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

TaRGET

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

Lead PI & Sponsor

Dr. Jason Roberts, PHRI, Hamilton Health Sciences

Local PI

Dr. Habib Khan

Research Staff

Megan Smith & Sara El-Richani

Objective

Arrhythmogenic cardiomyopathy (ACM) is a type of inherited heart problem where the heart’s muscle is replaced by fibrous and potentially fatty tissue. People with this condition are at risk of dangerous fast heartbeats, sudden cardiac death, and heart failure. The purpose of the TaRGET study is to determine if tideglusib compared to placebo will reduce the average number of PVCs per 24 hours in ACM patients.

Target Number of Patients

10

Currently Enrolled

1

Primary Outcomes

  • To show that tideglusib reduces mean PVCs per 24 hours on 7-day Holter monitoring compared to placebo at 6 months of treatment

Secondary Outcomes

  • To show improvement in ventricular strain on echocardiography
  • To show reduction in the frequency of implantable cardioverter-defibrillator (ICD) therapies (shocks or anti-tachycardia pacing))
  • To show reduction in the frequency of sustained ventricular tachycardia

Inclusion Criteria

  • Age ≥ 18 years
  • Increased risk of stroke, defined as a CHA2DS2-VASc score of ≥ 4
  • A pathogenic or likely pathogenic desmosomal (PKP2, DSG2, DSC2, DSP, or JUP*) rare variant OR the TMEM43-p.S358L variant
  • 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 randomization

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

The most common subtype of ACM mainly involves the right ventricle and is called arrhythmogenic right ventricular cardiomyopathy
(ARVC). Both genetics (inherited traits) and things in the environment, like exercise, can play a role in causing ACM. Many different
genes can contribute to ACM, but the most common ones are linked to a special part of heart cells that help them stick together. The
standard or usual treatment for ACM is placement of a defibrillator inside the body (an implantable cardioverter defibrillator or ICD),
which can deliver an electric shock to patients when a dangerous fast heart rhythm develops. To prevent dangerous fast heart
rhythms and avoid painful shocks, medicines that affect the electrical activity of the heart (called anti-arrhythmic drugs) can be given.
Although these medicines can help stabilize the heart’s electricity and reduce the chances of dangerous fast heart beats, they do not
help the underlying heart muscle problem, which continues to progress. The result is that, as the heart muscle problem progresses,
the dangerous fast heartbeats can no longer be controlled by medicines and patients start suffering from shocks again.
Tideglusib is a new type of drug that has shown promise in treating myotonic dystrophy, a disease that affects the regular muscles of
the body and causes weakness.

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