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Phase III clinical study of TY-0201 in patients with chronic atrial fibrillation -Confirmatory Study-

Phase III clinical study of TY-0201 in patients with chronic atrial fibrillation -Confirmatory Study-

220

Patients with chronic atrial fibrillation

Consent was obtained from 303 subjects and 220 subjects were assigned to treatment groups (TY-0201 4 mg: 55 subjects, TY-0201 8 mg: 55 subjects, bisoprolol fumarate oral preparation (BO) 2.5 mg: 55 subjects, BO 5 mg: 55 subjects). The remaining subjects were either judged as being ineligible or withdrew their consent. All randomized subjects received the study drug and 218 subjects completed the study. Study drug dosage for the TY-0201 treatment groups was initiated at 4 mg once daily and for the BO treatment groups at 2.5 mg once daily. The need for whether to increase the dosage was judged following 2 weeks of treatment. The dosage was increased for 29 subjects in the TY-0201 8 mg group and for 31 subjects in the BO 5 mg group. The evaluation for each treatment group was conducted by pooling all subjects within a group, i.e. whether or not the dosage was increased.

The incidence of adverse events for the TY-0201 4 mg and 8 mg and the bisoprolol fumarate oral preparation(BO) 2.5 mg and 5 mg groups were 25.5, 21.8, 27.3 and 29.1%, respectively. The corresponding incidence of adverse drug reactions were 10.9, 9.1, 9.1 and 5.5%, respectively. The evaluation for each treatment group was conducted by pooling all subjects within a group, i.e. whether or not the dosage was increased.

Adjusted means of changes in 24 hour mean heart rate from baseline in the TY-0201 4 mg, TY-0201 8 mg, BO 2.5 mg, and BO 5 mg groups were -12.3, -13.8, -12.7, and -14.3bpm, respectively.The differences between values for the TY-0201 4 mg, and BO 2.5 mg groups and between values for the TY-0201 8 mg and BO 5 mg groups were estimated to be 0.5 (95% confidence interval, -1.9 to 2.9) bpm and 0.5 (-1.9 to 2.9) bpm, respectively. These differences did not exceed the upper limit of the non-inferiority margin, and accordingly, TY-0201 was verified to be non-inferior to the BO. Furthermore, the effect of decreasing the heart rate was larger in the TY-0201 8 mg group as compared with the TY-0201 4 mg group. The evaluation for each treatment group was conducted by pooling all subjects within a group, i.e. whether or not the dosage was increased.

There was a significant reduction in the mean heart rate, as measured by a 24-hour Holter ECG monitor over 24 hours and averaged each hour, from before administration of the study drugs. The changes in heart rate at rest from before administration of the study drug until final evaluation at end of treatment for the TY-0201 4 mg, TY-0201 8 mg, BO 2.5 mg and BO 5 mg groups were -15.2, -17.4, -12.6 and -16.0 bpm, respectively, and these reductions in heart rates were all significant. The percentage of subjects who reached the target heart rate at the final evaluation for each of the TY-0201 4 mg and 8 mg, BO 2.5 mg and 5 mg groups were 56.4, 54.5, 60.0 and 58.2%, respectively. The evaluation for each treatment group was conducted by pooling all subjects within a group, i.e. whether or not the dosage was increased.

TY-0201 was confirmed to be non-inferior to the BO for reducing the heart rate in Japanese patients with persistent or permanent atrial fibrillation. Furthermore, the treatments were considered to be tolerable from a safety point of view.

Dec. 24, 2018

https://doi.org/10.1016/j.jjcc.2018.11.009

No

TOA EIYO LTD.

ct_info@toaeiyo.co.jp

TOA EIYO LTD.

ct_info@toaeiyo.co.jp

completed

Feb. 23, 2015

Interventional

Multicenter, randomized, double-blind, parallel-group, comparative study

treatment purpose

3

(1) Patients with chronic (persistent or permanent) atrial fibrillation.
(2) Resting heart rate: >=80 bpm
(3) Outpatients

(1) Patients with any of the following findings related to heart disease.
1) Acute coronary syndrome, coronary revascularization or variant angina within 6 months prior to informed consent.
2) Cardioversion or catheter ablation within 3 months prior to informed consent.
3) Heart rate control with a pacemaker, etc.
4) Severe arrhythmia, cardiogenic shock, heart failure, cardiomyopathy, myocarditis or reduced cardiac function, or aortic or mitral valve stenosis or regurgitation at a moderate level or higher.
(2) Patients with a history of a cerebrovascular event (except an asymptomatic cerebrovascular event).
(3) Systolic blood pressure < 110 mmHg.
(4) Patients with a disease for which anticoagulant therapy is contraindicated.
(5) Patients with poor skin condition at the patch application site or history of dermatitis caused by a topical agent.

Both

Chronic atrial fibrillation

investigational material(s)
Generic name etc : TY-0201
INN of investigational material : Bisoprolol
Therapeutic category code : 212 Antiarrhythmic agents
Dosage and Administration for Investigational material : Once daily transdermal application

control material(s)
Generic name etc : Bisoprolol fumarate
INN of investigational material : Bisoprolol
Therapeutic category code : 212 Antiarrhythmic agents
Dosage and Administration for Investigational material : Once daily oral administration

efficacy
The change of mean heart rate as determined by 24 hours holter electrocardiogram.

safety
efficacy
(1) Diurnal variation in heart rate as determined by 24 hours holter electrocardiogram.
Resting heart rate
Achievement rate to the target heart rate level.
(2) Adverse events and adverse drug reactions.

Jan. 22, 2015