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

Arrhythmogenic Right Ventricular Cardiomyopathy Clinical Trial

— TaRGET  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06174220
• Other study ID #: PHRI.TaRGET
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: April 1, 2024
• Est. completion date: July 1, 2026

Study information

• Verified date: February 2024
• Source: Hamilton Health Sciences Corporation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 120
• Est. completion date: July 1, 2026
• Est. primary completion date: February 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Arrhythmogenic Right Ventricular Cardiomyopathy
• Arrhythmogenic Right Ventricular Dysplasia
• Cardiomyopathies

Intervention

Drug:
• Tideglusib
Tideglusib 1g po daily
• Placebo
Matching placebo 1g po daily

Locations

Country	Name	City	State
Canada	Foothills Medical Centre	Calgary	Alberta
Canada	Queen Elizabeth II Health Sciences Centre	Halifax	Nova Scotia
Canada	Hamilton General Hospital	Hamilton	Ontario
Canada	Kingston General Hospital	Kingston	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	Hopital du Sacré-Coeur de Montréal	Montréal	Quebec
Canada	McGill University Health Centre	Montréal	Quebec
Canada	Montreal Heart Institute	Montréal	Quebec
Canada	Southlake Regional Health Centre	Newmarket	Ontario
Canada	University of Ottawa Heart Institute	Ottawa	Ontario
Canada	University Institute of Cardiology and Pneumology of Quebec	Québec City	Quebec
Canada	Scarborough Health Network	Scarborough	Ontario
Canada	Health Sciences Centre	St John's	Newfoundland and Labrador
Canada	St. Michael's Hospital	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	Toronto General Hospital	Toronto	Ontario
Canada	St. Paul's Hospital	Vancouver	British Columbia
Canada	Victoria Cardiac Arrhythmia Trials Inc.	Victoria	British Columbia
Canada	Saint Boniface Hospital	Winnipeg	Manitoba

Sponsors (6)

Lead Sponsor	Collaborator
Hamilton Health Sciences Corporation	AMO Pharma, Canadian Institutes of Health Research (CIHR), Canadian SADS, Hearts in Rhythm Organization (HiRO), Population Health Research Institute

Country where clinical trial is conducted

Canada, 

References & Publications (5)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	PVC burden	Change in mean PVC count per 24 hours on 7-day Holter	Baseline and 6 months
Secondary	Ventricular strain	Change in ventricular strain on echocardiography	Baseline and 6 months
Secondary	Implantable cardioverter-defibrillator (ICD) therapies	Number of ICD therapies (shock or anti-tachycardia pacing)	Baseline and 6 months
Secondary	Sustained ventricular tachycardia (VT) events	Number of sustained VT events (defined as symptomatic or duration > 30 seconds and > 100bpm)	Baseline and 6 months