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

• ClinicalTrials.gov Identifier: NCT06174220
• Recruitment Status: Not yet recruiting
• First Posted: December 18, 2023
• Last Update Posted: February 22, 2024
• Sponsor: Hamilton Health Sciences Corporation
• Collaborators: 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

Study Description

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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)

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Canada, Alberta

Foothills Medical Centre

Calgary, Alberta, Canada, T2N 2T9

Principal Investigator: Erkan Ilhan, MD

Sub-Investigator: Patrick Champagne, MD

Canada, British Columbia

St. Paul's Hospital

Vancouver, British Columbia, Canada, V6Z 1Y6

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 Cardiac Arrhythmia Trials Inc.

Victoria, British Columbia, Canada, V8Z 0B9

Contact: Rona Herzog rherzog@catrials.org

Principal Investigator: Martin van Zyl, MD

Sub-Investigator: Karan Shetty, MD

Canada, Manitoba

Saint Boniface Hospital

Winnipeg, Manitoba, Canada, R2H 2A6

Principal Investigator: Collette Seifer, MD

Principal Investigator: Clarence Khoo, MD

Sub-Investigator: Steven Promislow, MD

Canada, Newfoundland and Labrador

Health Sciences Centre

St John's, Newfoundland and Labrador, Canada, A1B 3V6

Principal Investigator: Stephen Duffett, MD

Principal Investigator: Sean Connors, MD

Principal Investigator: Kathy Hodgkinson, PhD

Sub-Investigator: Ashar Pirzada, MD

Canada, Nova Scotia

Queen Elizabeth II Health Sciences Centre

Halifax, Nova Scotia, Canada, B3H 2Y9

Principal Investigator: David Lee, MD

Principal Investigator: Ciorsti MacIntyre, MD

Sub-Investigator: Daniel Belliveau, MD

Canada, Ontario

Hamilton General Hospital

Hamilton, Ontario, Canada, L8L 2X2

Principal Investigator: Jason D Roberts, MD MAS

Principal Investigator: Jeff S Healey, MD

Sub-Investigator: Javier Ganame, MD

Kingston General Hospital

Kingston, Ontario, Canada, K7L 2V7

Principal Investigator: Chris Simpson, MD

Sub-Investigator: Amar Thakrar, MD

London Health Sciences Centre

London, Ontario, Canada, N6A 5A5

Principal Investigator: Habib R Khan, MD

Southlake Regional Health Centre

Newmarket, Ontario, Canada, L3Y 2P9

Principal Investigator: Mouhannad Sadek, MD

Sub-Investigator: Molly Thangaroopan, MD

University of Ottawa Heart Institute

Ottawa, Ontario, Canada, K1Y 4W7

Principal Investigator: Simon Hansom, MD

Principal Investigator: Martin Green, MD

Sub-Investigator: Lawrence Lau, MD

Scarborough Health Network

Scarborough, Ontario, Canada, M1E 4B9

Principal Investigator: Bhavanesh Makanjee, MD

Principal Investigator: Derek Yung, MD

Sub-Investigator: Natalie Ho, MD

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada, M4N 3M5

Principal Investigator: Christopher Cheung, MD

Sub-Investigator: Idan Roifman, MD

St. Michael's Hospital

Toronto, Ontario, Canada, M5B 1W8

Principal Investigator: Paul Angaran, MD

Sub-Investigator: Geraldine Ong, MD

Toronto General Hospital

Toronto, Ontario, Canada, M5G 2C4

Principal Investigator: Michael H Gollob, MD

Principal Investigator: Danna Spears, MD

Sub-Investigator: Anna Woo, MD

Canada, Quebec

Montreal Heart Institute

Montréal, Quebec, Canada, H1T 1C8

Principal Investigator: Julia Cadrin-Tourigny, MD PhD

Principal Investigator: Rafik Tadros, MD PhD

Sub-Investigator: Marie Chaix, MD

McGill University Health Centre

Montréal, Quebec, Canada, H4A 3J1

Principal Investigator: Jacqueline Joza, MD

Sub-Investigator: Michael Chetrit, MD

Hopital du Sacré-Coeur de Montréal

Montréal, Quebec, Canada, H4J 1C5

Principal Investigator: Leila Laroussi, MD

Principal Investigator: Alexios Hadjis, MD

Sub-Investigator: Nadia Boule-Laghlazi, MD

University Institute of Cardiology and Pneumology of Quebec

Québec City, Quebec, Canada, G1V 4G5

Principal Investigator: Christian Steinberg, MD

Sub-Investigator: Jonathan Beaudoin, MD

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

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

More Information

Publications:

Krahn AD, Wilde AAM, Calkins H, La Gerche A, Cadrin-Tourigny J, Roberts JD, Han HC. Arrhythmogenic Right Ventricular Cardiomyopathy. JACC Clin Electrophysiol. 2022 Apr;8(4):533-553. doi: 10.1016/j.jacep.2021.12.002.

Asimaki A, Kapoor S, Plovie E, Karin Arndt A, Adams E, Liu Z, James CA, Judge DP, Calkins H, Churko J, Wu JC, MacRae CA, Kleber AG, Saffitz JE. Identification of a new modulator of the intercalated disc in a zebrafish model of arrhythmogenic cardiomyopathy. Sci Transl Med. 2014 Jun 11;6(240):240ra74. doi: 10.1126/scitranslmed.3008008. Erratum In: Sci Transl Med. 2014 Nov 5;6(261):261er6.

Chelko SP, Asimaki A, Andersen P, Bedja D, Amat-Alarcon N, DeMazumder D, Jasti R, MacRae CA, Leber R, Kleber AG, Saffitz JE, Judge DP. Central role for GSK3beta in the pathogenesis of arrhythmogenic cardiomyopathy. JCI Insight. 2016 Apr 21;1(5):e85923. doi: 10.1172/jci.insight.85923.

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.

Padron-Barthe L, Villalba-Orero M, Gomez-Salinero JM, Dominguez F, Roman M, Larrasa-Alonso J, Ortiz-Sanchez P, Martinez F, Lopez-Olaneta M, Bonzon-Kulichenko E, Vazquez J, Marti-Gomez C, Santiago DJ, Prados B, Giovinazzo G, Gomez-Gaviro MV, Priori S, Garcia-Pavia P, Lara-Pezzi E. Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3beta. Circulation. 2019 Oct;140(14):1188-1204. doi: 10.1161/CIRCULATIONAHA.119.040366. Epub 2019 Sep 5.

• Responsible Party: Hamilton Health Sciences Corporation
• ClinicalTrials.gov Identifier: NCT06174220
• Other Study ID Numbers: PHRI.TaRGET
• First Posted: December 18, 2023
• Last Update Posted: February 22, 2024
• Last Verified: February 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

Cardiomyopathies; Arrhythmogenic Right Ventricular Dysplasia; Heart Diseases; Cardiovascular Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Congenital Abnormalities