title: Cardiac Effects of Siponimod (BAF312) Re-initiation After Variable Periods of Drug Discontinuation in Healthy Subjects.
abstract: OBJECTIVE
  The goal of this study was to investigate the effect of siponimod treatment re-initiation on the initial negative chronotropic effects and cardiac rhythm after variable drug discontinuation periods.
  
  
  METHODS
  This partially double-blind, randomized, placebo-controlled study was conducted in healthy subjects. Siponimod doses (0.5-4.0 mg) and placebo were evaluated in combination with drug discontinuation periods ranging from 48 to 192 hours. Twelve-lead Holter ECGs were performed from 1.5 hours before until 24 hours after single-dose re-initiation. Atrioventricular blocks (AVBs) and sinus pauses (RR >2 seconds) were categorized according to dose level, discontinuation period, and resting and nonresting hours.
  
  
  RESULTS
  Of the enrolled 138 subjects, 117 were evaluated. Demographic and baseline characteristics were comparable between the treatment groups. Subjects rechallenged at the combination of 4 mg/192 hours (highest investigated dose and longest discontinuation period [7 missed doses]) exhibited the highest decrease in pooled, placebo-adjusted heart rate (HR) of 14.53 beats/min. The magnitude of the negative chronotropic effect of siponimod re-initiation was dependent on both dose and duration of treatment discontinuation. Regardless of the dose, the placebo-adjusted HR reduction at re-initiation of drug treatment after up to 96 hours of drug discontinuation remained <10 beats/min. Except for 1 outlier for HR decrease under the 96-hour/placebo combination, no outliers were observed for any combination up to and including the 96-hour discontinuation periods. Most of the AVBs and sinus pauses were observed during nocturnal hours concurrent with increased vagal tone. All detected AVBs and sinus pauses were asymptomatic and not considered clinically relevant.
  
  
  CONCLUSIONS
  Siponimod could be safely re-initiated without retitration after drug discontinuation periods up to 96 hours. Retitration is required if patients miss ≥ 4 consecutive doses.
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. Electronic address: eric.legangneux@novartis.com.
authors.forename: Eric
authors.initials: E
authors.lastname: Legangneux
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Kasra
authors.initials: K
authors.lastname: Shakeri-Nejad
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Aslanis
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Sagkriotis
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pezous
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Brendani
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Rhett
authors.initials: R
authors.lastname: Behrje
authors.affiliation: Comprehensive Clinical Development, Miramar, Florida.
authors.forename: Maria
authors.initials: M
authors.lastname: Gutierrez
mesh_terms: D000328:Adult; D001384:Azetidines / Q000008:administration & dosage* / Q000494:pharmacology; D001593:Benzyl Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D001384:Azetidines; D001593:Benzyl Compounds; C578989:siponimod
keywords: BAF312; atrioventricular block; bradycardia; drug discontinuation; drug re-initiation; heart rate; sinus pause; siponimod