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HEARTBiT: Multi-Marker Blood Test for Acute Cardiac Transplant Rejection (HEARTBiT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03575910
Recruitment Status : Recruiting
First Posted : July 3, 2018
Last Update Posted : June 19, 2019
Canadian Institutes of Health Research (CIHR)
PROOF Centre of Excellence
Duke University
University of Nebraska
Toronto General Hospital
St. Paul's Hospital, Canada
Information provided by (Responsible Party):
Bruce McManus, University of British Columbia

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.

Condition or disease
Heart Transplant Failure and Rejection Heart Failure Heart Diseases Heart Failure,Congestive Transplant; Failure, Heart Transplant Failure

Detailed Description:


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.

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Study Type : Observational
Estimated Enrollment : 400 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: HEARTBiT: A Novel Multi-Marker Blood Test for Management of Acute Cardiac Allograft Rejection
Actual Study Start Date : August 9, 2018
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : June 30, 2023

Resource links provided by the National Library of Medicine

Acute Rejection (AR)
Heart transplant patients diagnosed with an ISHLT grade 2R or 3R via endomyocardial biopsy.
Mild Rejection (MR)
Heart transplant patients diagnosed with an ISHLT grade 1R via endomyocardial biopsy.
Non-Rejection (NR)
Heart transplant patients diagnosed with an ISHLT grade 0R via endomyocardial biopsy.

Primary Outcome Measures :
  1. Comparison of the HEARTBiT Biomarker Panel Score (BPS) between acute rejection and non-rejection/mild-rejection samples on the NanoString platform. [ Time Frame: Within 5 years ]
    The performance of HEARTBiT, a custom 9-RNA biomarker assay developed on the NanoString platform, will be evaluated in an environment suitable for clinical translation using a sample size of ~4000 newly collected samples from 400 HT patients. Performance will be assessed by applying an algorithm that combines the quantitative data of the 9 RNA into a single BPS. This score aggregates the influence of all RNAs and will be associated with an estimated probability that AR is occurring in the transplant recipient. The algorithm will establish a single cutoff thus producing a final binary test result (AR or NR/MR), or, if possible, two cutoffs to separate AR, MR and NR as ordered variables.

Biospecimen Retention:   Samples With DNA

Whole blood samples to be collected in four (4) tubes (approx. 15mL or 3 teaspoons) consisting of:

  1. 1 - 6 mL lavender top (EDTA) tube (plasma)
  2. 1 - 4 mL red top tube (serum)
  3. 2 - 2.5 mL PAXgene tubes (RNA)

Blood processing (fractionation) of plasma and serum tubes following SOP guidelines will result in collection of:

8 - 0.5mL plasma aliquots

1 - 0.5mL buffy coat DNA sample 6 - 0.5mL serum aliquots

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03575910

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Contact: Sara Assadian, MHS, CCRP 604-682-2344 ext 62557
Contact: Karen Lam, PhD 604-682-2344 ext 62612

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United States, Nebraska
University of Nebraska Medical Center Recruiting
Omaha, Nebraska, United States, 68198
Contact: Sandra J Strizek, BSRT, RRT    402-559-0983   
Canada, British Columbia
St. Paul's Hospital Recruiting
Vancouver, British Columbia, Canada, V6Z 1Y6
Contact: Sara Assadian, MHS, CCRP    604-682-2344 ext 62557   
Principal Investigator: Bruce M McManus, MD, PhD         
Canada, Ontario
Ottawa Heart Institute Recruiting
Ottawa, Ontario, Canada, K1Y4W7
Contact: Heather Cosgrove    6136967000 ext 14790   
Toronto General Hospital UHN Recruiting
Toronto, Ontario, Canada, M5G 2C4
Contact: Natalia Nugaeva, PhD, CCRP    416-340-4800 ext 3403   
Sponsors and Collaborators
University of British Columbia
Canadian Institutes of Health Research (CIHR)
PROOF Centre of Excellence
Duke University
University of Nebraska
Toronto General Hospital
St. Paul's Hospital, Canada
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Principal Investigator: Bruce McManus, MD, PhD University of British Columbia

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Responsible Party: Bruce McManus, Professor, University of British Columbia Identifier: NCT03575910    
Other Study ID Numbers: PROOF
First Posted: July 3, 2018    Key Record Dates
Last Update Posted: June 19, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bruce McManus, University of British Columbia:
Acute cardiac rejection
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases