Clinical trial NCT03575910: HEARTBiT: Multi-Marker Blood Test for Acute Cardiac Transplant Rejection
Official title: HEARTBiT: A Novel Multi-Marker Blood Test for Management of Acute Cardiac Allograft Rejection
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Heart Transplant Failure and Rejection
Heart Failure
Heart Diseases
Heart Failure，Congestive
Transplant; Failure, Heart
Transplant Failure
Keywords: Heart
Transplantation
Acute cardiac rejection
Biomarkers
Genomics
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: PROOF Centre of Excellence
name: Duke University
name: University of Nebraska
name: Toronto General Hospital
name: St. Paul's Hospital, Canada
First posted: 2018-07-03
Enrollment: 196
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: It is anticipated that up to 400 heart transplant recipients will be enrolled as participants. Given the prevalence of treatable AR observed at the recruiting sites, 40-50 AR and 350 NR/MR are expected, excluding the time course (first year post-transplant) samples. Additionally, we plan on enrolling 30 normal control subjects. Comparisons will be made between AR, MR, and NR samples from independent patients.

Brief summary: Heart transplantation is a life saving therapy for people with end stage heart failure. Acute rejection, a process where the immune system recognizes the transplanted heart as foreign and mounts a response against it, remains a clinical problem despite improvements in immunosuppressive drugs. Acute rejection occurs in 20-30% of patients within the first 3 months post-transplant, and is currently detected by highly invasive heart tissue biopsies that happen 12-15 times in the first year post-transplant. Replacing the biopsy with a simple blood test is of utmost value to patients and will reduce healthcare costs. The goal of our project is to develop a new blood test to monitor heart transplant rejection. Advances in biotechnology have enabled simultaneous measurement of many molecules (e.g., proteins, nucleic acids) in blood, driving the development of new diagnostics. Our team is a leader in using computational tools to combine information from numerous biological molecules and clinical data to generate "biomarker panels" that are more powerful than existing diagnostic tests. Our sophisticated analytic methods has recently derived HEARTBiT, a promising test of acute rejection comprising 9 RNA biomarkers, from the measurement of 30,000 blood molecules in 150 Canadian heart transplant patients. Our objective is to study a custom-built HEARTBiT test in a setting and on a technology that enable clinical adoption. We will evaluate the new test on 400 new patients from 5 North American transplant centres. We will also track patients' HEARTBiT scores over time to help predict future rejection, and explore use of proteins and micoRNAs to improve HEARTBiT. Our work will provide the basis for a future clinical trial. The significance of this work rests in that it will provide a tool to identify acute cardiac rejection in a fast, accurate, cost-effective and minimally invasive manner, allowing for facile long-term monitoring and therapy tailoring for heart transplant patients.

Detailed description: Rationale:

Cardiac transplantation remains the main intervention for those with end-stage heart failure. Maintenance immunosuppression is given to all transplant recipients to prevent acute rejection and loss of the allograft. Despite great improvements in immunosuppressive therapies, acute rejection remains a clinical problem and occurs at varying severity in 20-30% of patients within the first 3 months post-transplant. Timely detection of moderate rejection allows for treatment to be modified, preventing organ damage, graft failure and patient death. The current method to monitor for rejection remains the endomyocardial biopsy (EMB), a highly invasive and costly procedure that poses physical risks and emotional stress to patients, who must undergo 12-15 such tests during the first year post-transplant. EMB detects rejection only when tissue damage has occurred, and lacks sensitivity as it provides information about tiny pieces of the endomyocardium. Clearly, patients and clinicians would benefit from an effective, cheaper, less invasive diagnostic test that can indicate when an EMB is not needed.

Our team used unbiased omics strategies and computational tools to identify potential biomarkers of treatable acute rejection (ISHLT grade 2R or higher) in peripheral blood. We hypothesize that there are distinctive RNA and protein signatures in blood that can be developed into a simple test to accurately indicate when heart transplant patients do not require EMB, and that studying these biomarkers in a clinically relevant setting will facilitate clinical adoption.

Our Specific Aims are to:

1. Evaluate the performance of HEARTBiT, a custom 9-mRNA biomarker test developed on the NanoString platform, in an environment suitable for clinical translation, on \>4000 newly collected samples from 400 patients across North America
2. Examine the biomarker panel score and individual biomarkers serially across the first year post-transplant to identify predictive signatures of rejection and characterize underlying biology
3. Develop and assess 5 promising protein biomarker candidates on NanoString, test 7 candidate miRNAs, and evaluate combinatorial RNA-protein classifier performance metrics to improve HEARTBiT

Expertise: Our team at the Centre of Excellence for Prevention of Organ Failure has over 10 years experience in computational analysis of omics and clinical data to create biomarker tests that out-perform current gold standards. Our Biomarkers in Transplantation (BiT) study has been continuously funded by competitive grants, philanthropy and industry between 2004-2017 and has generated many publications related to heart and kidney transplant rejection. Via our collaborators, we will have access to a Canadian Blood Services facility for testing our biomarkers, and patient samples from 5 major transplant sites (St. Paul's/Vancouver, Toronto, Nebraska, Newark Beth Israel, Duke).

Outcomes: The HEARTBiT test will be ready for clinical utility studies. The test will have significant clinical and socioeconomic value by reducing EMBs for transplant patients and enabling the tailoring of therapy. Insights into the biology of immune rejection will also be enhanced.

Eligibility criteria: Heart Transplant Subjects:

Inclusion Criteria

* recipients who are ≥ 19 years of age
* willing and able to provide informed consent

Exclusion Criteria

* recipients under 19 years of age
* recipients who have received multiple, different solid organ transplants (i.e. a heart and a kidney)
* recipients who are HIV positive
* recipients of organs from donors who test positive for HIV

Normal Subjects:

Inclusion Criteria

* all individuals who are ≥ 19 years of age
* willing and able to provide informed consent

Primary outcomes:
measure: Comparison of the HEARTBiT Biomarker Panel Score (BPS) between acute rejection and non-rejection/mild-rejection samples on the NanoString platform.
timeFrame: Within 5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Ottawa
country: Canada
facility: Ottawa Heart Institute
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital UHN
state: Ontario
Study officials:
affiliation: University of British Columbia
name: Scott Tebbutt, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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