A PHASE 2A, INVESTIGATOR AND SUBJECT BLINDED, SPONSOR UNBLINDED, PLACEBO-CONTROLLED, CLINICAL STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF CRD-4730 IN PARTICIPANTS WITH CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA

The primary objective of this study is to assess the **safety** and **tolerability** of CRD-4730 when administered to participants with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). This is clinically relevant as CPVT is a life-threatening condition characterized by stress-induced ventricular arrhythmias, and evaluating the safety profile of CRD-4730 is crucial for determining its potential as a therapeutic option.

Secondary objectives include:

• To assess the effect of CRD-4730 on the inducibility of ventricular arrhythmias during the exercise stress test in participants with CPVT.
• To assess the pharmacokinetics of CRD-4730 in this patient population.

The clinical trial involves a total of **9 participants** diagnosed with **Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on a confirmed CPVT diagnosis, verified through genetic screening for a known RyR2 mutation and a clinical phenotype consistent with CPVT. The trial population is required to have been on a stable dose of any anti-arrhythmic medication, excluding amiodarone, for at least four weeks prior to screening. Participants must also be capable of performing an exercise stress test (EST) that identifies frequent premature ventricular contractions or higher-grade ventricular arrhythmias. The study includes individuals who are part of a vulnerable population, and all participants must adhere to contraceptive requirements. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided additional information regarding the general health status of the participants.

The clinical trial is a **Phase 2A**, investigator and subject-blinded, sponsor-unblinded, placebo-controlled study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of **CRD-4730** in participants with **Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)**. The trial is structured as a randomized, double-blind, controlled study, ensuring that neither the participants nor the investigators are aware of the treatment assignments, while the sponsor remains unblinded. The trial is expected to commence recruitment on March 29, 2024, and conclude by January 15, 2025, with an estimated duration of participant involvement of up to 22 days.

Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, confirmed CPVT diagnosis, and ability to perform an exercise stress test (EST) with specific ventricular arrhythmia (VA) characteristics. Following successful screening, participants will be randomized to receive either CRD-4730 or a placebo, administered orally in capsule form. The study includes follow-up visits to monitor safety and efficacy, with primary endpoints focusing on adverse events, clinical laboratory test results, vital signs, ECG results, and physical examination findings. Secondary endpoints include changes in VA score from baseline to specified days and plasma concentrations of CRD-4730 over time.

The end-of-study visit will assess the overall safety and tolerability of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial aims to generate data supporting a marketing authorization for CRD-4730, with the sponsor having a legitimate economic interest in the trial's outcomes.

The clinical trial involves the administration of **CRD-4730**, an investigational medication developed by Cardurion Pharmaceuticals Inc. This medication is formulated as a **capsule** and is intended for oral administration. The active substance, CRD-4730, is of chemical origin. Participants in the trial will receive a maximum daily dose of 600 mg, with a total maximum dose of 900 mg over the course of the treatment period, which spans up to 22 days. The primary objective of the trial is to evaluate the safety and tolerability of CRD-4730 in individuals diagnosed with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo** is utilized in this study to serve as a comparator. The placebo consists of the encapsulation of microcrystalline cellulose into HPMC capsules, designed to match the appearance of the CRD-4730 active capsules. This ensures blinding of both the investigator and the participants, maintaining the integrity of the study design. The placebo does not contain any active pharmaceutical ingredients and is used to assess the efficacy and safety of the investigational drug by comparison. The administration of the placebo follows the same oral route and dosing schedule as the active treatment, ensuring consistency across the study arms.

Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include the evaluation of adverse events, clinical laboratory test results such as hematology, serum chemistry, and urinalysis, vital sign measurements, 12-lead electrocardiogram (ECG) results, and physical examination findings. These parameters will be collected and analyzed to determine the safety and tolerability of **CRD-4730** in participants with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT).

Secondary endpoints focus on the change in ventricular arrhythmia (VA) score from baseline to Day 1, Day 8, and Day 15, as well as the plasma concentrations of **CRD-4730** over time for each treatment period. These measurements will provide insights into the pharmacokinetics and pharmacodynamics of the investigational product. The efficacy assessments will be conducted at specified timepoints to ensure comprehensive data collection and analysis throughout the trial duration.