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Atrial Fibrillation
March 26, 2012
Xention issued results from a phase I trial of XEN-D0103 for the treatment of atrial fibrillation. This combined single- and multiple-ascending oral dose study enrolled 30 healthy subjects in the UK. The study evaluated the safety and pharmacokinetics of various dosages of XEN-D0103. Treatment was well tolerated and demonstrated good pharmacokinetic properties. No significant adverse events were reported. An analysis of electrocardiogram data collected from the first cohort of 30 healthy subjects indicated that XEN-D0103 had no effect on the QTcF interval. This absence of any detectable effect on QTcF confirmed the atrial selectivity of XEN-D0103.
June 27, 2011
Bristol-Myers Squibb and Pfizer released initial results from a phase III trial of Eliquis for atrial fibrillation and stroke prevention. This double-blind, international, head-to-head trial, ARISTOTLE, enrolled 18,201 subjects with atrial fibrillation and at least one additional risk factor for stroke. The subjects received either Eliquis 5 mg twice daily (2.5 mg twice daily in selected subjects) or dose-adjusted warfarin. Eliquis met the primary endpoint of non-inferiority to warfarin on the combined outcome of stroke (ischemic, hemorrhagic or unspecified type) and systemic embolism. Eliquis also met the key secondary endpoints of superiority on efficacy and on ISTH (International Society on Thrombosis and Haemostasis) major bleeding compared to warfarin.
January 12, 2009
Sanofi-Aventis reported positive results from a phase III trial of Multaq (dronedarone) for the treatment of atrial fibrillation (AF). This short term, randomized, double-blind, parallel group study, dubbed DIONYSOS, enrolled 504 subjects with documented atrial fibrillation for more than 72 hours. The subjects received dronedarone (400 mg twice daily) or amiodarone (600mg loading dose daily for 28 days, then 200mg daily thereafter) over seven months. The primary endpoint was ECG-documented atrial fibrillation recurrence (or maintenance of sinus rhythm) and premature study drug discontinuation. The primary endpoint was reached by 73.9% of subjects in the dronedarone arm as compared to 55.3% in the amiodarone arm (p<0.001). Atrial fibrillation after electrical cardioversion occurred in 36.5% of subjects in the dronedarone arm versus 24.3 % of those in the amiodarone arm. Treatment with amiodarone also led to more premature drug discontinuations compared to treatment with dronedarone. A 20% decrease favoring dronedarone versus amiodarone was observed in safety endpoints including thyroid, hepatic, pulmonary, neurological, skin, ocular, and gastrointestinal adverse events as well as premature study drug discontinuation due to any adverse event (83 versus 107, p≡0.1291). An NDA and MAA are currently under review by the FDA and EMEA, respectively.
May 26, 2008
Sanofi-Aventis issued positive results from a phase III trial of Multaq for the treatment of atrial fibrillation/ arrhythmia. This double-blind, placebo controlled, randomized study, dubbed ATHENA, enrolled 4,628 subjects across several international sites. The subjects received Multaq 400 mg twice daily or placebo with a maximum follow-up of 30 months. The results showed that treatment with Multaq significantly decreased the risk of cardiovascular hospitalizations or death from any cause by 24% (p=0.00000002), meeting the study's primary endpoint. Several secondary endpoints were reached as well, including a significant decrease in the risk of cardiovascular death by 30% (p=0.03) with Multaq plus standard therapy. Multaq also significantly decreased the risk of arrhythmic death by 45% (p=0.01) and there were numerically fewer deaths (16%) from any cause in the Multaq group compared to placebo (p=0.17). First cardiovascular hospitalization was reduced by 25% (p=0.000000009). Treatment was well tolerated with an adverse event profile similar to placebo. Based on the results Sanofi-Aventis plans to submit an MAA with the EMEA and an NDA with the FDA in the third quarter of 2008.
June 11, 2007
Cardiome and Astellas issued positiveresults from a phase III trial of intravenous vernakalant forthe treatment of atrial fibrillation or atrial flutter between 24 hours and 7days following coronary artery bypass graft (CABG) or valve replacement surgery.This trial, dubbed ACT 2, enrolled 190 subjects who received vernakalant or placebo.The primary endpoint, conversion to normal heart rhythm within 90 minutes, wasreached. Of the subjects receiving vernakalant, 45% achieved this endpoint comparedto 15% of placebo subjects within the same time period (p=0.0002). Of the subjectswho converted to normal heart rhythm, the median time to conversion was 12 minutesfrom the initiation of dosing. A NDA for vernakalant (iv) is currently under reviewby the FDA.
Forest and Paion reported negative results from a phase III trial of desmoteplase, dubbed DIAS2, for the treatment of Acute Ischemic Stroke. This blinded, randomized, placebo-controlled, dose-ranging trial enrolled 186 subjects internationally. Subjects received either placebo or desmoteplase (90 mcg/kg or 125 mcg/kg) as an intravenous bolus 3-9 hours after onset of stroke. The primary endpoint was clinical improvement at day 90 when compared to placebo. This was defined for each subject as achievement of all three of the following criteria: improvement of greater than or equal to 8 points from baseline on the National Institutes of Health Stroke Scale (NIHSS) or NIHSS score less than or equal to 1; Modified Rankin Scale (MRS) of 0-2 and Barthel Index (BI) score of 75 - 100. Those who reached all three endpoints were defined as responders. This primary endpoint was not met. Clinical response was seen in 47.7% of the subjects receiving 90 mcg/kg of desmoteplase, 36.4% of the subjects receiving 125 mcg/kg of desmoteplase and 46% of those on placebo. The companies plan to thoroughly review the results in order to determine a future course of action.
