NCT06188689

Brief Summary

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.

Trial Health

83
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
400

participants targeted

Target at P75+ for not_applicable

Timeline
22mo left

Started Feb 2023

Longer than P75 for not_applicable

Geographic Reach
7 countries

18 active sites

Status
recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Progress64%
Feb 2023Mar 2028

Study Start

First participant enrolled

February 2, 2023

Completed
11 months until next milestone

First Submitted

Initial submission to the registry

December 18, 2023

Completed
16 days until next milestone

First Posted

Study publicly available on registry

January 3, 2024

Completed
3.9 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 1, 2027

Expected
3 months until next milestone

Study Completion

Last participant's last visit for all outcomes

March 1, 2028

Last Updated

May 5, 2026

Status Verified

December 1, 2025

Enrollment Period

4.8 years

First QC Date

December 18, 2023

Last Update Submit

April 29, 2026

Conditions

Calcium Release Deficiency Syndrome (CRDS)

Keywords

cardiac arrhythmia, sudden cardiac death, cardiac ryanodine receptor, unexplained cardiac arrest

Outcome Measures

Primary Outcomes (2)

  • ΔT-wave amplitude value

    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

    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 Outcomes (2)

  • Absolute QT value

    At time of pacing maneuver

  • Absolute T-wave amplitude

    At time of pacing maneuver

Study Arms (1)

Pacing

EXPERIMENTAL

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

Interventions

PacingDIAGNOSTIC_TEST

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).

Pacing

Eligibility Criteria

Sexall
Healthy VolunteersNo
Age GroupsChild (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

  • Unable to provide informed consent
  • Cohort 2: Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Cases
  • 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
  • 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)
  • 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\*
  • 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
  • Undergoing an invasive electrophysiology study
  • Ventricular cardiomyopathy
  • +6 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (18)

University of California

San Francisco, California, 94143, United States

RECRUITING

Mayo Clinic

Rochester, Minnesota, 55905, United States

RECRUITING

University of Washington

Seattle, Washington, 98195, United States

RECRUITING

Antwerp University Hospital

Edegem, Antwerp, 2650, Belgium

RECRUITING

Universitair Ziekenhuis Brussel

Brussels, 1090, Belgium

RECRUITING

University of Calgary

Calgary, Alberta, T2N 1N4, Canada

RECRUITING

Children's & Women's Health Centre of British Columbia

Vancouver, British Columbia, V6H 3N1, Canada

RECRUITING

The University of British Columbia

Vancouver, British Columbia, V6T 1Z3, Canada

RECRUITING

Hamilton General Hospital

Hamilton, Ontario, L8L 2X2, Canada

RECRUITING

London Health Sciences Centre - University Hospital

London, Ontario, N6A 5A5, Canada

RECRUITING

Ottawa Heart Institute

Ottawa, Ontario, K1Y 4W7, Canada

RECRUITING

Toronto General Hospital

Toronto, Ontario, M5G 2C4, Canada

RECRUITING

Montréal Heart Institute

Montreal, Quebec, H1T 1C8, Canada

RECRUITING

Institut Universitaire de Cardiologie et de Pneumologie de Québec-Université Laval

Québec, Quebec, G1V 4G5, Canada

RECRUITING

Aarhus University Hospital

Aarhus, DK-8200 N, Denmark

RECRUITING

CHU de Bordeaux

Bordeaux, New Aquitaine, 33404, France

RECRUITING

Shaare Zedek Medical Center

Jerusalem, 9103102, Israel

RECRUITING

Oxford University Hospitals

Oxford, Oxfordshire, OX3 9DU, United Kingdom

RECRUITING

Related Publications (5)

  • Sun B, Yao J, Ni M, Wei J, Zhong X, Guo W, Zhang L, Wang R, Belke D, Chen YX, Lieve KVV, Broendberg AK, Roston TM, Blankoff I, Kammeraad JA, von Alvensleben JC, Lazarte J, Vallmitjana A, Bohne LJ, Rose RA, Benitez R, Hove-Madsen L, Napolitano C, Hegele RA, Fill M, Sanatani S, Wilde AAM, Roberts JD, Priori SG, Jensen HK, Chen SRW. Cardiac ryanodine receptor calcium release deficiency syndrome. Sci Transl Med. 2021 Feb 3;13(579):eaba7287. doi: 10.1126/scitranslmed.aba7287.

