Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01804699 |
| Other study ID # |
H12-03189 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 2013 |
| Est. completion date |
August 2020 |
Study information
| Verified date |
November 2020 |
| Source |
University of British Columbia |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited condition that may
cause life threatening irregular heart rhythms that often manifest as unexpected cardiac
arrest or sudden death in early adulthood. The condition is difficult to diagnose and often
is not noticed until a family member suffers a cardiac arrest or death.
The Canadian National ARVC registry will collect data from Inherited Heart Rhythm Clinics
across Canada.
STUDY OBJECTIVES:
Primary:
1. To determine the natural history of ARVC (short/intermediate term), including risk of
symptomatic arrhythmias and sudden death, for patients with the phenotype and those gene
positive patients without phenotype evidence of disease.
2. To understand risk factors for sudden death/appropriate ICD use in ARVC, including test
characteristics/performance and their relationship to outcomes (ECG, Holter, signal
averaged ECG, loop recorders, imaging, voltage mapping, T wave alternans, cardiac biopsy
and biomarkers).
3. To establish a phenotype genotype correlation, including comparison of patients with
disease causing mutations, variants of unknown significance (VUS) and Task Force
Criteria (TFC) positive, gene negative patients
Description:
BACKGROUND:
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a familial condition characterized
by onset of life threatening ventricular arrhythmias in early adulthood, presenting with
ventricular tachycardia, cardiac arrest or sudden death1. The disease is diagnosed with a
wide range of tests that focus on imaging the right ventricle and assessing for ambient
arrhythmia or abnormal electrical substrate.
These factors are collated into a score that forms the ARVC Task Force Criteria, known to be
specific but not sensitive 2, 3. These criteria have been revised in 2010, introducing a
broader and more quantitative approach to diagnosis including genetic testing results,
intended to enhance sensitivity without reducing specificity 4. An online tool for Task Force
Criteria calculation has been developed by the Principal Investigator that enables
calculation in real time, with export to PDF and excel format, free for public use
(http://qstatistic.com/pdg/public.php?rep=arvc_cri).These criteria take into account
electrocardiographic and imaging findings, along with tissue analysis and family history.
They account for findings from genetic testing, confounded in part by the unknown
significance of a positive genetic test in the absence of a phenotype in a disease with
variable penetrance and expressivity 2, 4-12. The disease is predominantly caused by defects
in cell-cell adhesion.
PROJECT APPROVAL PROCESS: For new projects and further analysis
New projects and proposals for the Canadian National ARVC Registry will be reviewed on a
case-by-case basis by the Steering Committee. The following items must be included with each
new proposal:
1. Project description with necessary background, hypotheses and methodology/protocol
2. A comprehensive list of funding source(s) with a detailed budget
3. Local Research Ethics Board (REB) approval
PATIENT RECRUITMENT & SCREENING PROCESS:
1. Patients will be approached to participate in the Registry in specialty clinics who are
involved in the Registry across Canada.
2. Once informed consent is obtained ARVC affected patients will undergo baseline data
collection including:
1. Collection of standard clinical testing for ARVC (if affected patient) according to
local clinical practice i.e. MRI, ECG etc. Family members will undergo screening as
deemed necessary by the local investigator
2. Baseline clinical history
3. Family history and exercise history
4. A family pedigree will be constructed.
5. An online tool for pedigree construction has been developed by the Principal
Investigator Dr. Andrew Krahn that enables creation of pedigrees in real time as
well as the linking of patients in a genetics database, with export to PDF format,
(demonstration version at https://ocrr.ca/pdg/i.php?loc=dmo, contact
kgibbs@providencehealth.bc.ca for access)
6. Patients will be enrolled in the database as prevalent cases that were previously
identified, or incident cases
7. Other testing if applicable
3. Genetic Information (if applicable). Once informed consent has been obtained patients
will undergo baseline data collection and will be invited to participate in the optional
DNA biobanking arm of the study
4. Genetic Screening for ARVC is a standard clinical evaluation for individuals with ARVC
as well as their 1st degree family members this will be done clinically and sent to
commercial laboratories as per the standard at each of the enrolling centres
5. If the participant consents to the biobanking arm of the study an additional blood
sample (Please see the ARVC Lab Manual for details) will be collected at baseline and
stored for subsequent analysis. These analyses may include measurement of serum Troponin
T, NT-pro-BNP, C-reactive protein and other biomarkers to determine their association
with the progression of disease; both in terms of cardiac structure (i.e. change in
right ventricular volume) and electrical substrate (i.e. number of ICD shocks) over
time.
DATA COLLECTION:
Baseline:
1. Patients will be required to provide written informed consent to participate in the
study.
2. The local Research Ethics Board (REB) must approve all informed consent documents.
3. All demographic information, clinical testing and genetic results will be entered into a
password-protected database.
