Evaluation of A Clinical Diagnostic Test for CRDS (DIAGNOSE CRDS)

May 28, 2026 updated by: Population Health Research Institute

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

Calcium Release Deficiency Syndrome (CRDS) is a novel inherited arrhythmia syndrome secondary to RyR2 loss-of-function that confers a risk of sudden cardiac death. Diagnosis of CRDS presently requires cellular-based in vitro confirmation that an RyR2 variant causes loss-of-function. We hypothesize that CRDS can be diagnosed clinically through evaluation of the repolarization response to brief tachycardia, mediated by cardiac pacing, and a subsequent pause.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

RyR2 loss-of-function variants have recently been established as causative for a new disease termed calcium release deficiency syndrome (CRDS) that confers a risk of malignant ventricular arrhythmias and sudden cardiac death. RyR2 encodes the cardiac ryanodine receptor, the calcium release channel on the sarcoplasmic reticulum that mediates excitation-contraction coupling through calcium-induced calcium-release. In contrast to CRDS, pathogenic RyR2 gain-of-function variants result in an autosomal dominant form of catecholaminergic polymorphic ventricular tachycardia (CPVT). The adrenergic-mediated ventricular arrhythmias characteristic of CPVT can be readily reproduced on exercise stress testing (EST), making EST the standard clinical diagnostic tool for CPVT.

In contrast to CPVT, the CRDS clinical phenotype is concealed with standard cardiac testing tools and its diagnosis presently requires cellular-based in vitro confirmation that an RyR2 variant causes loss-of-function. Beyond the significant time delay associated with in vitro functional analysis, this testing requires specialized expertise that is not widely available and remains research-based, making it impractical for routine use in clinical care. In this overall context, it is likely that the vast majority of global CRDS cases have yet to be diagnosed.

A prior report of an "atypical CPVT" family carrying an RyR2-p.M4109R variant observed marked and transient repolarization changes following pacing mediated tachycardia and a subsequent pause. Since publication of this report, in vitro characterization of the RyR2-p.M4109R variant has confirmed its being loss-of-function and the familial diagnosis has been revised to CRDS. Driven by these observations and promising preliminary findings, the DIAGNOSE CRDS study seeks to further investigate this apparent electrocardiographic signature of CRDS following brief tachycardia and subsequent pause as a potential method to clinically diagnose the condition.

Study Type

Interventional

Enrollment (Estimated)

