Evaluation of CRD-4730 Safety and Tolerability in Catecholaminergic Polymorphic Ventricular Tachycardia: A Phase 2 Double-Blind, Placebo-Controlled Crossover Study
- Trial ID
- 2024-515564-32-00
- Protocol
- CRD-4730-202
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and **tolerability** of CRD-4730 in participants diagnosed with **catecholaminergic polymorphic ventricular tachycardia** (CPVT) following repeated dose administration. This is clinically relevant as CPVT is a life-threatening condition characterized by stress-induced ventricular arrhythmias, and assessing the safety profile of CRD-4730 is crucial for determining its potential as a therapeutic option.
Secondary objectives include:
- Assessing the effect of CRD-4730 on the inducibility of ventricular arrhythmias during an exercise stress test after repeated dosing in participants with CPVT.
- Evaluating the pharmacokinetics of CRD-4730 following repeated dose administration in the same patient population.
Participants
The clinical trial involves a total of **6 participants** diagnosed with **Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)**. The study population includes both male and female subjects who are **18 years of age or older** and are considered to be in good general health aside from their CPVT diagnosis. Participants were selected based on their ability to understand and provide informed consent, and they must have a confirmed CPVT diagnosis through genetic screening for a pathogenic ryanodine receptor (RYR2) mutation. Additionally, participants are required to have been on a stable dose of at least one antiarrhythmic medication, excluding amiodarone, for at least four weeks prior to screening. The trial does not include a vulnerable population, and lifestyle considerations such as diet and physical activity are not specified. The selection criteria ensure that participants can perform an exercise stress test (EST) where specific ventricular arrhythmias are identified. The trial aims to assess the safety and tolerability of CRD-4730 following repeated dose administration in this specific patient population.
Plans and Procedures
The clinical trial is a **Phase 2**, double-blind, repeat-dose, placebo-controlled crossover study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of **CRD-4730** in participants diagnosed with **catecholaminergic polymorphic ventricular tachycardia** (CPVT). The trial involves the administration of CRD-4730, a potent and specific small molecule inhibitor of calcium/calmodulin-dependent protein kinase II, in tablet form, with a maximum daily dose of 400 mg and a total dose not exceeding 5400 mg over a 30-day treatment period. The study is structured to include a matching placebo to ensure the integrity of the double-blind design.
The trial is expected to commence recruitment on May 1, 2025, and conclude by September 30, 2026. Participants will be involved in the study for a period that includes screening, treatment, and follow-up phases. The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as age, health status, and a confirmed CPVT diagnosis. Participants must also demonstrate the ability to perform an exercise stress test (EST) with specific ventricular arrhythmia criteria. Following the screening, participants will undergo multiple treatment visits where they will receive either CRD-4730 or placebo in a crossover manner, allowing for comprehensive assessment of the drug's effects.
Follow-up visits will be scheduled to monitor the participants' response to the treatment, focusing on the primary endpoint of assessing the number and severity of treatment-emergent adverse events (TEAEs) related to the study drug. Secondary endpoints include changes in ventricular arrhythmia (VA) scores during EST and plasma concentrations of CRD-4730 over time. The end-of-study visit will conclude the participant's involvement, ensuring all safety and efficacy data are collected and analyzed. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial's design and procedures are meticulously crafted to ensure the collection of robust data while maintaining participant safety and adherence to ethical standards.
Treatment
The clinical trial involves the administration of **CRD-4730**, an experimental medication developed by Cardurion Pharmaceuticals Inc. **CRD-4730** is a potent and specific small molecule inhibitor of calcium/calmodulin-dependent protein kinase II. It is formulated as a **tablet** for **oral use**. The maximum daily dose is 400 mg, with a total maximum dose of 5400 mg over a treatment period of 30 days. The medication is administered to participants with catecholaminergic polymorphic ventricular tachycardia (CPVT) to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamics. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.
The study also includes a **placebo** group, utilizing a **CRD-4730 matching placebo**. The placebo is designed to mimic the appearance of the active medication but does not contain any active substance. The use of a placebo allows for a double-blind, placebo-controlled crossover study design, which is essential for assessing the true effects of the experimental medication. Participants are randomly assigned to receive either the active medication or the placebo, with crossover to the alternate treatment after a specified period, ensuring that each participant serves as their own control.