    PMID: 33536282RESULT

  • Nof E, Belhassen B, Arad M, Bhuiyan ZA, Antzelevitch C, Rosso R, Fogelman R, Luria D, El-Ani D, Mannens MM, Viskin S, Eldar M, Wilde AA, Glikson M. Postpacing abnormal repolarization in catecholaminergic polymorphic ventricular tachycardia associated with a mutation in the cardiac ryanodine receptor gene. Heart Rhythm. 2011 Oct;8(10):1546-52. doi: 10.1016/j.hrthm.2011.05.016. Epub 2011 May 26.

    PMID: 21699856RESULT

  • Ormerod JOM, Ormondroyd E, Li Y, Taylor J, Wei J, Guo W, Wang R, Sarton CNS, McGuire K, Dreau HMP, Taylor JC, Ginks MR, Rajappan K, Chen SRW, Watkins H. Provocation Testing and Therapeutic Response in a Newly Described Channelopathy: RyR2 Calcium Release Deficiency Syndrome. Circ Genom Precis Med. 2022 Feb;15(1):e003589. doi: 10.1161/CIRCGEN.121.003589. Epub 2021 Dec 24.

    PMID: 34949103RESULT

  • Roston TM, Wei J, Guo W, Li Y, Zhong X, Wang R, Estillore JP, Peltenburg PJ, Noguer FRI, Till J, Eckhardt LL, Orland KM, Hamilton R, LaPage MJ, Krahn AD, Tadros R, Vinocur JM, Kallas D, Franciosi S, Roberts JD, Wilde AAM, Jensen HK, Sanatani S, Chen SRW. Clinical and Functional Characterization of Ryanodine Receptor 2 Variants Implicated in Calcium-Release Deficiency Syndrome. JAMA Cardiol. 2022 Jan 1;7(1):84-92. doi: 10.1001/jamacardio.2021.4458.

    PMID: 34730774RESULT

  • Ni M, Dadon Z, Ormerod JOM, Saenen J, Hoeksema WF, Antiperovitch P, Tadros R, Christiansen MK, Steinberg C, Arnaud M, Tian S, Sun B, Estillore JP, Wang R, Khan HR, Roston TM, Mazzanti A, Giudicessi JR, Siontis KC, Alak A, Acosta JG, Divakara Menon SM, Tan NS, van der Werf C, Nazer B, Vivekanantham H, Pandya T, Cunningham J, Gula LJ, Wong JA, Amit G, Scheinman MM, Krahn AD, Ackerman MJ, Priori SG, Gollob MH, Healey JS, Sacher F, Nof E, Glikson M, Wilde AAM, Watkins H, Jensen HK, Postema PG, Belhassen B, Chen SRW, Roberts JD. A Clinical Diagnostic Test for Calcium Release Deficiency Syndrome. JAMA. 2024 Jul 16;332(3):204-213. doi: 10.1001/jama.2024.8599.

    PMID: 38900490DERIVED

MeSH Terms

Conditions

Arrhythmias, CardiacDeath, Sudden, Cardiac

Condition Hierarchy (Ancestors)

Heart DiseasesCardiovascular DiseasesPathologic ProcessesPathological Conditions, Signs and SymptomsHeart ArrestDeath, SuddenDeath

Study Officials

  • Ziv Dadon, MD

    Shaare Zedek Medical Center

    STUDY DIRECTOR

  • Jason D Roberts, MD MAS

    McMaster University

    PRINCIPAL INVESTIGATOR

  • Wayne Chen, PhD

    University of Calgary

    PRINCIPAL INVESTIGATOR

Central Study Contacts

Jason Roberts, MD MAS

CONTACT

905-297-3479jason.roberts@phri.ca

Study Design

Study Type
interventional
Phase
not applicable
Allocation
NA
Masking
NONE
Purpose
DIAGNOSTIC
Intervention Model
SINGLE GROUP
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

December 18, 2023

First Posted

January 3, 2024

Study Start

February 2, 2023

Primary Completion (Estimated)

December 1, 2027

Study Completion (Estimated)

March 1, 2028

Last Updated

May 5, 2026

Record last verified: 2025-12

Data Sharing

IPD Sharing
Will not share

Locations

GB(1)CA(9)US(3)FR(1)IL(1)DK(1)BE(2)