Treatment of an Inherited Ventricular Arrhythmia

NCT05122975 | Terminated Phase 2 FDA Drug

• 2 other identifiers: CL2-210-011R01FD007279-01
• Study Type: interventional
• Target: 8
• Locations: 2 countries
• Sites: 2

Brief Summary

The goal of the proposed project is to determine the safety and tolerability as well as the preliminary efficacy of a novel small molecule drug, S48168 (ARM210), for the treatment of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT1). This disease is associated with fatal changes in heart rhythms leading to sudden death with exercise or excessive excitement. It is due to mutations in the Ryanodine Receptor calcium release channel, which cause leaky channels leading to the disease. S48168 (ARM210) repairs these leaky channels and can be a disease-modifying therapy restoring normal function to the channels. This result would allow patients with CPVT to live normal, active lives. Funding Source- FDA OOPD.

Conditions

Catecholaminergic Polymorphic Ventricular Tachycardia Type 1

Keywords

Ventricular Arrhythmia; Calcium; Ryanodine Receptor 2

Outcome Measures

Primary Outcomes (1)

• The effect of S48168 (ARM210) treatment on the amount and complexity of exercise-• Change in ectopy score from baseline to Day 28 versus placebo (pre-dose Period 1 baseline to Day 28 Period 1 versus Day 28 Period 2

  Analysis of ECG recordings during exercise testing examining for abnormal beats occurring with exercise, such as premature ventricular contractions (PVCs). The scale is as follows: Ectopy Scoring Scale (0-4) No ectopy 0 Isolated PVCs 1 Bigeminy 2 Couplets 3 Non-sustained VT 4 van der Werf, C., et al. (2011). "Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia." J Am Coll Cardiol 57(22): 2244-2254.

  28 days

Secondary Outcomes (1)

• Incidence of Treatment-Emergent Adverse Events

  28 days

Other Outcomes (4)

• The pharmacokinetics (PK) of a 28-day administration of S48168 (ARM210) in patients

  28 days

• Total Plasma Drug Exposure of a 28-day administration of S48168 (ARM210) in patients

  28 days

• Evaluation of a novel expanded ectopy scale in exercise stress tests which qualifies both the ectopy and the heart rate at which it occurs.

  28 days

Study Arms (2)

S48168 (ARM210) once daily for 28 days

EXPERIMENTAL

Oral dose of S48168 (ARM210) once daily on top of standard of care regimen for 28 days.

Drug: S48168 (ARM210)

Matching Placebo once daily for 28 days

PLACEBO COMPARATOR

Oral dose of placebo once daily on top of standard of care regimen for 28 days.

Drug: Matching Placebo

Interventions

S48168 (ARM210) DRUG

Ryanodine Receptor modulator

S48168 (ARM210) once daily for 28 days

Matching Placebo DRUG

Placebo of same size and consistency as S48168 (ARM210)

Matching Placebo once daily for 28 days

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must meet all the following conditions to be eligible for enrollment into the study:
• Participant must be 18 to 65 years of age inclusive, at the time of signing the informed consent.
• Participants who are willing and able to comply with scheduled visits, study drug administration plan, study restrictions, and study procedures.
• Participants have a confirmed genetic diagnosis of CPVT1 and supporting clinical phenotype, including residual ventricular ectopy (a complexity score ≥ 2; requiring at minimum the presence of PVCs in bigeminy on exercise stress test) on a stable (at least 1 month) standard-of-care, CPVT1-directed treatment regimen as decided by their CPVT treating physician.
• Have a body mass index (BMI) ≤ 36 kg/m2 (inclusive) at screening.
• Male participants agree to not donate sperm from the first day of dosing of study drug until 5 half-lives plus 90 days (approximately 94 days) after the last dose of study drug.
• Female participants:
• eligible to participate if she is not pregnant or breastfeeding, and uses one of the following highly effective birth control methods (from the first dose until 5 half-lives plus 90 days (approximately 94 days):
• Prescribed hormonal oral contraceptives, vaginal ring, or transdermal patch.
• Intrauterine device (IUD).
• Intrauterine hormone-releasing system (IUS).
• Depot/implantable hormone (e.g., Depo-Provera®, Implanon).
• Bilateral tubal occlusion/ligation.
• Sexual abstinence.
• Refraining from heterosexual intercourse during the entire period of risk associated with the study requirements.

You may not qualify if:

• The presence of any of the following conditions will exclude a participant from study enrollment:
• History or presence of alcoholism or drug abuse within the past 2 years prior to the first dose of study drug.
• History or presence of hypersensitivity or idiosyncratic reaction to the study drug, related compounds, or inactive ingredients.
• ALT or AST levels three times above the upper limits of normal (ULN) at screening (isolated elevations of total bilirubin \< 2 X ULN with direct bilirubin below the ULN will be included). A recheck for confirmation is allowed.
• History of documented, EEG-confirmed epileptic seizures.
• Currently has uncontrolled diabetes defined as HbA1c \> 7% at screening visit or diabetic neuropathy.
• Estimated creatinine clearance \< 40mL/minute at screening visit.
• Clinically significant abnormality on their screening and/or prior to first dosing resting ECG, other than hypertensive related, or heart failure (ejection fraction \< 30%) or other clinically significant structural heart disease.
• History of myocardial infarction in the last five years, or evidence of congestive heart failure.
• Ongoing medical condition that is deemed by the PI to interfere with the conduct or assessments of the study or safety of the subject.
• Unable to refrain from or anticipates the use of:
• Any non-approved medicines (prescribed standard-of-care for CPVT is approved) and/or dietary supplements beginning 14 days prior to the first dose of study drug and throughout the study. Thyroid hormone replacement medication may be permitted if subject has been on same stable dose for the last 3 months prior to the first dose of study drug.
• Any drugs known to be significant inducers or inhibitors of CYP2C8 enzymes for 28 days prior to the first dose of study drug and throughout the study. Is currently taking any drug which raises gastric pH, including proton pump inhibitors or H2 antagonists. Antacids may be used if taken at night.
• Participation in clinical trials for other therapeutic investigational drugs simultaneously or within the 4 weeks prior to the first dose of study drug.
• Plasma donation within 7 days prior to the first dose of study drug.

Sponsors & Collaborators

• RyCarma Therapeutics, Inc.: lead

Study Sites (2)

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Amsterdam University Medical Center

Amsterdam-Zuidoost, 91105, Netherlands

Location

Study Officials

• Michael J Ackerman, MD PhD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: S48168 and exact matching placebo
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 22, 2021
• First Posted: November 17, 2021
• Study Start: August 1, 2023
• Primary Completion: April 1, 2024
• Study Completion: April 1, 2024
• Last Updated: September 19, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1); US (1)