September 25, 2006
Cardiome released positive results from a phase IIa trial of RSD1235 for the treatment of atrial fibrillation. This double-blind, placebo-controlled, randomized, dose-ranging trial enrolled 171 subjects who received either a 300mg or 600mg dose of RSD1235 or placebo, administered orally, twice per day, for 28 days. Safety data were positive, with treatment well tolerated in both dosing groups. Reported serious adverse events occurred in only 4% of the 300mg group and 5% of the 600mg group. Efficacy data revealed that in the 300mg and 600mg dosing group, 61% of the subjects reached normal heart rhythm, versus 43% of those on placebo (p=0.048 and p=0.060, respectively). Based on these results Cardiome plans to submit a NDA to the FDA.
May 2, 2005
Cardiome Pharma announced positive results of a phase Ib trial of a controlled-release oral formulation of RSD1235, for the maintenance of normal heart rhythm following atrial fibrillation (AF). The company is also investigating an intravenous formulation of the drug, for the acute treatment of AF, which is currently in phase III development. Trial data yielded stable pharmacokinetics and a positive tolerability profile both following post-meal and fasting administration to both normal and slow drug metabolizers. This open-label study enrolled healthy volunteers, and was designed to investigate the safety, tolerability, pharmacokinetics, and optimum dosing regimen of the drug in patients with varying drug metabolism rates and food intake. The company announced plans to initiate a phase II trials of the drug during the second half of 2005.
January 3, 2005
Cardiome Pharma and Fujisawa Healthcare reported results from a phase III trial with RSD1235, an Ion channel modulator being investigated for the treatment of atrial fibrillation (AF). The study, called ACT 1, enrolled 426 subjects with AF at 45 sites in the U.S., Canada and Scandinavia. The study examined three sub-groups, including 237 subjects with recent-onset AF (more than 3 hrs but less than 7 days), 119 patients with longer-term AF (more than 7 days but less than 45 days) and 60 patients with atrial flutter. Results showed that 52% of the 234 subjects with recent-onset AF achieved a normal heart rhythm compared with 4% of subjects given placebo. In the overall population, 38% of RSD1235 treated subjects demonstrated termination of AF, compared to 3% of placebo patients. In addition, 8% of RSD1235 treated subjects in the longer-term AF population achieved AF termination compared to 0% of placebo subjects. In the recent-onset AF population, 52% of those who were dosed with RSD1235 achieved a normal heart rhythm, as compared to 4% of placebo patients. There were no cases of drug-related "Torsades de Pointes", an arrhythmia which is an occasional side effect of many current anti-arrhythmia drugs. Serious adverse events were reported in 13% of subjects receiving RSD1235 compared to 18% subjects on placebo. Serious drug-related adverse events occurred in 0% of placebo patients and 1.4% of patients receiving RSD1235. The primary endpoint in ACT 1 was conversion of recent-onset AF to normal heart rhythm for a period of at least 1 minute.
The Medicines Company reported primary results from a phase III trial investigating Clevelox (clevidipine), an intravenous drug being evaluated for the control of blood pressure. The placebo-controlled, doubled blind, randomized study, called ESCAPE-1, enrolled subjects before they underwent cardiac surgery. Results showed that patients with high blood pressure treated with Clevelox achieved treatment success 92.5% of the time versus 17.3% with placebo, measured by at least a 15% reduction in blood pressure. In November 2004, The company reported similar primary results of ESCAPE-2, a trial of Clevelox conducted in post-operative patients. The complete Clevelox phase III program consists of five clinical trials, including three trials, know as ECLIPSE, which are currently enrolling patients. Full data will be published and presented under scientific peer review. Pending positive results, the Medicines Company plans on filing an NDA with the FDA shortly.
September 9, 2002
Results of a phase II clinical study of RSD1235 showed that the drug was effective in terminating atrial fibrillation (AF). The study, which involved 56 subjects, compared three treatment groups: RSD1235 at a low dose, RSD1235 at a high dose, and placebo. The primary endpoint - the ability of RSD1235 to terminate atrial fibrillation within 30 minutes of infusion - was achieved in the high-dose group, with 61% of those treated experiencing termination of atrial fibrillation. 11% and 5% of the low-dose group and placebo group, respectively, experienced termination of AF. The 11% was not statistically significant compared to placebo. Similarly, the high-dose group alone reached statistical significance for the secondary endpoints, which evaluated the heart rhythm at 30 minutes, one hour and 24 hours post-infusion. 10 out of 11 subjects in the high-dose group whose AF was terminated remained in normal sinus rhythm at those time intervals. RSD1235 is being developed by Cardiome Pharma.
December 17, 2001
Interim results from a phase II trial for stroke prevention indicate that AstraZeneca's Exanta (ximelagatran) showed 0.9 strokes and 0.4 transient ischemic attacks (TIAs) per 100 treatment years (three events) compared to 2.6 strokes and 2.6 TIAs per 100 treatment years (four events) for warfarin. The long-term trial, known as SPORTIF IV, compared Exanta to warfarin for the prevention of strokes in subjects with chronic nonvalvular atrial fibrillation (NVAF). In the trial, 125 subjects with chronic NVAF and at least one additional stroke risk factor received fixed-dose Exanta and 42 subjects received warfarin.
