COR-ART: A multicenter, randomized, double-blind, placebo-controlled dose-ranging study to evaluate single oral doses of vanoxerine for conversion of recent-onset atrial fibrillation or flu Q3 tter to normal sinus rhythm Howard C. Dittric Q4 h, MD, * Gregory K. Feld, MD, † Tristram Bahnson, MD, ‡ John Camm, MD, § Sergey Golitsyn, MD, ║ Amos Katz, MD, ¶ Jason Koontz, MD, PhD, ‡ Peter R. Kowey, MD, ** Albert L. Waldo, MD, PhD (Hon), †† Arthur Brown, MD, PhD * Q1 From * ChanRx, Inc., Cleveland, Ohio, † University of California, San Diego, La Jolla, California, ‡ Duke University, Durham, North Carolina, § St. George’s University of London, London, England, ║ Russian Cardiologic Research and Production Complex of Rosmedtechnologiy, Moscow, Russia, ¶ Barzilai Medical Center, Ashkelon, Israel, ** Jefferson Medical College, Philadelphia, Pennsylvania, and †† University Hospital Cleveland, Cleveland, Ohio. BACKGROUND Restoration of sinus rhythm (SR) in patients with atrial fibrillation/atrial flutter (AF/AFL) is limited principally to direct current cardioversion. The multi-ion channel blocker vanox- erine may prove an effective alternative. OBJECTIVE The purpose of this study was to assess vanoxerine, a 1,4-dialkylpiperazine derivative, for acute conversion of recent- onset, symptomatic AF and AFL. METHODS One hundred four subjects with symptomatic AF/AFL for o7 days were randomized sequentially to single oral doses of vanoxerine 200, 300, and 400 mg or placebo. Holter monitors were examined for conversion to SR and proarrhythmia through Z24 hours. RESULTS Conversion to SR was dose related: 18.2%, 44.0%, and 52.0% within 4 hours, and 59.1%, 64.0%, and 84.0% within 24 hours, for the 200-, 300-, and 400-mg groups, respectively. This was significantly higher than placebo for the 300- and 400-mg groups within 4 hours (12.5% for placebo; P ¼ .0138 and P ¼ .0028, respectively) and for all doses within 24 hours (31.3% for placebo; P ¼ .0421, P ¼ .0138, P ¼ .0001 for 200-, 300-, and 400-mg vanoxerine groups, respectively). Although vanoxerine caused significant dose-dependent QTcF Q5 prolongation, monomor- phic or polymorphic ventricular tachycardia did not occur. Adverse events were mild and self-limited, with only the highest dose having a greater frequency than placebo. CONCLUSION Oral vanoxerine converted AF/AFL to SR at a high rate, was well tolerated, and caused no ventricular proarrhythmia. KEYWORDS Arrhythmia; Atrial fibrillation; Atrial flutter; Cardioversion; Vanoxerine ABBREVIATIONS AF ¼ atrial fibrillation; AFL ¼ atrial flutter; DC ¼ direct current; ECG ¼ electrocardiogram; SR ¼ sinus rhythm; VT ¼ ventricular tachycardia (Heart Rhythm 2015;0:0–8) I 2015 Heart Rhythm Society. All rights reserved. Introduction Atrial fibrillation (AF) is a growing burden. 1 Although new antith Q6 rombotic drugs have been developed, few exist for restoration of sinus rhythm (SR), in part because of the risk of proarrhythmia (ie, polymorphic ventricular tachycardia), limited efficacy, and the development of catheter ablation to maintain SR. Rate control may be sufficient for some individuals, but many patients, particularly those with structural heart disease or symptoms, require rhythm control. Direct current (DC) cardioversion typically is used for AF/atrial flutter (AFL), especially in patients with structural heart disease in whom pharmacologic therapy is potentially dangerous, but adds the risk of anesthesia. Current pharma- cologic therapy is limited, and the most effective agents (eg, ibutilide) have a risk for proarrhythmia and may be contra- indicated in patients with structural heart disease. Thus, there exists a need for a safe effective drug that can be used for restoration of SR in patients with recent-onset, symptomatic AF/AFL, including those with structural heart disease. Such a drug should be easy to administer, have 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 Funding for this study was provided by ChanRx. Drs. Dittrich and Brown are consultants/shareholders in ChanRx. Drs. Bahnson, Camm, Feld Koontz, Kowey, and Waldo are consultants to ChanRx. Drs. Golitsyn and Katz are investigators for ChanRx. ClinicalTrials.gov Identifier: NCT01691313. Address reprint requests and correspondence: Dr. Howard C. Dittrich, ChanRx, Inc., 644 Arenas St, La Jolla, CA USA 92037. E-mail address: howard@imager.com. 1547-5271/$-see front matter B 2015 Heart Rhythm Society. All rights reserved. http://dx.doi.org/10.1016/j.hrthm.2015.02.014