Effectiveness of CRD-4730 in Participants With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

Study Overview
=================
Brief Summary
-----------------
This is a Phase 2, multicenter, double-blind, sponsor unblinded, placebo-controlled, single-dose clinical study of CRD-4730 to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of CRD-4730 when administered as single oral doses to participants with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The study will have 2 cohorts in which participants with CPVT will participate in a 3-period, randomized 2-sequence study. Each participant will receive 2 different doses of CRD-4730 and 1 dose of matching placebo, with each study drug administered as a single dose.

Official Title
-----------------
A Phase 2A, Investigator & Subject Blinded, Sponsor Unblinded, Placebo-Controlled, Clinical Study to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics of CRD-4730 in Participants With Catecholaminergic Polymorphic Ventricular Tachycardia

Conditions
-----------------
CPVT1, Heart Defects, Congenital, Heart Diseases, Ventricular Tachycardia

Intervention / Treatment
-----------------
* Drug: CRD-4730
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males or Females ≥18 years of age, at screening. Confirmed CPVT diagnosis, based on genetic screening for a known RyR2 mutation and a clinical phenotype consistent with CPVT at screening. Ability to perform an Exercise Stress Test (EST) during which exercise-induced ventricular couplets or higher-grade VA (equivalent to a VA score ≥3) are identified by the investigator. Stable doses of any anti-arrhythmic medication, except amiodarone, for 4 weeks prior to screening. Adhere to all contraceptive criteria. Exclusion Criteria: Clinically significant structural heart disease, diagnosis of heart failure, or clinically significant coronary artery disease. History of a myocardial infarction, cerebrovascular accident, or transient ischemic attack within 3 months of screening. History of malignancy within the past 5 years at screening (except successfully treated basal cell carcinoma or non-metastatic squamous cell carcinoma of the skin or cervical carcinoma in situ). Female participant that is pregnant or lactating/ breastfeeding, or has plans to do so during the study or within 3 months following last dose of study drug. Use of amiodarone with 3 months prior to screening. NOTE: other protocol defined Inclusion/ Exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: 3-period randomized 2-sequence study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose 1<br>CRD-4730 Dose 1 capsule | Drug: CRD-4730<br>* Oral CRD-4730 in capsule form<br>|
| Experimental: Dose 2<br>CRD-4730 Dose 2 capsule | Drug: CRD-4730<br>* Oral CRD-4730 in capsule form<br>|
| Placebo Comparator: Dose 3<br>Placebo capsule to match CRD-4730 | Drug: Placebo<br>* Placebo to match CRD-4730 in capsule form<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Emergent Adverse Events (TEAEs) | The number of participants with TEAEs including drug-related AEs, serious AEs (SAEs), and AEs leading to study drug discontinuation will be assessed. | Baseline to Day 22 | 
| Changes in Laboratory Assessments | The number of participants who have normal/ abnormal values at Baseline compared to normal/ abnormal values post-Baseline will be assessed for hematology, serum chemistry and urinalysis. | Baseline to Day 15 | 
| Changes in Vital Signs Measurement: Systolic and Diastolic blood pressure | Percent change from Baseline to post Baseline will be assessed for systolic and diastolic blood pressure | Baseline to Day 15 | 
| Changes in Vital Signs Measurement: Pulse Rate | Percent change from Baseline to post Baseline will be assessed for pulse rate | Baseline to Day 15 | 
| Changes in Vital Signs Measurement: Respiratory Rate | Percent change from Baseline to post Baseline will be assessed for respiratory rate | Baseline to Day 15 | 
| Changes in Vital Signs Measurement: Body Temperature | Percent change from Baseline to post Baseline will be assessed for body temperature | Baseline to Day 15 | 
| Changes in Physical Exam | General physical exams will be carried out to detect any abnormalities in the cardiovascular, respiratory and other body systems | Baseline to Day 22 | 
| Changes in Electrocardiogram (ECG) Measurements | Number of participants who have normal/abnormal ECG measurements at Baseline will be compared to normal/abnormal ECG measurement post Baseline | Baseline to Day 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Ventricular Arrhythmia (VA) score during Exercise Stress Test (EST) | The VA score is a physician administered score on a scale of 0-5 with higher numbers being worse. | Baseline to Day 1 | 
| Change in Ventricular Arrhythmia (VA) score during Exercise Stress Test (EST) | The VA score is a physician administered score on a scale of 0-5 with higher numbers being worse. | Baseline to Day 8 | 
| Change in Ventricular Arrhythmia (VA) score during Exercise Stress Test (EST) | The VA score is a physician administered score on a scale of 0-5 with higher numbers being worse. | Baseline to Day 15 | 
| Assessment of PK effect | Plasma concentrations of CRD-4730 over time for each treatment period | Baseline through Day 15 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CaMKII, Catecholaminergic polymorphic VT, Ventricular Tachycardia, CRD-4730