Efficacy
Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint focuses on the number and severity of treatment-emergent adverse events (TEAEs) related to the study drug treatment. Secondary endpoints include the change in ventricular arrhythmia (VA) score during exercise stress testing (EST) from baseline to specified days, as well as the plasma concentrations of **CRD-4730** over time for each treatment period. These parameters will be measured and collected at predetermined timepoints throughout the study. The analysis will involve comparing baseline values to those obtained at subsequent timepoints to evaluate the efficacy of the treatment. The study is designed to ensure that data collection and analysis are conducted in a manner that is consistent with the objectives of assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of **CRD-4730** in participants with catecholaminergic polymorphic ventricular tachycardia (CPVT).
Inclusion and Exclusion Criteria
Inclusion Criteria
- The participant is capable of understanding the written informed consent, provides signed and witnessed written informed consent, and agrees to comply with protocol requirements.
- The participant is male or female, ≥18 years of age and of legal adult age in accordance with local requirements.
- The participant is considered by the Investigator to be in good general health, aside from their CPVT diagnosis, as determined by medical history, clinical laboratory test results, vital sign measurements, 12-lead electrocardiogram (ECG) results, and physical examination findings at Screening.
- The participant has a confirmed CPVT diagnosis, based on genetic screening for a pathogenic ryanodine receptor (RYR2) mutation and a clinical phenotype consistent with CPVT at Screening. Previous CPVT genetic testing documented in medical history is acceptable if confirmed by the Investigator and documented in the study source records.
- The participant can perform an EST during which frequent premature ventricular contractions (PVCs; ≥10 per minute), ventricular bigeminy, or higher-grade VA (equivalent to a VA score ≥2) are identified by the Investigator. Please refer to the complete VA scoring system in the full protocol
- The participant has been on a stable dose of at least 1 antiarrhythmic medication (including beta blockers but not amiodarone) for 4 weeks prior to Screening, unless the participant has been unable to tolerate antiarrhythmic therapy previously
- Female participants must meet at least 1 of the following criteria: a. Is postmenopausal (defined as amenorrhea for 12 consecutive months and follicle stimulating hormone (FSH) >40 mIU/mL before first dose of study drug) for at least 1 year before screening visit. b. Is permanently sterile (hysterectomy, bilateral salpingectomy, bilateral oophorectomy). c. Agrees to practice 1 highly effective method of birth control AND 1 additional effective (barrier) method of contraception at the same time until 5 half-lives (approximately 3 days) plus the estimated period of 1 menstruation cycle, defined as 30 days (33 days total), after the last dose of study drug. d. Has a sterilized male partner (defined as having had a bilateral orchidectomy), if the partner is the sole sexual partner. e. Agrees to practice true abstinence. Additionally, females who are women of childbearing potential (WOCBP) must not donate ova from Screening until 30 days plus 5 half-lives (33 days total) after the last dose of study drug. A female is considered a WOCBP (ie, fertile) following menarche and until becoming postmenopausal, unless permanently sterile as defined in Inclusion Criterion 7b.
- Male participants must meet at least 1 of the following criteria: a. Is sterilized (defined as having had a bilateral orchidectomy) and agrees to use a male condom from Screening until 5 half-lives (3 days total) after the last dose of study drug. b. Agrees to all of the following: i. Male participants with a WOCBP partner must agree to use a male condom (with or without a spermicidal agent) from Screening until 90 days (the estimated time period of the spermatogenesis cycle) plus 5 half-lives (93 days total) after the last dose of study drug; additionally, a WOCBP partner should use a highly effective method during this same time period. ii. Male participants with a partner who cannot become pregnant (a woman who is not a WOCBP or a male partner) must agree to use a male condom during sexual intercourse from Screening until 5 half-lives (3 days total) after the last dose of study drug. iii. Male participants must agree not to donate sperm from the first study drug administration until 90 days plus 5 half-lives (93 days total) after the last dose of study drug. c. Agrees to practice true abstinenceand agrees not to donate sperm from the first dose of study drug until 93 days after the last dose of study drug..
Exclusion Criteria
- The participant has any medical or psychiatric condition that, in the opinion of the Investigator, could jeopardize or would compromise the participant’s ability to participate in the study.
- The participant has hepatic impairment defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × (upper limit of normal [ULN]) and/or total bilirubin >1.5 × ULN at Screening (unless secondary to confirmed Gilbert syndrome).
- The participant has any clinically significant illness, in the opinion of the Investigator, occurring within 28 days prior to the Screening visit (window: Day -21 to Day -1) and up to the first day of study drug administration (Day 1).
