N-of-1 in ATS and MEPPC

Optimal Drug Therapy for the Suppression of Ventricular Arrhythmias in Andersen-Tawil Syndrome and Multifocal Ectopic Purkinje-related Premature Contractions: a Series of N-of-1 Trials

Rationale: Andersen-Tawil syndrome (ATS) is a very rare heritable cardiac arrhythmia syndrome that is characterized by the triad of periodic paralysis, physical dysmorphisms, and ventricular arrhythmias, including bidirectional ventricular tachycardia (VT), polymorphic VT, and frequent multifocal premature ventricular contractions (PVCs). Multifocal ectopic Purkinje-related premature contractions (MEPPC) is a very rare syndrome characterized by frequent multifocal PVCs with relatively narrow QRS width. In both conditions, patients most often present with palpitations, but syncope and sudden cardiac arrest have also been reported. Left untreated, the large burden of PVCs can lead to PVC-induced cardiomyopathy. A number of therapeutic strategies are suggested in these conditions, but there is a lack of high-quality evidence on their efficacy.

Objective: To investigate the efficacy of various therapeutic strategies for reducing ventricular ectopy burden in patients with ATS or MEPPC.

Study design: Aggregated series of randomized, open-label N-of-1 trials. Each N-of-1 trial will consist of at least 2 treatment sets, each of which comprise two 7-day periods of treatment with therapy A and B, in a semi-randomized, counterbalanced order.

Study population: Adult patients with ATS or MEPPC on flecainide therapy.

Intervention: For ATS, flecainide monotherapy will be compared with combination therapy of flecainide and a β-blocker or calcium channel blocker. For MEPPC, flecainide monotherapy will be compared with combination therapy of flecainide and a β-blocker or calcium channel blocker (phase 1), and flecainide will be compared with quinidine (phase 2).

Main study endpoint: Ventricular ectopy burden on electrocardiographic monitoring.

Study Overview

• Status: Not yet recruiting
• Conditions: Andersen Tawil Syndrome; Multifocal Ectopic Purkinje-related Premature Contractions
• Intervention / Treatment: Drug: Flecainide + beta-blocker; Drug: Flecainide

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Christian van der Werf, MD PhD; Phone Number: +31 020 566 9111; Email: c.vanderwerf@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. One of the following two primary diagnostic criteria A. Clinical diagnosis of ATS. Genetically confirmed diagnosis (i.e. class 4 or 5 KCNJ2 variant) is not required B. Clinical diagnosis of MEPPC and carrier of associated class 4 or 5 SCN5A variant
2. Has demonstrated a disease phenotype of ATS or MEPPC including ventricular arrhythmia burden at any point during follow-up on Holter monitor or other rhythm monitoring device (i.e. loop recorder, ECG patch)
3. Is currently treated with flecainide
4. Age ≥ 18 years

Exclusion Criteria:

• Pregnancy
• Contra-indication to study medication (see section 7.4)
• Significant structural heart disease (left ventricular ejection fraction <50%, history or signs of coronary ischemia, suspicion or definitive diagnosis of cardiomyopathy, or moderate/severe valve regurgitation)
• Suspicion or definitive diagnosis of another (heritable) arrhythmia syndrome, e.g. Brugada syndrome, early repolarization syndrome or catecholaminergic polymorphic ventricular tachycardia
• Presence of a short (<350 ms) or prolonged (>480 ms) heart-rate corrected QT interval on the resting ECG at baseline
• History of therapy refractory ventricular arrhythmia or intolerable side-effects on an adequate dose of any study medication, as determined by the treating cardiologist
• Serious known comorbid disease with a life expectancy of less than two years
• Ongoing medical condition that is deemed by the principal investigator to interfere with the conduct or assessments of the study or safety of the subjects
• Circumstances that prevent follow-up
• Inability to take orally administered tablets
• Inability to provide informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Flecainide + beta-blocker	Drug: Flecainide + beta-blocker; Flecainide + beta-blocker
Experimental: Flecainide monotherapy	Drug: Flecainide; Flecainide monotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Ventricular ectopy burden	5 24-hour periods per treatment period

Secondary Outcome Measures

Outcome Measure	Time Frame
Duration of longest ventricular tachycardia	5 24-hour periods per treatment period

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2025
• Primary Completion (Estimated): October 1, 2025
• Study Completion (Estimated): October 1, 2025

Study Registration Dates

• First Submitted: December 29, 2023
• First Submitted That Met QC Criteria: January 4, 2024
• First Posted (Actual): January 16, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 27, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiac Conduction System Disease; Urogenital Diseases; Cardiovascular Diseases; Pathologic Processes; Female Urogenital Diseases and Pregnancy Complications; Heart Diseases; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Disease; Arrhythmias, Cardiac; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Long QT Syndrome; Premature Birth; Syndrome; Cardiac Complexes, Premature; Andersen Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Anti-Arrhythmia Agents; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Membrane Transport Modulators; Adrenergic Agents; Adrenergic Antagonists; Adrenergic beta-Antagonists; Flecainide
• Other Study ID Numbers: ATS2023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No