJ, Mehra MR, Billingham M, Marboe CC, Berry G, Kobashigawa J, Johnson FL, Starling RC, Murali S, Pauly DF, Baron H, Wohlgemuth JG, Woodward RN, Klingler TM, Walther D, Lal PG, Rosenberg S, Hunt S; CARGO Investigators. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am J Transplant. 2006 Jan;6(1):150-60. doi: 10.1111/j.1600-6143.2005.01175.x.
• Evans RW, Williams GE, Baron HM, Deng MC, Eisen HJ, Hunt SA, Khan MM, Kobashigawa JA, Marton EN, Mehra MR, Mital SR. The economic implications of noninvasive molecular testing for cardiac allograft rejection. Am J Transplant. 2005 Jun;5(6):1553-8. doi: 10.1111/j.1600-6143.2005.00869.x.
• Marboe CC, Billingham M, Eisen H, Deng MC, Baron H, Mehra M, Hunt S, Wohlgemuth J, Mahmood I, Prentice J, Berry G. Nodular endocardial infiltrates (Quilty lesions) cause significant variability in diagnosis of ISHLT Grade 2 and 3A rejection in cardiac allograft recipients. J Heart Lung Transplant. 2005 Jul;24(7 Suppl):S219-26. doi: 10.1016/j.healun.2005.04.001.

Helpful Links

• Information on molecular expression testing
• Sponsor's website

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Anticipated): December 1, 2011
• Study Completion (Anticipated): December 1, 2011

Study Registration Dates

• First Submitted: August 19, 2009
• First Submitted That Met QC Criteria: August 19, 2009
• First Posted (Estimate): August 20, 2009

Study Record Updates

• Last Update Posted (Estimate): December 21, 2010
• Last Update Submitted That Met QC Criteria: December 20, 2010
• Last Verified: December 1, 2010

More Information

Terms related to this study

• Keywords: molecular expression testing; right ventricular endomyocardial biopsy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases
• Other Study ID Numbers: CA-0007