Targeted Therapy With Glycogen Synthase Kinase-3 Inhibition for Arrhythmogenic Cardiomyopathy (TaRGET)

February 20, 2024 updated by: Hamilton Health Sciences Corporation
The TaRGET study is a multi-centre, prospective, randomized, double-blind, placebo-controlled trial designed to evaluate the potential therapeutic efficacy of tideglusib, a glycogen synthase kinase-3 β inhibitor, in genotype positive arrhythmogenic cardiomyopathy.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Arrhythmogenic cardiomyopathy (ACM) is a heritable form of structural heart disease characterized by myocardial fibrosis that confers vulnerability to malignant ventricular arrhythmias and sudden cardiac death (SCD). A subgroup of cases preferentially involves the right ventricle and is termed arrhythmogenic right ventricular cardiomyopathy (ARVC). Although an increasingly diverse set of genes have been implicated in ACM, its most prominent genetic culprits are constituents of the desmosome, a specialized cellular structure within the intercalated disc that mediates intercellular adhesion. An additional ACM genetic subtype develops secondary to the TMEM43-p.S358L variant and is associated with an aggressive clinical phenotype, particularly among males.

Despite dramatic progress in unravelling the genetic underpinnings of ACM, insight into its pathophysiology remains modest. A lack of understanding of its operative biological pathways has rendered development of tailored treatments challenging, leading to approaches to medical therapy being largely adopted from those utilized for more common forms of cardiomyopathy. An implantable cardioverter defibrillator (ICD) is recommended for prevention of SCD for all ACM patients considered high risk for malignant ventricular arrhythmias, however does not address its underlying pathophysiology. Subsequent prevention of painful ICD shocks for ventricular tachycardia often requires interventions that may carry modest efficacy and significant risks for adverse events, including anti-arrhythmic drugs and invasive combined endo- and epicardial catheter ablation procedures.

In 2014, a high-throughput screen of a library of bioactive compounds against a zebrafish model of ACM identified a small molecule classified as a glycogen synthase kinase-3 (GSK3) inhibitor that successfully prevented and rescued the phenotype, findings that have subsequently been reproduced in a series of ACM murine models. GSK3 is an enzyme that modulates the activity of a broad spectrum of intracellular signaling pathways, including the canonical Wnt/β-catenin pathway, whose suppression has been suggested to exert an important role in ACM pathogenesis.

Tideglusib is an oral GSK3β inhibitor with an established safety profile in humans. Driven by promising findings observed for tideglusib in ACM mouse models, we now seek to evaluate its potential efficacy in a randomized clinical trial involving genotype positive ACM patients.

Study Type

Interventional

Enrollment (Estimated)

120

Phase

  • Phase 2

Contacts and Locations

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

Study Locations

  • Canada
    • Alberta
      • Calgary, Alberta, Canada, T2N 2T9
        • Foothills Medical Centre
        • Principal Investigator:
          • Erkan Ilhan, MD
        • Sub-Investigator:
          • Patrick Champagne, MD
    • British Columbia
      • Vancouver, British Columbia, Canada, V6Z 1Y6
        • St. Paul's Hospital
        • Principal Investigator:
          • Thomas M Roston, MD PhD
        • Principal Investigator:
          • Zachary Laksman, MD MSc
        • Principal Investigator:
          • Andrew D Krahn, MD
        • Sub-Investigator:
          • Gnalini Sathananthan, MD
      • Victoria, British Columbia, Canada, V8Z 0B9
        • Victoria Cardiac Arrhythmia Trials Inc.
        • Contact:
        • Principal Investigator:
          • Martin van Zyl, MD
        • Sub-Investigator:
          • Karan Shetty, MD
    • Manitoba
      • Winnipeg, Manitoba, Canada, R2H 2A6
        • Saint Boniface Hospital
        • Principal Investigator:
          • Collette Seifer, MD
        • Principal Investigator:
          • Clarence Khoo, MD
        • Sub-Investigator:
          • Steven Promislow, MD
    • Newfoundland and Labrador
      • St John's, Newfoundland and Labrador, Canada, A1B 3V6
        • Health Sciences Centre
        • Principal Investigator:
          • Stephen Duffett, MD
        • Principal Investigator:
          • Sean Connors, MD
        • Principal Investigator:
          • Kathy Hodgkinson, PhD
        • Sub-Investigator:
          • Ashar Pirzada, MD
    • Nova Scotia
      • Halifax, Nova Scotia, Canada, B3H 2Y9
        • Queen Elizabeth II Health Sciences Centre
        • Principal Investigator:
          • Ciorsti MacIntyre, MD
        • Principal Investigator:
          • David Lee, MD
        • Sub-Investigator:
          • Daniel Belliveau, MD
    • Ontario
      • Hamilton, Ontario, Canada, L8L 2X2
        • Hamilton General Hospital
        • Principal Investigator:
          • Jason D Roberts, MD MAS
        • Principal Investigator:
          • Jeff S Healey, MD
        • Sub-Investigator:
          • Javier Ganame, MD
      • Kingston, Ontario, Canada, K7L 2V7
        • Kingston General Hospital
        • Principal Investigator:
          • Chris Simpson, MD
        • Sub-Investigator:
          • Amar Thakrar, MD
      • London, Ontario, Canada, N6A 5A5
        • London Health Sciences Centre
        • Principal Investigator:
          • Habib R Khan, MD
      • Newmarket, Ontario, Canada, L3Y 2P9
        • Southlake Regional Health Centre
        • Principal Investigator:
          • Mouhannad Sadek, MD
        • Sub-Investigator:
          • Molly Thangaroopan, MD
      • Ottawa, Ontario, Canada, K1Y 4W7
        • University of Ottawa Heart Institute
        • Principal Investigator:
          • Simon Hansom, MD
        • Principal Investigator:
          • Martin Green, MD
        • Sub-Investigator:
          • Lawrence Lau, MD
      • Scarborough, Ontario, Canada, M1E 4B9
        • Scarborough Health Network
        • Principal Investigator:
          • Derek Yung, MD
        • Principal Investigator:
          • Bhavanesh Makanjee, MD
        • Sub-Investigator:
          • Natalie Ho, MD
      • Toronto, Ontario, Canada, M4N 3M5
        • Sunnybrook Health Sciences Centre
        • Principal Investigator:
          • Christopher Cheung, MD
        • Sub-Investigator:
          • Idan Roifman, MD
      • Toronto, Ontario, Canada, M5B 1W8
        • St. Michael's Hospital
        • Sub-Investigator:
          • Geraldine Ong, MD
        • Principal Investigator:
          • Paul Angaran, MD
      • Toronto, Ontario, Canada, M5G 2C4
        • Toronto General Hospital
        • Principal Investigator:
          • Michael H Gollob, MD
        • Principal Investigator:
          • Danna Spears, MD
        • Sub-Investigator:
          • Anna Woo, MD
    • Quebec
      • Montréal, Quebec, Canada, H4J 1C5
        • Hôpital du Sacré-Coeur de Montréal
        • Principal Investigator:
          • Leila Laroussi, MD
        • Principal Investigator:
          • Alexios Hadjis, MD
        • Sub-Investigator:
          • Nadia Boule-Laghlazi, MD
      • Montréal, Quebec, Canada, H1T 1C8
        • Montreal Heart Institute
        • Principal Investigator:
          • Julia Cadrin-Tourigny, MD PhD
        • Principal Investigator:
          • Rafik Tadros, MD PhD
        • Sub-Investigator:
          • Marie Chaix, MD
      • Montréal, Quebec, Canada, H4A 3J1
        • McGill University Health Centre
        • Principal Investigator:
          • Jacqueline Joza, MD
        • Sub-Investigator:
          • Michael Chetrit, MD
      • Québec City, Quebec, Canada, G1V 4G5
        • University Institute of Cardiology and Pneumology of Quebec
        • Sub-Investigator:
          • Jonathan Beaudoin, MD
        • Principal Investigator:
          • Christian Steinberg, 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

