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

NCT03575910 | Completed

• 1 other identifier: PROOF
• Study Type: observational
• Target: 196
• Locations: 2 countries
• Sites: 4

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.

Conditions

Heart Failure; Heart Diseases; Heart Transplant Failure and Rejection; Heart Failure，Congestive; Transplant; Failure, Heart; Transplant Failure

Keywords

Heart; Transplantation; Acute cardiac rejection; Biomarkers; Genomics

Outcome Measures

Primary Outcomes (1)

• Comparison of the HEARTBiT Biomarker Panel Score (BPS) between acute rejection and non-rejection/mild-rejection samples on the NanoString platform.

  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.

  Within 5 years

Study Arms (3)

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.

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

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

You may not qualify if:

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

Sponsors & Collaborators

• Canadian Institutes of Health Research (CIHR): collaborator
• Duke University: collaborator
• University of Nebraska: collaborator
• Toronto General Hospital: collaborator
• St. Paul's Hospital, Canada: collaborator
• University of British Columbia: lead
• PROOF Centre of Excellence: collaborator

Study Sites (4)

University of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

Location

St. Paul's Hospital

Vancouver, British Columbia, V6Z 1Y6, Canada

Location

Ottawa Heart Institute

Ottawa, Ontario, K1Y4W7, Canada

Location

Toronto General Hospital UHN

Toronto, Ontario, M5G 2C4, Canada

Location

Related Publications (12)

• Sukma Dewi I, Gidlof O, Hollander Z, Lam KK, Benson MD, Braun OO, Nilsson J, Tebbutt SJ, Ng RT, Ohman J, McManus BM, Smith JG. Immunological Serum Protein Profiles for Noninvasive Detection of Acute Cellular Rejection After Heart Transplantation. J Am Coll Cardiol. 2017 Dec 12;70(23):2946-2947. doi: 10.1016/j.jacc.2017.10.012. No abstract available.

  PMID: 29216990 BACKGROUND

• Toma M, Mak GJ, Chen V, Hollander Z, Shannon CP, Lam KKY, Ng RT, Tebbutt SJ, Wilson-McManus JE, Ignaszewski A, Anderson T, Dyck JRB, Howlett J, Ezekowitz J, McManus BM, Oudit GY. Differentiating heart failure phenotypes using sex-specific transcriptomic and proteomic biomarker panels. ESC Heart Fail. 2017 Aug;4(3):301-311. doi: 10.1002/ehf2.12136. Epub 2017 Mar 4.

  PMID: 28772032 BACKGROUND

• Sukma Dewi I, Hollander Z, Lam KK, McManus JW, Tebbutt SJ, Ng RT, Keown PA, McMaster RW, McManus BM, Gidlof O, Ohman J. Association of Serum MiR-142-3p and MiR-101-3p Levels with Acute Cellular Rejection after Heart Transplantation. PLoS One. 2017 Jan 26;12(1):e0170842. doi: 10.1371/journal.pone.0170842. eCollection 2017.

  PMID: 28125729 BACKGROUND

• Sukma Dewi I, Celik S, Karlsson A, Hollander Z, Lam K, McManus JW, Tebbutt S, Ng R, Keown P, McMaster R, McManus B, Ohman J, Gidlof O. Exosomal miR-142-3p is increased during cardiac allograft rejection and augments vascular permeability through down-regulation of endothelial RAB11FIP2 expression. Cardiovasc Res. 2017 Apr 1;113(5):440-452. doi: 10.1093/cvr/cvw244.

  PMID: 28073833 BACKGROUND

• Hollander Z, Lazarova M, Lam KK, Ignaszewski A, Oudit GY, Dyck JR, Schreiner G, Pauwels J, Chen V, Cohen Freue GV, Ng RT, Wilson-McManus JE, Balshaw R, Tebbutt SJ, McMaster RW, Keown PA, McManus BM; NCE CECR PROOF Prevention of Organ Failure (PROOF) Centre of Excellence. Proteomic biomarkers of recovered heart function. Eur J Heart Fail. 2014 May;16(5):551-9. doi: 10.1002/ejhf.65. Epub 2014 Feb 23.

