A randomized, double-blind, placebo-controlled trial assessing the efficacy of S66913 in patients with paroxysmal atrial fibrillation

A. John Camm, Paul Dorian, Stefan H. Hohnloser, Peter R. Kowey, Benoît Tyl, Yongbin Ni, Victoria Vandzhura, Pierre Maison-Blanche, Mirko de Melis, Prash Sanders

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Aims Antiarrhythmic drugs (AADs) for the treatment of atrial fibrillation (AF) are associated with limited efficacy and adverse effects. Inhibition of the atrial current I Kur, absent from the ventricle, is expected to be antiarrhythmic, without adverse cardiac effects, particularly ventricular pro-arrhythmic effects. Methods and results A randomized clinical trial in symptomatic paroxysmal AF patients being considered for ablation. The primary endpoint was AF burden (AFB) as measured by insertable continuous monitoring (ICM) devices. Screened patients had an ICM implanted and were included if AFB was between 1% and 70% after 4 weeks of recording. They were randomly allocated to 4-week treatment of a selective I Kur inhibitor S66913 (5 mg, 25 mg, or 100 mg orally per day) or placebo. The study was to enroll 160 patients. The study was terminated prematurely, due to non-study related preclinical safety concerns, after 58 patients had been enrolled. The median AFB ranged from 4.3% to 10.3% at baseline in the four treatment groups. S66913 had no significant effect on AFB or on AFB plus atrial tachycardia (AT) burden, at any dosage; nor on any secondary endpoints including the number and duration of AT or AF episodes, and symptoms. The drug was well tolerated with no safety concern during the treatment or the extended clinical follow-up. Conclusions DIAGRAF-IKUR was the first study to show that using ICM to assess the effect of an AAD is feasible. The selective I Kur inhibitor S66913 was safe but had no clinically meaningful effect at the time of early termination of the study.

LanguageEnglish
Pages21-28
Number of pages8
JournalEuropean Heart Journal - Cardiovascular Pharmacotherapy
Volume5
Issue number1
DOIs
Publication statusPublished - 1 Jan 2019

Keywords

  • Antiarrhythmic drug
  • Atrial fibrillation
  • Atrial fibrillation burden
  • I Kur inhibitor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pharmacology (medical)

Cite this

Camm, A. John ; Dorian, Paul ; Hohnloser, Stefan H. ; Kowey, Peter R. ; Tyl, Benoît ; Ni, Yongbin ; Vandzhura, Victoria ; Maison-Blanche, Pierre ; de Melis, Mirko ; Sanders, Prash. / A randomized, double-blind, placebo-controlled trial assessing the efficacy of S66913 in patients with paroxysmal atrial fibrillation. In: European Heart Journal - Cardiovascular Pharmacotherapy. 2019 ; Vol. 5, No. 1. pp. 21-28.
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abstract = "Aims Antiarrhythmic drugs (AADs) for the treatment of atrial fibrillation (AF) are associated with limited efficacy and adverse effects. Inhibition of the atrial current I Kur, absent from the ventricle, is expected to be antiarrhythmic, without adverse cardiac effects, particularly ventricular pro-arrhythmic effects. Methods and results A randomized clinical trial in symptomatic paroxysmal AF patients being considered for ablation. The primary endpoint was AF burden (AFB) as measured by insertable continuous monitoring (ICM) devices. Screened patients had an ICM implanted and were included if AFB was between 1{\%} and 70{\%} after 4 weeks of recording. They were randomly allocated to 4-week treatment of a selective I Kur inhibitor S66913 (5 mg, 25 mg, or 100 mg orally per day) or placebo. The study was to enroll 160 patients. The study was terminated prematurely, due to non-study related preclinical safety concerns, after 58 patients had been enrolled. The median AFB ranged from 4.3{\%} to 10.3{\%} at baseline in the four treatment groups. S66913 had no significant effect on AFB or on AFB plus atrial tachycardia (AT) burden, at any dosage; nor on any secondary endpoints including the number and duration of AT or AF episodes, and symptoms. The drug was well tolerated with no safety concern during the treatment or the extended clinical follow-up. Conclusions DIAGRAF-IKUR was the first study to show that using ICM to assess the effect of an AAD is feasible. The selective I Kur inhibitor S66913 was safe but had no clinically meaningful effect at the time of early termination of the study.",
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Camm, AJ, Dorian, P, Hohnloser, SH, Kowey, PR, Tyl, B, Ni, Y, Vandzhura, V, Maison-Blanche, P, de Melis, M & Sanders, P 2019, 'A randomized, double-blind, placebo-controlled trial assessing the efficacy of S66913 in patients with paroxysmal atrial fibrillation', European Heart Journal - Cardiovascular Pharmacotherapy, vol. 5, no. 1, pp. 21-28. https://doi.org/10.1093/ehjcvp/pvy022

