Clinical trial NCT05100420: Hypertrophic Cardiomyopathy Registry, Biobank and Imaging Data Repository
Official title: Hearts in Rhythm Organization Hypertrophic Cardiomyopathy Registry, Biobank and Imaging Data Repository (HiRO-HCM)
Study type: OBSERVATIONAL
Overall status: ENROLLING_BY_INVITATION
Conditions: Hypertrophic Cardiomyopathy
Hypertrophic Obstructive Cardiomyopathy
Familial Hypertrophic Cardiomyopathy
Cardiomyopathies
Keywords: Genetics
Echocardiography
Cardiac magnetic resonance imaging
Biomarker
Sudden cardiac death
Genome-wide association study
Risk prediction model
Lead sponsor: Montreal Heart Institute
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
First posted: 2021-10-29
Enrollment: 2000
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: FAMILY_BASED
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The HiRO-HCM registry, biobank and imaging data repository is a multicenter collaboration that will prospectively enroll patients with HCM as well as those carrying genetic variants predisposing to HCM.

Brief summary: The Hearts in Rhythm Organization (HiRO) is a national network of Canadian researchers/clinicians, working towards a better understanding of the rare genetic causes of sudden cardiac death (SCD). The HiRO Hypertrophic Cardiomyopathy registry, biobank and imaging data repository (HiRO-HCM) is a multicenter study that will prospectively enroll patients with HCM as well as those carrying sarcomeric gene variants predisposing to HCM.

The objectives of HiRO-HCM are:

1. to better understand the natural history of the disease and identify clinical markers and biomarkers for adverse outcomes;
2. to derive and validate risk prediction models for disease expression, complications and response to therapy;
3. to better define the genetic architecture of sarcomeric and non-sarcomeric HCM.

Detailed description: PATIENT ENROLLMENT:

Eligible patients will be included from HiRO sites or collaborating centres. Patients will be contacted by the local investigator or a research coordinator. Willing individuals will be interviewed by the research coordinator and given information about HiRO-HCM. The consent form will be reviewed and discussed with the coordinator. The investigators will also be available for any questions that the coordinator is unable to answer. Potential participants will have sufficient time to consider participating in HiRO-HCM. Written informed consent will be obtained from eligible patients or legal guardians. Participants will be able to withdraw their participation at any time.

BASELINE DATA COLLECTION:

Clinical data will be collected from willing/consented registry participants. All demographic and medical information pertaining to the cardiac history and comorbidities of eligible patients will be collected at baseline, including clinical information, diagnostic test results, genetic testing results, family history and ethnicity, as well as current and previous treatments. Healthcare information will be coded in compliance with Canada's Tri-Council Policy Statement criteria: direct identifiers will be removed and replaced with a unique study code that does not use personal information such as the participant's health number, social insurance number or name. The coded data will be transferred into the clinical research database using a web-based electronic case report form (eCRF), using REDcap. The clinical research database will be managed by the Montreal Health Innovations Coordinating Center (MHICC; mhicc.org). Study participants will be identified by subject number only (research HiRO-HCM ID). The research ID uniquely identifying each subject eCRF within the database will be attributed in REDcap but the master list of registry participants with their study identifiers will be kept separately from the clinical research database. This master list will be stored in an encrypted file within the research office of each site investigators under their supervision. Only the site investigators and their local research staff will have access to this list.

BIOSPECIMEN COLLECTION:

Consented participants will undergo biosampling at enrollment for the primary purpose of DNA isolation and genetic studies. The preferred biosampling method is blood sampling using a standard venipuncture. Blood sampling allows for high quality DNA extraction as well as collection of plasma for future circulating biomarkers studies. As an alternative to blood sampling, collection of saliva using DNA genotek kits, or equivalent, is allowed in the following contexts:

* Patient enrollment is performed remotely. This is particularly relevant in the context of the ongoing SARS-CoV-2 pandemic, where physical distancing is preferred.
* Patient is a child \<14 years old without planned clinically indicated blood sampling.

Participants for which saliva collection is chosen should be made aware of the possibility to request a blood sample in the future.

The HiRO-HCM biobank will be directed by the Beaulieu-Saucier Pharmacogenomics Center (PGx; http://www.pharmacogenomics.ca), operating under Good Laboratory/Clinical Practices (GLP/GCP) standards.

DNA isolation and long-term storage will be done at PGx, while long-term storage of plasma samples will be done at the MHI research center, in dedicated freezers located in a room with restricted access. Samples of subjects that withdraw their participation will be destroyed.

IMAGING DATA TRANSFER:

For all consented participants, de-identified transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) imaging data will be transferred to the Montreal Heart Institute imaging core-lab for central interpretation and long term storage. At minimum, the following imaging studies are requested:

1. First available TTE
2. First available CMR, preferably with gadolinium injection
3. Last available TTE
4. Last available CMR, preferably with gadolinium injection

For patients that underwent alcohol septal ablation, surgical myectomy and/or cardiac transplantation, the last available TTE and CMR studies prior to all these interventions should also be transferred.

