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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT06174220
Recruitment Status : Not yet recruiting
First Posted : December 18, 2023
Last Update Posted : February 22, 2024
Population Health Research Institute
Canadian Institutes of Health Research (CIHR)
AMO Pharma
Hearts in Rhythm Organization (HiRO)
Canadian SADS
Information provided by (Responsible Party):
Hamilton Health Sciences Corporation

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Arrhythmogenic Cardiomyopathy Arrhythmogenic Right Ventricular Cardiomyopathy Drug: Tideglusib Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients will be randomized in a 1:1 ratio using an automated central, web-based system within 30 days of completing their baseline Holter. Randomization will be stratified by TMEM43-p.S358L variant status.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Targeted Therapy With Glycogen Synthase Kinase-3 Inhibition for Arrhythmogenic Cardiomyopathy
Estimated Study Start Date : April 1, 2024
Estimated Primary Completion Date : February 1, 2026
Estimated Study Completion Date : July 1, 2026

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

Primary Outcome Measures :
  1. PVC burden [ Time Frame: Baseline and 6 months ]
    Change in mean PVC count per 24 hours on 7-day Holter

Secondary Outcome Measures :
  1. Ventricular strain [ Time Frame: Baseline and 6 months ]
    Change in ventricular strain on echocardiography

  2. Implantable cardioverter-defibrillator (ICD) therapies [ Time Frame: Baseline and 6 months ]
    Number of ICD therapies (shock or anti-tachycardia pacing)

  3. 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)

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT06174220

Show Show 19 study locations
Sponsors and Collaborators
Hamilton Health Sciences Corporation
Population Health Research Institute
Canadian Institutes of Health Research (CIHR)
AMO Pharma
Hearts in Rhythm Organization (HiRO)
Canadian SADS
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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
Roberts JD, Murphy NP, Hamilton RM, Lubbers ER, James CA, Kline CF, Gollob MH, Krahn AD, Sturm AC, Musa H, El-Refaey M, Koenig S, Aneq MA, Hoorntje ET, Graw SL, Davies RW, Rafiq MA, Koopmann TT, Aafaqi S, Fatah M, Chiasson DA, Taylor MR, Simmons SL, Han M, van Opbergen CJ, Wold LE, Sinagra G, Mittal K, Tichnell C, Murray B, Codima A, Nazer B, Nguyen DT, Marcus FI, Sobriera N, Lodder EM, van den Berg MP, Spears DA, Robinson JF, Ursell PC, Green AK, Skanes AC, Tang AS, Gardner MJ, Hegele RA, van Veen TA, Wilde AA, Healey JS, Janssen PM, Mestroni L, van Tintelen JP, Calkins H, Judge DP, Hund TJ, Scheinman MM, Mohler PJ. Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy. J Clin Invest. 2019 Jul 2;129(8):3171-3184. doi: 10.1172/JCI125538. eCollection 2019 Jul 2.

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Responsible Party: Hamilton Health Sciences Corporation Identifier: NCT06174220    
Other Study ID Numbers: PHRI.TaRGET
First Posted: December 18, 2023    Key Record Dates
Last Update Posted: February 22, 2024
Last Verified: February 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hamilton Health Sciences Corporation:
sudden cardiac death, ventricular cardiomyopathy, genetics, arrhythmia
Additional relevant MeSH terms:
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Arrhythmogenic Right Ventricular Dysplasia
Heart Diseases
Cardiovascular Diseases
Heart Defects, Congenital
Cardiovascular Abnormalities
Congenital Abnormalities