Donor-Derived Cell-free DNA to DETect REjection in Cardiac Transplantation

Study Overview
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Brief Summary
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The study objective is to demonstrate that rejection surveillance of heart transplant recipients with Prospera dd-cfDNA is non-inferior to rejection surveillance with endomyocardial biopsy and histology in the first post-transplant year.

Detailed Description
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Subjects will be enrolled into the study while on the transplant waiting list prior to heart transplantation. All subjects will follow the center's standard of care surveillance schedule from transplant through 4 post-transplantation. EMB during this phase is expected to occur roughly weekly. Subjects will be randomized in a 1:1 ratio 30 days (± 7 days) post-transplant to Prospera surveillance (Study Group) versus EMB surveillance (Control Group, standard clinical care). Rejection surveillance (Prospera testing in the Study Group and EMB in the Control Group) will be performed at times corresponding to the institutional standard of care schedule for rejection surveillance. Study Group: Prospera Surveillance (300 Subjects) Subjects will undergo Prospera testing at times corresponding to the institution's graft surveillance schedule. Prospera test results will be provided to the clinical team. Prospera cfDNA level < 0.15% will be interpreted as negative and a surveillance EMB will be omitted. Prospera cfDNA ≥ 0.15% will be followed by EMB. A for-cause EMB can be done per the clinical team's discretion at any time. Control Group: EMB Surveillance (standard of care) (300 Subjects) Subjects will undergo surveillance EMB per the institution's standard clinical care. For subjects in both groups, research blood samples will be obtained at the time of each Prospera or EMB surveillance visit. Study central laboratory or central review will include: Central pathology review (all EMBs in both Groups) Central testing of DSA (at randomization and months 6 and12) Echocardiography review (at randomization and months 12 for echocardiography component of primary endpoint) The study intervention will be during the first 12 months post-transplant.

Official Title
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Donor-Derived Cell-free DNA to DETect REjection in Cardiac Transplantation

Conditions
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Heart Transplant Failure and Rejection

Intervention / Treatment
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* Diagnostic Test: Prospera Transplant Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age 18 years or older at the time of signing informed consent. On the heart transplant waiting list and expected to receive a heart transplant. Able to read, understand and provide written informed consent. Able and willing to comply with the study visit schedule, study procedures and study requirements. Exclusion Criteria: Heart transplantation has been performed. Concurrent multiple solid organ or tissue transplant Prior history of any organ or cellular transplantation. Planned use of other commercially available or investigational cfDNA or gene expression profile assays. Pregnant. Hemodynamically unstable or other serious medical condition that may adversely affect the subject's ability to participate in the study

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prospera Surveillance<br>Subjects will undergo Prospera testing in accordance with the institution's Control Group EMB surveillance standard of care schedule, which is expected to be approximately every other week months 2 and 3, then monthly through months 4 through 6, then every 1-3 months during months 7 through 12. Prospera test results will be provided to investigators. Prospera cfDNA level < 0.15 % will be interpreted as negative, and screening EMB will be omitted. EMB will be performed for cfDNA level ≥ 0.15 %. At any time, the clinical team may perform for cause EMB for standard clinical indications (e.g., evidence of graft failure) as per the treating team's discretion. Additional research blood samples will be collected for research purposes; the results of testing performed on research samples will not be provided to investigators. | Diagnostic Test: Prospera Transplant Assessment<br>* Prospera™ detects allograft rejection noninvasively and with high accuracy by measuring the fraction of dd-cfDNA in the patient's blood, without the need for prior donor or recipient genotyping. Prospera is a commercially available LDT developed by Natera, Inc. Natera is a laboratory certified under the Clinical Laboratory Improvement Amendments (CLIA).<br>|
| No Intervention: EMB Surveillance<br>Subjects will undergo surveillance EMB per the institution's standard clinical care, which is expected to be approximately every other week months 2 and 3, then monthly through months 4 through 6, then every 1-3 months during months 7 through 12. Research blood samples will be obtained at the time of each EMB. At any time, the clinical team may perform for cause EMB for standard clinical indications (e.g., evidence of graft failure) as per the treating team's discretion. Research blood samples will be collected for research purposes; the results of testing performed on research samples will not be provided to investigators. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Demonstrate the use of Prospera for post-transplant surveillance is non-inferior to the current standard of care, EMB surveillance, with respect to the primary composite endpoint. | The primary endpoint of the study is a composite endpoint defined as the first occurrence of one or more of the following events after transplant: Treated rejection with graft dysfunction and/or graft dysfunction requiring treatment with pulse dose steroids, monoclonal antibodies, plasmapheresis, and/or intravenous immunoglobulin (IVIg) Treated rejection without graft dysfunction Graft dysfunction Re-transplantation Death Clinical endpoints are defined as follows: Rejection: ISHLT ACR Grade ≥ 2R or AMR Grade ≥ pAMR1 Graft dysfunction: LVEF decline >10% from baseline and < 50% absolute LVEF by echocardiography Re-transplantation: being listed for re-transplant or being re-transplanted | 12 months |