IMAGE: A Comparison of AlloMap Molecular Testing and Traditional Biopsy-based Surveillance for Heart Transplant Rejection

Heart Diseases Clinical Trial

Official title:

Invasive Monitoring Attenuation Through Gene Expression (IMAGE) Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00351559
• Other study ID #: CA-0004
• Status: Completed
• Phase: N/A
• First received: July 11, 2006
• Last updated: November 18, 2009
• Start date: January 2005
• Est. completion date: October 2009

Study information

• Verified date: November 2009
• Source: XDx
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

This study is designed to evaluate the safety and efficacy of a leukocyte gene expression profiling method in the monitoring of asymptomatic heart transplant patients for acute rejection.

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. With a higher incidence of acute cellular rejection (ACR) in the first six months post-transplant, ACR continues to occur beyond the first year post-transplant. However, the optimal strategy for detecting rejection during this period of lower risk period for ACR is still controversial. 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 629
• Est. completion date: October 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Heart transplant recipients who are > 6 months to 5 years (> 6-60 months) post-transplant.

2. Age = 18 years.

3. Stable outpatient being seen for routine monitoring of rejection. Stability is defined as absence of prior or current evidence of either severe cardiac allograft vasculopathy (CAV) or antibody-mediated rejection (AMR) with associated hemodynamic compromise.

1. Severe CAV is defined as either

• > 50% left main stenosis;

• = 50% stenosis in = 2 primary vessels (proximal 1/3 or middle 1/3 of the LAD or LCx, RCA to takeoff of PDA in right-dominant coronary circulations) or

• Isolated branch stenoses of > 50% in all 3 systems (diagonal branches, obtuse marginal branches, distal 1/3 of LAD or LCx, PDA, PLB, and RCA to takeoff of PDA in non-dominant systems).

2. AMR with associated hemodynamic compromise is defined as AMR (defined according to local criteria) with either

• A left ventricular ejection fraction (LVEF) = 30% or at least 25% lower than the baseline value,

• A cardiac index < 2 l/min/m2, or

• The use of inotropic agents to support circulation.

4. Left ventricular ejection fraction = 45% by Echocardiography, Multiple Gated Acquisition (MUGA) scan, or ventriculography at study entry (baseline / enrollment study).

Exclusion Criteria:

1. Patients < 7 calendar months after heart transplantation.

2. Any clinical signs of declining graft function:

1. Symptoms of Congestive Heart Failure (CHF) at the enrollment visit.

2. Signs of decompensated heart failure, including the development of a new S3 gallop at the enrollment visit.

3. Elevated right heart pressures with diminished cardiac index < 2.2 L/min/m2 that is new compared to a previous measurement within 6 months.

4. Decrease in LVEF as measured by echocardiography: = 25% compared to prior measurement within 6 months.

3. Rejection therapy for biopsy-proven ISHLT Grade 3A or higher during the preceding 2 months.

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 enrollment.

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 enrollment.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Graft Rejection
• Heart Diseases

Intervention

Device:
• AlloMap molecular expression testing

Procedure:
• Right ventricular endomyocardial biopsy

Locations

Country	Name	City	State
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago	Chicago	Illinois
United States	The Cleveland Clinic	Cleveland	Ohio
United States	Texas Heart Institute at St. Luke's Episcopal Hospital	Houston	Texas
United States	Mid America Heart Institute - St. Luke's Hospital	Kansas City	Missouri
United States	Intermountain Medical Center	Murray	Utah
United States	Columbia University Medical Center - New York Presbyterian Hospital	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	VA Palo Alto Health Care System	Palo Alto	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Barnes Jewish Hospital - Washington University	St. Louis	Missouri
United States	Stanford University Medical Center	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
XDx

Country where clinical trial is conducted

United States, 

References & Publications (4)

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. — View Citation

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. — View Citation

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. — View Citation

Pham MX, Deng MC, Kfoury AG, Teuteberg JJ, Starling RC, Valantine H. Molecular testing for long-term rejection surveillance in heart transplant recipients: design of the Invasive Monitoring Attenuation Through Gene Expression (IMAGE) trial. J Heart Lung Transplant. 2007 Aug;26(8):808-14. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time from study enrollment to the earliest date of decrease in left ventricle function (left ventricular ejection fraction [LVEF] decrease = 25% from baseline)
Primary	Time from study enrollment to the development of clinically overt rejection (heart failure, hemodynamic compromise)
Primary	Time from study enrollment to death from any cause
Secondary	Number of deaths and cause of death
Secondary	Number of biopsies planned and performed
Secondary	Time to and number of biopsy-related complications, including bleeding, perforation and tamponade requiring pericardiocentesis, worsening of tricuspid regurgitation (TR) by 1 grade above 2+ or new TR at least 3+ or greater

External Links

•   Click here for more information on gene expression testing
•   Sponsor's web site