A randomized, double-blind, placebo-controlled trial assessing the efficacy of S66913 in patients with paroxysmal atrial fibrillation. / Camm, A. John; Dorian, Paul; Hohnloser, Stefan H.; Kowey, Peter R.; Tyl, Benoît; Ni, Yongbin; Vandzhura, Victoria; Maison-Blanche, Pierre; de Melis, Mirko; Sanders, Prash.

In: European Heart Journal - Cardiovascular Pharmacotherapy, Vol. 5, No. 1, 01.01.2019, p. 21-28.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A randomized, double-blind, placebo-controlled trial assessing the efficacy of S66913 in patients with paroxysmal atrial fibrillation

AU - Camm, A. John

AU - Dorian, Paul

AU - Hohnloser, Stefan H.

AU - Kowey, Peter R.

AU - Tyl, Benoît

AU - Ni, Yongbin

AU - Vandzhura, Victoria

AU - Maison-Blanche, Pierre

AU - de Melis, Mirko

AU - Sanders, Prash

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Aims Antiarrhythmic drugs (AADs) for the treatment of atrial fibrillation (AF) are associated with limited efficacy and adverse effects. Inhibition of the atrial current I Kur, absent from the ventricle, is expected to be antiarrhythmic, without adverse cardiac effects, particularly ventricular pro-arrhythmic effects. Methods and results A randomized clinical trial in symptomatic paroxysmal AF patients being considered for ablation. The primary endpoint was AF burden (AFB) as measured by insertable continuous monitoring (ICM) devices. Screened patients had an ICM implanted and were included if AFB was between 1% and 70% after 4 weeks of recording. They were randomly allocated to 4-week treatment of a selective I Kur inhibitor S66913 (5 mg, 25 mg, or 100 mg orally per day) or placebo. The study was to enroll 160 patients. The study was terminated prematurely, due to non-study related preclinical safety concerns, after 58 patients had been enrolled. The median AFB ranged from 4.3% to 10.3% at baseline in the four treatment groups. S66913 had no significant effect on AFB or on AFB plus atrial tachycardia (AT) burden, at any dosage; nor on any secondary endpoints including the number and duration of AT or AF episodes, and symptoms. The drug was well tolerated with no safety concern during the treatment or the extended clinical follow-up. Conclusions DIAGRAF-IKUR was the first study to show that using ICM to assess the effect of an AAD is feasible. The selective I Kur inhibitor S66913 was safe but had no clinically meaningful effect at the time of early termination of the study.

AB - Aims Antiarrhythmic drugs (AADs) for the treatment of atrial fibrillation (AF) are associated with limited efficacy and adverse effects. Inhibition of the atrial current I Kur, absent from the ventricle, is expected to be antiarrhythmic, without adverse cardiac effects, particularly ventricular pro-arrhythmic effects. Methods and results A randomized clinical trial in symptomatic paroxysmal AF patients being considered for ablation. The primary endpoint was AF burden (AFB) as measured by insertable continuous monitoring (ICM) devices. Screened patients had an ICM implanted and were included if AFB was between 1% and 70% after 4 weeks of recording. They were randomly allocated to 4-week treatment of a selective I Kur inhibitor S66913 (5 mg, 25 mg, or 100 mg orally per day) or placebo. The study was to enroll 160 patients. The study was terminated prematurely, due to non-study related preclinical safety concerns, after 58 patients had been enrolled. The median AFB ranged from 4.3% to 10.3% at baseline in the four treatment groups. S66913 had no significant effect on AFB or on AFB plus atrial tachycardia (AT) burden, at any dosage; nor on any secondary endpoints including the number and duration of AT or AF episodes, and symptoms. The drug was well tolerated with no safety concern during the treatment or the extended clinical follow-up. Conclusions DIAGRAF-IKUR was the first study to show that using ICM to assess the effect of an AAD is feasible. The selective I Kur inhibitor S66913 was safe but had no clinically meaningful effect at the time of early termination of the study.

KW - Antiarrhythmic drug

KW - Atrial fibrillation

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