Digital Imaging and Communications in Medicine (DICOM) imaging data will be de-identified prior to transfer. De-identification will be performed at each site, by removing the patient's name and replacing the clinical identification number with the research HiRO-HCM ID. DICOM data will be stored using the Canadian Imaging network infrastructure (canadianimagingnetwork.org).

PATIENT FOLLOW-UP:

Participants with a clinical diagnosis of HCM are expected to undergo yearly clinic visits, as per standard care. Participants without yearly clinic visits will be contacted by phone. Follow-up visits will assess for living status, functional class, as well as for arrhythmic, heart failure and thromboembolic events. Follow-up data will be entered by the local investigator and/or research coordinator into an eCRF managed by the MHICC. De-identified documentation of clinical events including ECG, intracardiac tracing, clinical notes, imaging reports, and procedural reports will be uploaded to the database for centralized ad-hoc event adjudication.

De-identified DICOM images of TTE and CMR studies performed clinically during follow-up will be uploaded to the MHI imaging core-lab similarly as for baseline imaging studies.

For participants that will undergo septal myectomy for drug-refractory obstructive HCM, or cardiac transplantation, surgical tissue samples will be collected using the Qiagen PAXgene tissue preservation system or equivalent, allowing for future somatic DNA, RNA and proteomic analyses. The samples will be stored at the MHI research center.

Eligibility criteria: Inclusion Criteria:

Patients with (1) AND/OR (2)

1. Clinical diagnosis of HCM, defined as

   1. maximal LVWT ≥15mm, or
   2. maximal LVWT ≥13mm, in presence of a diagnosis of first degree relative with HCM, or
   3. septal wall thickness with z-score \>2 in a child

   AND/OR
2. Carrier of a pathogenic or likely pathogenic genetic variant in a sarcomeric gene (ACTC1, FHOD3, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2, TPM1). Variant classification should be performed by a certified diagnostic laboratory according to the American College of Medical Genetics and Genomics (ACMG) guidelines.

Exclusion Criteria:

1. Clinical or molecular diagnosis of Noonan syndrome or other Rasopathies
2. Clinical or molecular diagnosis of metabolic disease associated with cardiomyopathy, such as Pompe (GAA), Fabry (GLA), Danon (LAMP2), AMP-kinase (PRKAG2), and carnitine disorders
3. Clinical diagnosis of a neuromuscular disease associated with cardiomyopathy, such as Friedrich's ataxia
4. Clinical diagnosis of cardiac amyloidosis with or without the presence of genetic variants in TTR
5. Clinical or molecular diagnosis of mitochondrial cardiomyopathy
6. Diagnosis of HCM \>65 years old AND absence of pathogenic or likely pathogenic variant in a sarcomeric gene (as defined in inclusion criterion 1B above)
7. History of myocardial infarction
8. History of moderate or severe aortic stenosis
9. History of congenital heart defects requiring percutaneous or surgical correction
10. History of severe hypertension defined as a systolic blood pressure \>180 mmHg and/or diastolic blood pressure \>110 mmHg AND absence of pathogenic or likely pathogenic variant in a sarcomeric gene (as defined in inclusion criterion 1B above)
11. Refusal to provide informed consent or to provide a biospecimen for DNA analysis
12. No possibility to upload transthoracic echocardiogram or cardiac magnetic resonance imaging for core lab interpretation

Primary outcomes:
measure: Create a Canadian Research Database, a biobank and an imaging data repository for those affected by hypertrophic cardiomyopathy (HCM) or carrying a sarcomeric gene variant associated with HCM
timeFrame: 5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Edmonton
country: Canada
facility: Mazankowski Alberta Heart Institute
state: Alberta
city: Vancouver
country: Canada
facility: UBC St. Paul's Hospital
state: British Columbia
city: Victoria
country: Canada
facility: Vancouver Island Health Authority
state: British Columbia
city: Halifax
country: Canada
facility: IWK Health Centre
state: Nova Scotia
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: McMaster University
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: University of Ottawa Heart Institute
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier de l'Université de Montréal (CHUM)
state: Quebec
city: Montreal
country: Canada
facility: Hôpital Ste-Justine
state: Quebec
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Montreal
country: Canada
facility: Montreal Heart Institute
state: Quebec
city: Québec
country: Canada
facility: Institut Universitaire de Cardiologie et Pneumologie de Québec
state: Quebec
Study officials:
affiliation: Montreal Heart Institute
name: Rafik Tadros, Dr.
role: PRINCIPAL_INVESTIGATOR
References: