ACT 1: Atrial Arrhythmia Conversion Trial 1 - A New Antiarrhythmic Agent

May 16, 2005

May 16, 2005 — The rate- vs rhythm-control trials may support a strategy of rate control, but restoration of sinus rhythm (SR) in patients with atrial fibrillation (AF) is still a desirable goal. Now, a novel mixed ion channel antagonist, RSD1235, has demonstrated its effectiveness to convert recent-onset AF to SR in a large, international, phase 3, randomized, placebo-controlled clinical trial. Furthermore, the first presentation of the results of the Atrial arrhythmia Conversion Trial 1 (ACT 1) [1] confirm that RSD1235 has a rapid onset of action and is well tolerated.

RSD1235

RSD1235 is a novel, frequency-dependent sodium and early-activating potassium-channel blocker under joint development by Cardiome (Vancouver, Canada) and its partner, Astellas Pharma US (Deerfield, Illinois). The agent is intended as an acute-use, intravenous (IV) administration treatment to terminate AF and restore SR in AF patients. An oral formulation of RSD1235 is also under development for the long-term maintenance of normal SR following termination of AF.

ACT 1

ACT 1 was a phase 3, randomized, placebo-controlled, double-blind, multicenter trial initiated in August 2003 and carried out in 45 centers in Canada, Scandinavia, and the United States. Cochairs of the study steering committee were Denis Roy, MD (Montreal Heart Institute, Montreal, Quebec, Canada) and Craig M. Pratt, MD (Baylor College of Medicine, Houston, Texas). The study included patients aged > 18 years with electrocardiographic-documented AF (ranging in duration from 3 hrs to 45 days); patients were hemodynamically stable and on adequate anticoagulation therapy by US and European practice guidelines. Patients were excluded if they had long-QT syndrome, torsade de pointes, Brugada syndrome; bradycardia or sick sinus syndrome, unstable NYHA class IV heart failure; myocardial infarction, acute coronary syndrome, or cardiac surgery within the previous 30 days; failed electrical cardioversion; or typical atrial flutter.

ACT 1 randomized 356 patients in a 2:1 ratio to RSD1235 or placebo. Twenty patients did not receive the study drug, mostly due to spontaneous conversion. The remaining 336 patients were stratified by AF duration of either 3 hrs to 7 days or 8 to 45 days.

First infusion of study drug (RSD1235 3 mg/kg or placebo) was given over 10 min. A second 10-min infusion (RSD1235 2 mg/kg or placebo) was given 15 min later if the patient was still in AF. All drugs were infused in hospital, and continuous Holter monitoring was carried out for 24 hours. Rate control drugs and oral class I and III antiarrhythmic drugs were allowed.

Patients on IV RSD1235 More Likely to Convert to SR Than Placebo

The primary endpoint of the study, conversion of AF to SR within 90 min of study drug initiation in patients with AF duration 3 hrs to 7 days, was achieved by 52% of patients on RSD1235 compared with 4% of those on placebo ( Table 1). Patients on RSD1235 were 24% more likely to convert than those on placebo.

Table 1. Conversion of AF to Sinus Rhythm
Treatment Group AF Duration
3 hrs - 7 days 8 days - 45 days 3 hrs - 45 days
RSD1235 75/145 (52%) 6/76 (8%) 83/221 (38%)
Placebo 3/75 (4%) 0/40 (0%) 3/115 (3%)
P value < .0001 .092 < .0001

Of the RSD1235 patients in the 3 hrs to 7 days group who converted to SR within 90 min, 76% did so after the first infusion ( P < .0001 vs placebo). Median time to conversion was 11 min. Only 1 patient (1%) of the 75 RSD1235 patients who achieved the primary endpoint relapsed by 24 hrs.

Secondary endpoints included conversion within 90 min of dosing in patients with AF duration of 8 to 45 days. In this group of patients, the rate of conversion within 90 minutes was 8% in patients treated with RSD1235 vs 0% of placebo patients, but the difference was not statistically significant ( Table 2).

In the overall study population, however, the rate of successful conversion was significantly higher in the RSD1235 group than in the placebo group (38% vs 3%, respectively). Patients on RSD1235 were 21% more likely to convert than those on placebo.

Table 2. Conversion of AF to SR
Treatment Group AF duration
3 hrs - 7 days 8 days - 45 days 3 hrs - 45 day
RSD1235 75/145 (52%) 6/76 (8%) 83/221 (38%)
Placebo 3/75 (4%) 0/40 (0%) 3/115 (3%)
P value <.0001 .092 <.0001
Safety and Side Effects

During the 30-day follow-up period, after drug administration, 21 (18.3%) patients in the placebo group and 29 (13.1%) in the RSD1235 group experienced a serious adverse event (SAE). Most of these (17 and 22, respectively) were recurrence of AF requiring hospitalization. Three cardiac SAEs were related to RSD1235. There were no cases of drug-related torsade de pointes, but 2 cases of torsade de pointes were observed during the observation period; 1 occurred 48 hrs after drug administration and the other occurred 17 days following cardiac surgery. Three deaths, none drug related, were recorded during follow-up.