- The participant has acute or chronic hepatitis B (HBV; defined as hepatitis B surface antigen [HBsAg] reactive), acute or chronic hepatitis C virus (HCV; defined as detection of HCV antibody and RNA [qualitative]), or human immunodeficiency virus (HIV) infection. Note: Participants who have been effectively treated for and cleared/cured of hepatitis B or hepatitis C are eligible for enrollment. Participants must be negative for HBsAg and HCV RNA (if positive for HCV antibody; otherwise, a negative HCV antibody alone is sufficient).
- The female participant is pregnant, lactating/breastfeeding, or has plans to become pregnant during the study or within 3 months following the last study drug administration.
- The participant has participated in a previous clinical study and received investigational product within 30 days of dosing or 5 drug half-lives, whichever is longer.
- The participant has taken any antiarrhythmic drug in addition to their stable, chronic regimen unless it has been at least 5 half-lives since administration at the time of Screening.
- For participants who have received the COVID-19 vaccine, the most recent vaccine dose must be at least 14 days before the first dose of study drug.
- The participant has taken amiodarone within 3 months prior to Screening.
- The participant has taken strong inhibitors or inducers of cytochrome P450 (CYP)3A4 and P-glycoprotein within 14 days prior to the first dose of study drug.
- The participant has a history of relevant drug and/or food allergies or who experiences a serious hypersensitivity reaction, including anaphylaxis, to CRD-4730 or any of its excipients.
- The participant has any acute or chronic illness, aside from their CPVT diagnosis, which, in the opinion of the Investigator, may place the participant at risk because of participation in the study.
- 21.The participant has a history of alcohol, cannabis, or drug (other than caffeine) use disorder, in the opinion of the Investigator, within 12 months prior to Screening.
- 22.The participant has any other issues which, in the opinion of the Investigator, will make the participant ineligible for study participation.
- 23.The participant is an employee of the Sponsor, including employees contracted by the Sponsor (i.e., consultants), an employee of the CRO, or an employee of the study site.
- 24.Additional eligibility that applies to French participants: •Participants in France should not be deprived of their liberty by a judicial or administrative decision as per Art L 1121-6 of Code de la Santé Publique. • Participants in France should not be undergoing psychiatric care by virtue of a court order or an administrative order as per Art L 1121-6 of Code de la Santé Publique. • Participants in France should not be under legal protection or unable to give their consent as per Art L 1121-8 of Code de la Santé Publique. • Participants in France should be affiliated to a Social Security Scheme or be a beneficiary of one as per Art L1121-8-1 of Code de la Santé Publique.
- The participant has clinically significant structural heart disease, diagnosis of heart failure, or clinically significant coronary artery disease.
- The participant has a clinically significant abnormal ECG not explained by the diagnosis of CPVT at Screening (for example, clinically significant abnormal morphology consistent with an alternate diagnosis such as Brugada syndrome or arrhythmogenic right ventricular cardiomyopathy, or clinically significant abnormal intervals, such as prolonged QT [QTcF ≥ 450 ms for males and QTcF ≥ 460 ms for females] or long QT syndrome).
- The participant has a history of a myocardial infarction, cerebrovascular accident, or transient ischemic attack within 3 months of Screening.
- The participant undergoes implantable cardioverter-defibrillator (ICD) implantation or has sympathetic nerve denervation within 3 months of Screening.
- The participant has an anticipated change in exercise regimen or new exercise program during the course of the study.
- The participant has a history of malignancy within the past 5 years at Screening, with the exception of successfully treated basal cell carcinoma or nonmetastatic squamous cell carcinoma of the skin or cervical carcinoma in situ. Prior exposure to chest radiation for any malignancy is exclusionary.
- The participant has abnormal blood pressure, defined as supine symptomatic hypotension, systolic blood pressure >150 mm Hg or diastolic blood pressure >90 mm Hg, or symptomatic bradycardia or a heart rate >100 bpm at Screening and/or on Day 1. Blood pressure and pulse should be measured after the participant has been in the seated position after 5 minutes of rest.
- The participant has taken any medication that is known to cause prolongation of the QT interval (other than flecainide) within 14 days prior to the first dose of drug.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 01 Jan 2026 | 3 |
 Italy | Recruiting | 01 Jan 2026 | 1 |
 The Netherlands | Recruiting | 01 Jan 2026 | — |
 Spain | Recruiting | 01 Jan 2026 | 1 |
| Netherlands | — | — | 1 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CRD-4730 matching placebo | Placebo | N/A | — | — | — | N/A |
CRD-4730 | Test | TABLET | ORAL USE | 400 | 30 | PRD11747890 |