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.

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