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • A pathogenic or likely pathogenic desmosomal (PKP2, DSG2, DSC2, DSP, or JUP*) rare variant OR the TMEM43-p.S358L variant

    *JUP carriers must be homozygous or compound heterozygous

  • Mean ≥ 500 PVCs per 24 hours on a baseline screening 7-day Holter monitor
  • Clinical ACM diagnosis or recognition of genetic carrier status for ≥ 6 months prior to screening

Exclusion Criteria:

  • NYHA class IV heart failure
  • Ventricular scar secondary to coronary artery disease
  • Initiation, cessation, or dose change of a Class I or III anti-arrhythmic drug in the 3 months prior to screening
  • Any potentially harmful chronic liver disease
  • ALT value > 2X the upper limit of the normal reference range at Screening
  • Total bilirubin value greater than the upper limit of the normal reference range at Screening, unless documented Gilbert's syndrome. For individuals with Gilbert's syndrome, total bilirubin value greater than 2-fold the upper limit of the normal reference range at Screening.
  • A history of alcohol or illicit substance use disorders
  • Regular and long-term use of strong CYP3A4 inhibitors, including clarithromycin, telithromycin, ketoconazole, itraconazole, posaconazole, nefazodone, idinavir and ritonavir
  • Serum creatinine > 150 micromole/L or creatinine clearance ≤ 60 mL/min (according to Cockcroft-Gault formula) at Screening
  • Pregnant at time of enrollment and women of childbearing age who do not use a highly effective form of contraception
  • Males, engaged in sexual relations with a female of child-bearing potential, not using an acceptable contraceptive method if not surgically sterile
  • Patients unwilling to provide informed consent or comply with follow-up
  • Hypersensitivity to tideglusib or any components of its formulation, including allergy to strawberry

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: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Tideglusib
Randomization to Tideglusib 1g po daily or matching placebo
Drug: Tideglusib
Tideglusib 1g po daily
Placebo Comparator: Placebo
Randomization to matching placebo 1g po daily
Drug: Placebo
Matching placebo 1g po daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
PVC burden
Time Frame: Baseline and 6 months
Change in mean PVC count per 24 hours on 7-day Holter
Baseline and 6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Ventricular strain
Time Frame: Baseline and 6 months
Change in ventricular strain on echocardiography
Baseline and 6 months
Implantable cardioverter-defibrillator (ICD) therapies
Time Frame: Baseline and 6 months
Number of ICD therapies (shock or anti-tachycardia pacing)
Baseline and 6 months
Sustained ventricular tachycardia (VT) events
Time Frame: Baseline and 6 months
Number of sustained VT events (defined as symptomatic or duration > 30 seconds and > 100bpm)
Baseline and 6 months

Collaborators and Investigators

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

Sponsor

Hamilton Health Sciences Corporation

Collaborators

Canadian Institutes of Health Research (CIHR)
Population Health Research Institute
AMO Pharma
Hearts in Rhythm Organization (HiRO)
Canadian SADS

Investigators

  • Principal Investigator: Jason D Roberts, MD MAS, McMaster University and Population Health Research Institute
  • Study Chair: Stuart J Connolly, MD, McMaster University and Population Health Research Institute

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 (Estimated)

April 1, 2024

Primary Completion (Estimated)

February 1, 2026

Study Completion (Estimated)

July 1, 2026

Study Registration Dates

First Submitted

December 1, 2023

First Submitted That Met QC Criteria

December 8, 2023

First Posted (Actual)

December 18, 2023

Study Record Updates

Last Update Posted (Estimated)

February 22, 2024

Last Update Submitted That Met QC Criteria

February 20, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PHRI.TaRGET

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

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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