  PMID: 24574204 BACKGROUND

• Shin H, Gunther O, Hollander Z, Wilson-McManus JE, Ng RT, Balshaw R, Keown PA, McMaster R, McManus BM, Isbel NM, Knoll G, Tebbutt SJ. Longitudinal analysis of whole blood transcriptomes to explore molecular signatures associated with acute renal allograft rejection. Bioinform Biol Insights. 2014 Jan 22;8:17-33. doi: 10.4137/BBI.S13376.. eCollection 2014.

  PMID: 24526836 BACKGROUND

• Cohen Freue GV, Meredith A, Smith D, Bergman A, Sasaki M, Lam KK, Hollander Z, Opushneva N, Takhar M, Lin D, Wilson-McManus J, Balshaw R, Keown PA, Borchers CH, McManus B, Ng RT, McMaster WR; Biomarkers in Transplantation and the NCE CECR Prevention of Organ Failure Centre of Excellence Teams. Computational biomarker pipeline from discovery to clinical implementation: plasma proteomic biomarkers for cardiac transplantation. PLoS Comput Biol. 2013 Apr;9(4):e1002963. doi: 10.1371/journal.pcbi.1002963. Epub 2013 Apr 4.

  PMID: 23592955 BACKGROUND

• Hollander Z, Chen V, Sidhu K, Lin D, Ng RT, Balshaw R, Cohen-Freue GV, Ignaszewski A, Imai C, Kaan A, Tebbutt SJ, Wilson-McManus JE, McMaster RW, Keown PA, McManus BM; NCE CECR PROOF Centre of Excellence. Predicting acute cardiac rejection from donor heart and pre-transplant recipient blood gene expression. J Heart Lung Transplant. 2013 Feb;32(2):259-65. doi: 10.1016/j.healun.2012.11.008. Epub 2012 Dec 21.

  PMID: 23265908 BACKGROUND

• Shannon CP, Hollander Z, Wilson-McManus J, Balshaw R, Ng RT, McMaster R, McManus BM, Keown PA, Tebbutt SJ. White blood cell differentials enrich whole blood expression data in the context of acute cardiac allograft rejection. Bioinform Biol Insights. 2012;6:49-61. doi: 10.4137/BBI.S9197. Epub 2012 Apr 10.

  PMID: 22550401 BACKGROUND

• Lin D, Hollander Z, Meredith A, Stadnick E, Sasaki M, Cohen Freue G, Qasimi P, Mui A, Ng RT, Balshaw R, Wilson-McManus JE, Wishart D, Hau D, Keown PA, McMaster R, McManus BM; Biomarkers in Transplantation Team; NCE CECR PROOF Centre of Excellence. Molecular signatures of end-stage heart failure. J Card Fail. 2011 Oct;17(10):867-74. doi: 10.1016/j.cardfail.2011.07.001. Epub 2011 Sep 3.

  PMID: 21962426 BACKGROUND

• Hollander Z, Lin D, Chen V, Ng R, Wilson-McManus J, Ignaszewski A, Cohen Freue G, Balshaw R, Mui A, McMaster R, Keown PA, McManus BM; NCE CECR PROOF Centre of Excellence. Whole blood biomarkers of acute cardiac allograft rejection: double-crossing the biopsy. Transplantation. 2010 Dec 27;90(12):1388-93. doi: 10.1097/TP.0b013e3182003df6.

  PMID: 21076371 BACKGROUND

• Lin D, Hollander Z, Ng RT, Imai C, Ignaszewski A, Balshaw R, Freue GC, Wilson-McManus JE, Qasimi P, Meredith A, Mui A, Triche T, McMaster R, Keown PA, McManus BM; Biomarkers in Transplantation Team; NCE CECR Centre of Excellence for the Prevention of Organ Failure. Whole blood genomic biomarkers of acute cardiac allograft rejection. J Heart Lung Transplant. 2009 Sep;28(9):927-35. doi: 10.1016/j.healun.2009.04.025.

  PMID: 19716046 BACKGROUND

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

MeSH Terms

Conditions

Rejection, Psychology; Heart Failure; Heart Diseases

Condition Hierarchy (Ancestors)

Social Behavior; Behavior; Cardiovascular Diseases

Study Officials

• Scott Tebbutt, PhD

  University of British Columbia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 19, 2018
• First Posted: July 3, 2018
• Study Start: August 9, 2018
• Primary Completion: December 30, 2025
• Study Completion: March 30, 2026
• Last Updated: May 4, 2026

Record last verified: 2026-04

Locations

US (1); CA (3)