DEFINE-HT: Development of Non-invasive Cell-free DNA to Supplant Invasive Biopsy in Heart Transplantation

Sponsor

Natera, Inc. (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05309382

Collaborator

(none)

250

Enrollment

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This is a prospective, multicenter observational, unblinded, longitudinal cohort study. Subjects will be enrolled into the study prior to or at the time of heart transplantation. All subjects will follow the center's standard of care surveillance schedule. Blood samples will be collected for Prospera testing at the time any surveillance or for-cause testing, which may include endomyocardial biopsy (EMB), echocardiography or other cardiac imaging studies, and/or molecular testing, is performed.

Condition or Disease	Intervention/Treatment	Phase
Heart Transplant	Diagnostic Test: Prospera

Detailed Description

Subjects will undergo surveillance monitoring for rejection per the institution's standard clinical care schedule after transplant. Surveillance procedures may include EMB, imaging such as echocardiography, and/or molecular testing. Surveillance is expected to occur at this approximate schedule during the 12 months post-transplant:

Weekly during month 1
Every other week months 2-3
Monthly during months 4-6
Every 1-3 months during months 7-12

For-cause testing for rejection will be performed as clinically indicated and per the institution's standard clinical care. Prospera testing will be performed at the time each standard of care (SOC) rejection surveillance procedure and at the time of each for-cause testing for rejection. Prospera test results will be provided to the clinical team.

Additional blood samples for research only will be collected at the time of each Prospera blood sample collection. Results of testing performed on research blood samples will not be returned to investigators for use in clinical care.

Study central laboratory or central review for research purposes will include:

Central pathology review (all EMBs, includes for-cause EMBs).
Central echocardiography review at day 30 (± 14 days), month 6 (± 30 days) and month 12 (± 30 days) post-transplant.
Central testing of PRA/DSA pre-transplant (between enrollment and transplant), at day 30 (± 14 days), month 6 (± 30 days) and month 12 (± 30 days) post-transplant.

Central pathology and echocardiography review will be performed using uploaded images obtained from procedures performed as part of routine clinical care. Central pathology review, central echocardiography review and central laboratory PRA/DSA are for research purposes; these data will be reviewed during the analysis phase of the study and results will not be returned to investigators for use in clinical care.

The study period will start at enrollment and conclude with the final visit at 12 months +/- 30 days post-transplant.

This study will generate additional preliminary data to be used in the design and implementation of a subsequent confirmatory clinical utility trial.

The primary objectives are to:

Describe the association between Prospera dd-cfDNA measures and other diagnostic tests used to detect heart allograft rejection and/or injury, including histology, echocardiography and DSA, in the first post-transplant year
Inform rates of clinical outcomes in a contemporary cohort of adult heart transplant recipients to determine power for a future randomized, controlled clinical trial.

The secondary objectives are to determine:

The performance characteristics of the Prospera dd-cfDNA assay to discriminate biopsyproven acute rejection (AR).
The performance characteristics of the Prospera dd-cfDNA assay to discriminate acute cellular rejection (ACR).
The performance characteristics of the Prospera dd-cfDNA assay to discriminate antibody mediated rejection (AMR).
The association between dd-cfDNA levels and donor specific antibodies.
The association between dd-cfDNA levels and allograft dysfunction as measured by echocardiography.
The association between dd-cfDNA levels and allograft hemodynamics as measured by right heart catheterization.
The association between dd-cfDNA levels and future adverse clinical outcomes.
The effect of treatment for rejection on dd-cfDNA.
The variability of dd-cfDNA by patient characteristics, including race and gender.
The variability of dd-cfDNA across donor-recipient characteristics, including gender and race mismatch.
The association between dd-cfDNA (fraction and absolute level) and predicted heart mass.
The association between dd-cfDNA levels and time since transplant.
The association between dd-cfDNA levels and rejection with hemodynamic compromise (requiring inotropes and/or mechanical circulatory support).
The association between dd-cfDNA levels and incidence of cardiac allograft vasculopathy at one year.
The association between dd-cfDNA levels and different regimens of immunosuppression

Study Design

Study Type:

Observational

Anticipated Enrollment :

250 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Development of Non-invasive Cell-free DNA to Supplant Invasive Biopsy in Heart Transplant

Anticipated Study Start Date :

Jun 1, 2022

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Jun 1, 2024

Outcome Measures

Primary Outcome Measures

Primary Molecular Endpoint [1 year]
Percent and quantity of donor-derived cell-free DNA (dd-cfDNA) measured via the Prospera test.
Primary clinical endpoint* [12 months]
Incidence of the composite endpoint of treated rejection, graft dysfunction, re-transplantation, or death at 12 months after transplant. *Clinical endpoints are defined as follows: Treated rejection: treated biopsy proven rejection (ISHLT ACR Grade ≥ 2R or AMR Grade ≥ pAMR1) or biopsy-negative rejection treated with pulse-dose steroids, monoclonal antibodies, plasmapheresis and/or intravenous immunoglobulin (IVIg). Graft dysfunction: left ventricular ejection fraction (LVEF) decline >10% from baseline and < 50% absolute LVEF by echocardiography. Re-transplantation: being listed for re-transplant or being re-transplanted. Death due to any cause.

Secondary Outcome Measures

Secondary Endpoints [12 months]
The secondary endpoints are: Incidence of the individual components of the primary composite endpoint at 12 months after transplant. The incidence at 12 months of: Rejection with hemodynamic compromise (requiring inotropes and/or mechanical circulatory support); The development of de novo donor specific antibodies; Cardiac allograft vasculopathy.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 18 years or older at the time of signing informed consent.
Undergoing transplant evaluation or currently 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:

Concurrent multiple solid organ or tissue transplants.
Prior history of any organ or cellular transplantation.
Pregnant.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Natera, Inc.

Investigators

Study Director: Michael Olymbios, MD, Natera, Inc.
Principal Investigator: Palak Shah, MD, Inova Health Care Services
Study Chair: Josef Stehlik, MD, University of Utah

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Natera, Inc.

ClinicalTrials.gov Identifier:

NCT05309382

Other Study ID Numbers:

22-062-TRP

First Posted:

Apr 4, 2022

Last Update Posted:

Apr 25, 2022

Last Verified:

Apr 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Natera, Inc.

Study Results

No Results Posted as of Apr 25, 2022