Core Data Set (required):
The core data set consists of baseline and follow-up clinical testing that will establish
participant eligibility according to 2010 Revised Task Force Criteria. The core data set will
include the following:
1. Resting ECG
2. Signal averaged ECG
3. Transthoracic echocardiogram
4. Treadmill exercise test
5. 24 hour Holter monitor
6. Cardiac MRI
Additional test results (if clinically indicated):
The following comprises a typical list of additional test results that may be collected if
available. These test results can be collected if they are clinically indicated for the
participant(s).
1. Right ventricular angiography
2. Right ventricular biopsy
3. Right ventricular voltage map
4. Ability to induce ventricular tachycardia at Electrophysiologic testing
5. Transesophageal echocardiogram
6. T wave alternans
7. Cardiac CT scan
Genetic Testing and Results:
1. Optional blood drawn for banking at PHRI will be processed at each local site and
shipped in Cryovials for banking at PHRI in Hamilton, Ontario. Specimen(s) collected
(i.e. blood, saliva, DNA) will be processed locally before shipping to PHRI.
2. Blood drawn for standard clinical ARVC genetic testing at commercial laboratories in
Canada (For example: in Ontario both SickKids Department of Paediatric Laboratory
Medicine and CHEO Molecular Genetics Diagnostic Laboratory perform ARVC testing) can be
packaged and shipped according to each of the local sites labs independent
specifications.
3. Genetic testing results will be entered into a secure, password-protected database.
These results are further de-identified with a code list so that there is no linkage to
clinical data.
Follow-up:
Follow-up visits for the Registry will occur on an annual basis with the following testing:
1. Resting ECG
2. Signal averaged ECG
3. 24 hour Holter Monitor
4. Clinical History
5. Screening for any new cardiac symptoms, such as: syncope, palpitations, cardiac arrest,
ICD implant, ICD therapy and sudden death
Clinical follow-up data will be collected according to standard local practice. It is ideal
to reassess participants clinically, however if this is not feasible for some reason - a
telephone interview can be conducted to assess any new clinical findings or new events that
have taken place.
If the site wishes to conduct a telephone follow up - the following clinical testing is still
required for the annual follow up visit:
1. Resting ECG
2. Signal averaged ECG if possible
3. 24 hour Holter Monitor
ECGs and Holter tracings can be obtained from remote areas and the findings entered into the
database for annual follow up purposes.
3-Year Reassessment:
After 3 years participation in the study, participants will be reassessed based on the 2010
task force criteria. This includes the following:
1. Resting ECG
2. Signal averaged ECG
3. Transthoracic echocardiogram
4. Treadmill exercise test
5. 24 hour Holter monitor
6. Cardiac MRI
7. Clinical History
8. Screening for any new cardiac symptoms, such as: syncope, palpitations, cardiac arrest,
ICD implant, ICD therapy and sudden death
There is currently no obligation to enter data beyond the 3 year mark, however sites are
encouraged to continue follow up for participants indefinitely. The Registry is open-ended
and with local REB approval participant's follow up data can continue to be entered as long
as it is declared in the letter of information originally given to the participant.
DATA MANAGEMENT:
Data points for collection are present in the internet based database (see online demo at
https://www.qstatistic.com/arvc/demo ). The database is hosted on the University of British
Columbia Research Institute Vancouver British Columbia. The research institute is in
compliance with national Canadian PIPEDA privacy guidelines. Data will be entered directly
into the e-CRFs for electronic submission to a server located at UBC Research
Institute,Vancouver BC and will not collect any personal identifiers (password protected
internet based system).
Personal identifiers will not be collected and subject confidentiality will be further
ensured in addition to maintaining de-identification by utilizing subject identification code
numbers to correspond to data in the computerized files. Original files containing patient
information will remain on file with the participating Investigator.
Individual subject medical information obtained as a result of this trial is considered
confidential and disclosure to third parties is prohibited except for the following reason;
medical information may be given to the subject's personal physician or to other appropriate
medical personnel responsible for the subject's welfare. The eCRF (electronic clinical
research form) system works best in the Internet browser Firefox©. This Internet browser can
be downloaded from www.mozilla.org.
Access to the eCRFs will be issued once the site has local Ethics approval. .
ETHICAL CONSIDERATIONS
This trial will be conducted in compliance with the protocol, principles laid down in the
Declaration of Helsinki, Good Clinical Practice (GCP), as defined by the International
Conference on Harmonization (ICH), where applicable, and all other local regulatory
requirements. Before study initiation, the enrolling site Investigator must have written and
dated approval/favorable opinion from the Institutional Review Board/Independent Ethics
Committee (IRB/IEC) for the protocol, and consent form.
