Clinical trial NCT00351559: IMAGE: A Comparison of AlloMap Molecular Testing and Traditional Biopsy-based Surveillance for Heart Transplant Rejection
Official title: Invasive Monitoring Attenuation Through Gene Expression (IMAGE) Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Graft Rejection
Heart Diseases
Keywords: allograft
rejection
biopsy
gene
expression
cardiac
heart
transplant
Lead sponsor: XDx
Sponsor class: INDUSTRY
First posted: 2006-07-13
Enrollment: 629
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief 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.

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. 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).

Eligibility criteria: 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.

Primary outcomes:
measure: Time from study enrollment to the earliest date of decrease in left ventricle function (left ventricular ejection fraction [LVEF] decrease ≥ 25% from baseline)
measure: Time from study enrollment to the development of clinically overt rejection (heart failure, hemodynamic compromise)
measure: Time from study enrollment to death from any cause
Secondary outcomes:
measure: Number of deaths and cause of death
measure: Number of biopsies planned and performed
measure: 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
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Kansas City
country: United States
facility: Mid America Heart Institute - St. Luke's Hospital
state: Missouri
city: St. Louis
country: United States
facility: Barnes Jewish Hospital - Washington University
state: Missouri
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: New York
country: United States
facility: Columbia University Medical Center - New York Presbyterian Hospital
state: New York
city: Cleveland
country: United States
facility: The Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Houston
country: United States
facility: Texas Heart Institute at St. Luke's Episcopal Hospital
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
Study officials:
affiliation: Stanford University
name: Hannah A Valantine, MD, MRCP, FACC
role: STUDY_CHAIR
affiliation: VA Palo Alto Health Care System
name: Michael Pham, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Columbia University, New York Presbyterian Hospital
name: Mario C Deng, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh Medical Center
name: Jeffrey J Teuteberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Intermountain Medical Center
name: A G Kfoury, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Intermountain Medical Center
name: Dale G Renlund, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Cleveland Clinic
name: Randall C Starling, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Chicago
name: Allen Anderson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Thomas Cappola, MD, ScM
role: PRINCIPAL_INVESTIGATOR
affiliation: Mid America Heart Institute - St. Luke's Hospital
name: Andrew Kao, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Northwestern University
name: William G Cotts, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Texas Heart Institute at St. Luke's Episcopal Hospital
name: Roberta C Bogaev, M.D., FACC, FACP
role: PRINCIPAL_INVESTIGATOR
affiliation: Newark Beth Israel Medical Center
name: David Baran, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Barnes-Jewish Hospital
name: Greg Ewald, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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. doi: 10.1111/j.1600-6143.2005.00869.x.
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. doi: 10.1016/j.healun.2005.04.001.
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. doi: 10.1016/j.healun.2007.05.017.
citation: Deng MC, Elashoff B, Pham MX, Teuteberg JJ, Kfoury AG, Starling RC, Cappola TP, Kao A, Anderson AS, Cotts WG, Ewald GA, Baran DA, Bogaev RC, Shahzad K, Hiller D, Yee J, Valantine HA; IMAGE Study Group. Utility of gene expression profiling score variability to predict clinical events in heart transplant recipients. Transplantation. 2014 Mar 27;97(6):708-14. doi: 10.1097/01.TP.0000443897.29951.cf.
citation: 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.