400

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Belgium
      • Brussels, Belgium, 1090
        • Recruiting
        • Universitair Ziekenhuis Brussel
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
        • Principal Investigator:
          • Luigi Pannone, MD
    • Antwerp
      • Edegem, Antwerp, Belgium, 2650
        • Recruiting
        • Antwerp University Hospital
        • Principal Investigator:
          • Johan Saenen, MD, PhD
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
  • Canada
    • Alberta
      • Calgary, Alberta, Canada, T2N 1N4
        • Recruiting
        • University of Calgary
        • Principal Investigator:
          • Erkan Ilhan, MD
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
      • Edmonton, Alberta, Canada, T6G 2C8
        • Recruiting
        • Alberta Health Services
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
        • Principal Investigator:
          • Joseph Atallah, MD CM, MSc
    • British Columbia
      • Vancouver, British Columbia, Canada, V6T 1Z3
        • Recruiting
        • The University of British Columbia
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
        • Principal Investigator:
          • Thomas M Roston, MD
      • Vancouver, British Columbia, Canada, V6H 3N1
        • Recruiting
        • Children's & Women's Health Centre of British Columbia
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
        • Principal Investigator:
          • Shubhayan Sanatani, MD
    • Ontario
      • Hamilton, Ontario, Canada, L8L 2X2
        • Recruiting
        • Hamilton General Hospital
        • Principal Investigator:
          • Jason D Roberts, MD MAS
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
      • London, Ontario, Canada, N6A 5A5
        • Recruiting
        • London Health Sciences Centre - University Hospital
        • Principal Investigator:
          • Habib R Khan, MD
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
      • Ottawa, Ontario, Canada, K1Y 4W7
        • Recruiting
        • Ottawa Heart Institute
        • Principal Investigator:
          • Simon Hansom, MD
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
      • Toronto, Ontario, Canada, M5G 2C4
        • Recruiting
        • Toronto General Hospital
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
        • Principal Investigator:
          • Michael H. Gollob, MD, FRCP(C)
    • Quebec
      • Montreal, Quebec, Canada, H1T 1C8
        • Recruiting
        • Montreal Heart Institute
        • Principal Investigator:
          • Rafik Tadros, MD PhD
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
      • Québec, Quebec, Canada, G1V 4G5
        • Recruiting
        • Institut Universitaire de Cardiologie et de Pneumologie de Québec-Université Laval
        • Principal Investigator:
          • Christian Steinberg, MD
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
  • Denmark
      • Aarhus, Denmark, DK-8200 N
        • Recruiting
        • Aarhus University Hospital
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
        • Principal Investigator:
          • Henrik Jensen, MD
  • France
    • New Aquitaine
      • Bordeaux, New Aquitaine, France, 33404
        • Recruiting
        • CHU de Bordeaux
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
        • Principal Investigator:
          • Frédéric Sacher, MD
  • Israel
      • Jerusalem, Israel, 9103102
        • Recruiting
        • Shaare Zedek Medical Center
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
        • Principal Investigator:
          • Ziv Dadon, MD
  • United Kingdom
    • Oxfordshire
      • Oxford, Oxfordshire, United Kingdom, OX3 9DU
        • Recruiting
        • Oxford University Hospitals
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
        • Principal Investigator:
          • Julian Ormerod, BM, Bch, FRCP
  • United States
    • California
      • San Francisco, California, United States, 94143
        • Recruiting
        • University of California
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
        • Principal Investigator:
          • Vasanth Vedantham, MD, PhD
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Recruiting
        • Mayo Clinic
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
        • Principal Investigator:
          • John Giudicessi, MD, PhD
    • Washington
      • Seattle, Washington, United States, 98195
        • Recruiting
        • University of Washington
        • Contact:
          • Project Manager
          • Phone Number: 905-521-2100
          • Email: crds@phri.ca
        • Principal Investigator:
          • Uyanga Batnyam, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pacing
Separate ventricular and atrial pacing trains will be administered at different cycle lengths and the ventricular repolarization response on the first sinus beat following the subsequent pause will be evaluated.
Diagnostic test: Pacing
  1. Ventricular 10 beat burst at 500ms (120bpm)
  2. Ventricular 10 beat burst at 400ms (150bpm)
  3. Atrial 10 beat burst at 500ms (120bpm)
  4. Atrial 10 beat burst at 400ms (150bpm).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
ΔT-wave amplitude value
Time Frame: At time of pacing maneuver
T-wave amplitude on first post-pause sinus beat subtracted by the T-wave amplitude on the last sinus beat prior to pacing
At time of pacing maneuver
ΔQT value
Time Frame: At time of pacing maneuver
Absolute QT value on first post-pause sinus beat subtracted by the absolute QT value on the last sinus beat prior to pacing
At time of pacing maneuver

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Absolute QT value
Time Frame: At time of pacing maneuver
Absolute QT value on first post-pause sinus beat
At time of pacing maneuver
Absolute T-wave amplitude
Time Frame: At time of pacing maneuver
Absolute T-wave amplitude on first post-pause sinus beat
At time of pacing maneuver

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Population Health Research Institute

Collaborators

Canadian Institutes of Health Research (CIHR)

Investigators

  • Study Director: Ziv Dadon, MD, Shaare Zedek Medical Center
  • Principal Investigator: Jason D Roberts, MD MAS, McMaster University
  • Principal Investigator: Wayne Chen, PhD, University of Calgary

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 2, 2023

Primary Completion (Estimated)

December 1, 2027

Study Completion (Estimated)

March 1, 2028

Study Registration Dates

First Submitted

December 18, 2023

First Submitted That Met QC Criteria

December 18, 2023

First Posted (Actual)

January 3, 2024

Study Record Updates

Last Update Posted (Actual)

June 1, 2026

Last Update Submitted That Met QC Criteria

May 28, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 14546

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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