Evaluating a diagnostic test for Calcium Release Deficiency Syndrome

Evaluation of a Clinical Diagnostic Test for Calcium Release Deficiency Syndrome: The DIAGNOSE CRDS Study

This study is testing a new way to diagnose Calcium Release Deficiency Syndrome by looking at how the heart responds to fast pacing, aiming to make diagnosis easier for patients with this condition and similar heart issues.

Quick facts

• Phase: Not applicable
• Study type: Interventional
• Enrollment: 400 (estimated)
• Sex: All
• Sponsor: Population Health Research Institute (Academic / other)
• Locations: 18 sites (San Francisco, California and 17 other locations)
• Trial ID: NCT06188689 on ClinicalTrials.gov

What this trial studies

This study aims to evaluate a clinical diagnostic test for Calcium Release Deficiency Syndrome (CRDS), a newly identified inherited arrhythmia syndrome linked to RyR2 loss-of-function variants. The researchers hypothesize that CRDS can be diagnosed through the assessment of the heart's repolarization response to brief tachycardia induced by cardiac pacing. This approach seeks to provide a more accessible and timely diagnosis compared to the current in vitro testing methods, which are complex and not widely available. The study will involve multiple cohorts, including confirmed CRDS cases, patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), and survivors of unexplained cardiac arrest.

Who should consider this trial

Good fit: Ideal candidates include individuals with confirmed RyR2 loss-of-function variants or those with unexplained cardiac arrest after thorough cardiac evaluations.

Not a fit: Patients who do not have an RyR2 variant or those with other cardiac conditions unrelated to CRDS may not benefit from this study.

Why it matters

Potential benefit: If successful, this diagnostic test could lead to earlier and more accurate identification of patients with CRDS, potentially reducing the risk of sudden cardiac death.

How similar studies have performed: While the approach to diagnosing CRDS is novel, previous studies have successfully utilized similar pacing techniques for diagnosing other arrhythmias, indicating potential for success.

Eligibility criteria

Cohort 1: Calcium Release Deficiency Syndrome (CRDS) Cases

Inclusion criteria:

• Presence of an RyR2 variant confirmed to be loss-of-function on in vitro testing

Exclusion criteria:

• Unable to provide informed consent

Cohort 2: Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Cases

Inclusion criteria:

* Satisfy a clinical phenotype consistent with the Expert Consensus Statement
* Presence of a confirmed or presumed pathogenic gain-of-function RyR2 variant OR homozygous or compound heterozygous for likely pathogenic/pathogenic CASQ2 variants

Exclusion criteria:

* Unable to provide informed consent
* Use of a QT prolonging medication, aside from flecainide, at the time of the burst pacing maneuvers

Cohort 3: Survivors of Unexplained Cardiac Arrest (UCA)

Inclusion criteria:

* Cardiac arrest requiring cardioversion or defibrillation that remains unexplained following an ECG, echocardiogram, coronary assessment, cardiac MRI, and exercise treadmill test
* Undergone genetic testing that includes screening of RyR2\*

Exclusion criteria:

* Unable to provide informed consent
* Use of a QT prolonging medication at the time of the burst pacing maneuvers

  * Among survivors of UCA that possess a rare RyR2 variant in the absence of a CPVT phenotype, in vitro functional testing will be performed in order to confirm it is not loss- or gain-of-function (and will be arranged through the laboratory of Dr. Wayne Chen at the University of Calgary).

Cohort 4: SVT controls

Inclusion criteria:

• Undergoing an invasive electrophysiology study

Exclusion criteria:

* Ventricular cardiomyopathy
* Ventricular pre-excitation
* Long QT syndrome
* Use of a QT prolonging medication at the time of the EP study
* Use of a Class I or Class III anti-arrhythmic drug at the time of the EP study
* Known obstructive coronary artery disease (existing coronary stenosis \>50%)
* Unable to provide informed consent

Where this trial is running

San Francisco, California and 17 other locations

• University of California — San Francisco, California, United States (Recruiting)
• Mayo Clinic — Rochester, Minnesota, United States (Recruiting)
• University of Washington — Seattle, Washington, United States (Recruiting)
• Antwerp University Hospital — Edegem, Antwerp, Belgium (Recruiting)
• Universitair Ziekenhuis Brussel — Brussels, Belgium (Recruiting)
• University of Calgary — Calgary, Alberta, Canada (Recruiting)
• Children's & Women's Health Centre of British Columbia — Vancouver, British Columbia, Canada (Recruiting)
• The University of British Columbia — Vancouver, British Columbia, Canada (Recruiting)
• Hamilton General Hospital — Hamilton, Ontario, Canada (Recruiting)
• London Health Sciences Centre - University Hospital — London, Ontario, Canada (Recruiting)
• Ottawa Heart Institute — Ottawa, Ontario, Canada (Recruiting)
• Toronto General Hospital — Toronto, Ontario, Canada (Recruiting)
• Montréal Heart Institute — Montreal, Quebec, Canada (Recruiting)
• Institut Universitaire de Cardiologie et de Pneumologie de Québec-Université Laval — Québec, Quebec, Canada (Recruiting)
• Aarhus University Hospital — Aarhus, Denmark (Recruiting)
• CHU de Bordeaux — Bordeaux, New Aquitaine, France (Recruiting)
• Shaare Zedek Medical Center — Jerusalem, Israel (Recruiting)
• Oxford University Hospitals — Oxford, Oxfordshire, United Kingdom (Recruiting)

Study contacts

• Principal investigator: Jason D Roberts, MD MAS — McMaster University
• Study coordinator: Jason Roberts, MD MAS

Conditions Calcium Release Deficiency Syndrome; cardiac arrhythmia, sudden cardiac death, cardiac ryanodine receptor, unexplained cardiac arrest