During the first 24 hrs after study drug infusion, the most common noncardiac side effects associated with RSD1235 were dysgeusia (alteration in taste) (30%), paresthesia (11%), and sneezing (16%) ( Table 3). All of these were transient.

Table 3. Noncardiac Adverse Events (0- to 24-hr period)
System Organ Class Event Placebo RSD1235
Nervous system Dysgeusia 1 (1%) 66 (30%)
Paresthesia 0 (0%) 24 (11%)
Gastrointestinal Nausea 1 (1%) 20 (9%)
Respiratory Cough 1 (1%)1 11 (5%)
Sneezing 0 (0%) 36 (16%)
Skin Pruritus 0 (0%) 13 (6%)
Vascular Hypotension 4 (4%) 14 (6%)

Preliminary data for both QRS duration and QTcB showed minimal increases in both groups in the overall population.

ACT 1 vs CRAFT: Trials Yield Similar Results

The results of ACT 1 confirm those seen with RSD1235 in CRAFT, [2] a North American phase 2 trial in which 56 patients with AF of 3-72 hrs' duration were randomized to 1 of 2 RSD1235 doses (0.5 mg/kg followed by 1 mg/kg or 2 mg/kg followed by 3 mg/kg), administered intravenously over 10 minutes; the initial dose was followed by a second dose only if AF persisted. The primary endpoint of CRAFT was termination of AF during infusion or within 30 min after the last infusion.

In both trials, the median time to conversionin the AF patients treated with IV RSD1235 who met their primary endpoint was 11 min from the initiation of dosing. In addition, the relapse rate (within 24 hrs) among the RSD1235 patients who met the primary endpoint was low in both trials (0% in ACT 1 vs 1% in CRAFT).

Implications

Dwight W. Reynolds, MD (University of Oklahoma Health Sciences Center, Oklahoma City), program chair of Heart Rhythm 2005, described RSD1235 as "a promising new medication that can be used for the treatment of a troubling and common heart rhythm disorder. It appears this medication may well be both safe and effective for this purpose."

Future Development of RSD1235: ACTs 2 and 3

IV RSD1235 is currently being evaluated in 2 further phase 3 clinical trials. The second phase 3 trial, ACT 2, was initiated in March 2004 and will enroll approximately 210 patients with transient AF occurring after coronary artery bypass graft or valve replacement surgery. The efficacy and safety of IV RSD1235 for the termination of sustained atrial arrhythmia (duration 3-72 hrs) in patients 245 hrs to 7 days following cardiac surgery will be evaluated.

The final phase 3 study, ACT 3, was initiated in July 2004 as a second study in patients with AF or atrial flutter. Approximately 240 patients will be enrolled in this multicenter study, which will evaluate the safety and efficacy of IV RSD1235 to convert patients to SR. The rates of conversion to SR in patients with atrial arrhythmias for 3 hours to > 7 days and for 3 hours to > 45 days will be evaluated in the primary and secondary efficacy analyses.

The developers estimate that a new drug application (NDA) could be filed in the United States for IV RSD1235 during the first half of 2006.

Oral RSD1235 for Long-term Maintenance

A recently completed phase 1b study of the controlled-release oral formulation of RSD1235 has been completed. On the basis of this study, enrollment has begun into a phase 1c study that will evaluate safety and tolerability after multi-day dosing. The phase 1 program will determine the dosing regimen to be used in a phase 2 efficacy study planned to begin in the second half of 2005. Oral RSD1235 is designed to be used as a follow-on therapy to IV RSD1235 for the long-term maintenance of AF.

References
  1. Roy D, Pratt C, Wyse DG, et al; the ACT I Investigators. RSD1235 for conversion of atrial fibrillation. The Phase III Atrial Arrhythmia Conversion Trial. Program and abstracts from the Heart Rhythm 2005 26th Annual Scientific Sessions; May 4-7, 2005; New Orleans, Louisiana.

  2. Roy D, Rowe BH, Stiell IG, et al; CRAFT Investigators. A randomized, controlled trial of RSD1235, a novel anti-arrhythmic agent, in the treatment of recent onset atrial fibrillation. J Am Coll Cardiol. 2004;44:2355-2361.

By Linda Brookes, MSc

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