November 17, 2014
Cardiome Pharma released results of a
phase III study of Brinavess (vernakalant
intravenous, RSD 1235) in the Asia-Pacific
(A-P) region in patients with recent-onset
atrial fibrillation (AF) lasting three hours
to seven days. The study randomized 123
patients. Of the 111 treated patients, 53%
of those receiving an IV dose of Brinavess
converted to normal heart rhythm within
90 minutes, compared to 12% of placebo
patients (95% CI; 23%, 58%, p<0.001). The A-P
study data suggested Brinavess generally was
well-tolerated in the targeted patient population.
In the 30-day interval following drug administration,
serious adverse events occurred
in six (11%) placebo patients and seven (13%)
patients dosed with Brinavess. Potentially
drug-related serious adverse events occurred
in one (2%) patient receiving Brinavess. There
were no cases of drug-related torsades de
pointes, a well-characterized arrhythmia that
is an occasional side effect of many current
antiarrhythmic drugs. The company plans to
apply for Brinavess approvals in A-P countries
including Taiwan and Korea.
December 2, 2013
ChanRx issued results of a phase IIb study
of vanoxerine (GBR-12909) for the treatment
of atrial fibrillation. In the randomized,
placebo-controlled trial, 104 patients
with recent onset symptomatic atrial fibrillation
or atrial flutter were assigned to one
of three doses of vanoxerine or placebo.
Patients were measured for conversion to
normal sinus rhythm. There was a statistically
significant dose-dependent increase
in the conversion to normal sinus rhythm
(P-value for all doses=0.0005) compared
to placebo. The highest oral dose (400mg)
achieved a conversion rate of 76% at
eight hours and 84% within the first 24
hours, a rate approaching that of direct
current (DC) cardioversion. Patients taking
placebo achieved a 25% conversion rate at
eight hours and a 38% conversion rate at
Daiichi Sankyo reported results of a phase
III study of edoxaban for the prevention
of stroke or systemic embolic events
(SEE) in patients with non-valvular atrial
fibrillation (NVAF). The three-arm, randomized,
global phase III trial study compared two
edoxaban treatment arms, 60mg and
30mg, with warfarin in 21,105 patients
with NVAF for a median of 2.8 years. The
edoxaban 60mg treatment arm had an annual
incidence of stroke or SEE of 1.18% v.
1.50% for warfarin (hazard ratio [HR], 0.79;
97.5% confidence interval [CI], 0.63 to
0.99; p<0.001 for non-inferiority), and significantly
reduced major bleeding by 20%
(2.75% v. 3.43% per year, respectively) (HR,
0.80; 95% CI, 0.71 to 0.91; p<0.001 for superiority).
The edoxaban 30mg treatment
arm had an annual incidence of stroke or
SEE of 1.61% v. 1.50% for warfarin (HR,
1.07; 97.5% CI, 0.87 to 1.31; p=0.005 for
non-inferiority), and significantly reduced
major bleeding by 53% (1.61% v. 3.43%
per year, respectively) (HR, 0.47; 95% CI,
0.41 to 0.55; p<0.001 for superiority). The
primary net clinical outcome (defined in
the study protocol as the composite of
death, stroke, SEE or major bleeding) was
8.11% per year for warfarin, 7.26% per
year for the edoxaban 60mg treatment
arm (p=0.003) and 6.79% per year for the
edoxaban 30mg treatment arm (p<0.001).
An NDA will be submitted in the U.S.,
Japan and Europe.
October 21, 2013
Cardiome Pharma reported results of an open label study comparing vernakalant intravenous (IV) to oral propafenone and oral flecainide in patients with atrial fibrillation. Subjects received a single oral dose of 600mg of propafenone (N=50), a single oral dose of 300mg of flecainide (N=50), or vernakalant IV (N=50) in an initial dose of 3mg/kg for 10 minutes and an additional 2mg/kg if atrial fibrillation had not resolved within 15 minutes. The conversion rate approximated 80% in both the propafenone and flecainide groups at eight hours v. 90% in the vernakalant group at two hours. This difference was not statistically significant at eight hours. Patients treated with vernakalant IV experienced a shorter median hospital length of stay, 243 minutes (interquartile range [IQR], 190-276) v. 422 minutes (IQR, 341- 739) for the patients treated with propafenone and 410 minutes (IQR, 330-727) for the patients treated with flecainide (p<0.01).
June 24, 2013
Boehringer Ingelheim Pharmaceuticals reported results from RELY-ABLE, an extension trial of Pradaxa (dabigatran etexilate mesylate) for non-valvular atrial fibrillation (NVAF). RELY-ABLE was a global extension trial of 5,851 dabigatran-treated patients across 35 countries who continued on from the 12,091 patients in the original RE-LY study. RE-LY was a global, phase III, randomized trial of 18,113 patients enrolled in 951 centers in 44 countries, investigating whether dabigatran etexilate (two blinded doses) was as effective as open-label warfarin INR 2.0 - 3.0 for stroke prevention. Patients enrolled in RELY-ABLE continued PRADAXA therapy, as dosed in RE-LY, for an additional 2.3 years, bringing the mean duration of treatment to 4.3 years. 2,937 patients received PRADAXA 150mg twice daily and 2,914 received dabigatran 110mg twice daily. Rates of major bleeding, the primary endpoint, were 3.74% (n=238) per year with PRADAXA 150mg and 2.99% (n=190) per year with dabigatran 110mg (HR 1.26, 95% CI: 1.04-1.53). Major gastrointestinal bleeding occurred at rates of 1.54% (n=98) per year with PRADAXA 150mg and 1.56% (n=99) per year with dabigatran 110mg.
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.