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A phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study of DU-176b in patients with non-valvular atrial fibrillation (NVAF) aged 80 years or older who are ineligible for available oral anticoagulation therapy

A Phase 3 Study of DU-176b

984

Major demographic and other baseline characteristics were balanced between the treatment groups. Overall, the mean age was 86.6 years and the eldest subject was 100 years old. The percentage of female subjects was 57.4%. The mean weight was 50.58 kg, and the mean CLcr was 36.295 mL/min. Overall, 7.6% of subjects concomitantly received at least one P-gp inhibitor. Overall, 31.2% of subjects had permanent AF, 21.7% of subjects had persistent AF, and 47.1% of subjects had paroxysmal AF. The mean CHADS2 score was 3.1. Overall, 72.0% of subjects had a score of <=3 and 28.0% of subjects had a score of >=4. Overall, 24.0% of subjects had a history of TIA or cerebral infarction, 82.3% had hypertension, 54.6% had congestive cardiac failure, and 22.9% had diabetes mellitus. Overall, 43.0% of subjects had a history of oral anticoagulant treatment. The most common oral anticoagulant was warfarin (24.7%), followed by apixaban (10.9%), edoxaban (8.8%), and rivaroxaban (8.0%). The most common risk factors for bleeding was concomitant use of one antiplatelet drug (53.8%), followed by severe renal impairment (41.0%), low body weight (38.0%), continuous use of acidic NSAIDs (32.2%), and a history of bleeding in a critical area or organ (22.6%). Percentages of the subjects with a history of intracranial bleeding or gastrointestinal bleeding was 8.1% and 12.9%, respectively. The mean HAS-BLED score was 2.3, with 37.4% of subjects having a HAS-BLED score of >=3. According to frailty assessment, 40.9% of subjects were frail and 48.9% were pre-frail. The subjects assessed as robust accounted for only 6.2%. Overall, 51.4% of subjects required certified long-term care insurance.

A total of 984 subjects were randomized and assigned to the edoxabanor placebo group (492 subjects each). Of the randomized subjects, 2 subjects in the placebo group never received the study drug. Conversely, a total of 982 (492 and 490) subjects received at least one dose of the study drug. A total of 681 (341 [69.3%] and 340 [69.1%]) subjects underwent the examination at completion of study drug administration and completed the study. A total of 303 (151 [30.7%] and 152 [30.9%]) subjects discontinued the study. The most common reason for study discontinuation was withdrawal of consent (16.1%), followed by death (13.7%).

The annual incidence of major bleedings was 3.3%/yr in the edoxaban group and 1.8%/yr in the placebo group during the "on-treatment period." The annual incidence of major bleedings was higher in the edoxaban group than in the placebo group (HR, 1.869; 95% CI, 0.898 to 3.891, Cox proportional hazards model, P = 0.0946). The annual incidence of intracranial hemorrhage was low in both treatment groups (0.3%/yr and 0.6%/yr). The annual incidence of intracranial hemorrhage was comparable between the treatment groups (HR, 0.499; 95% CI, 0.092 to 2.720). The annual incidence of gastrointestinal bleedings was 2.3%/yr in the edoxaban group and 0.8%/yr in the placebo group during the "on-treatment period." The annual incidence of major bleedings was higher in the edoxaban group than in the placebo group (HR, 2.854; 95% CI, 1.033 to 7.884, Cox proportional hazards model, P = 0.043). No fatal bleedings were reported in the edoxaban group, whereas the annual incidence of fatal bleedings was 0.3%/yr in the placebo group. The annual incidence of major bleedings or clinically relevant non-major bleedings was 17.7%/yr in the edoxaban group and 10.7%/yr in the placebo group during the "on-treatment period." The annual incidence was higher in the edoxaban group than in the placebo group (HR, 1.651; 95% CI, 1.200 to 2.270; Cox proportional hazards model, P = 0.0021). At least one non-bleeding TEAE was reported in 90.7% (446/492) subjects in the edoxaban group and 91.6% (449/490) subjects in the placebo group. The incidence of non-bleeding TEAEs was comparable between the treatment groups. Common non-bleeding TEAEs (% incidence in the edoxaban and placebo groups) were nasopharyngitis (22.6% versus 24.7%), constipation (10.6% versus 9.2%), back pain (10.0% versus 6.3%), pneumonia (9.6% versus 10.8%), and cardiac failure (9.1% versus 8.4%).

In ITT Analysis Set, stroke or SEE occurred in 15 subjects in the edoxaban group (2.3%/yr) and 44 subjects in the placebo group (6.7%/yr) during the overall study period. The annual incidence of composite event of stroke and SEE was significantly lower in the edoxaban group than in the placebo group (hazard ratio [HR], 0.339; 95% CI, 0.188 to 0.608; Cox proportional hazards model, P = 0.0003). edoxaban 15 mg once daily was superior to placebo in reducing the occurrence of the composite endpoint of stroke and SEE. In ITT Analysis Set, stroke occurred in 12 subjects in the edoxaban group (1.8%/yr) and 40 subjects in the placebo group (6.0%/yr) during the overall study period. Fewer stroke events were reported in the edoxaban group than in the placebo group, with the point estimate of a hazard ratio of less than 1.0 (HR, 0.299; 95% CI, 0.157 to 0.570). In ITT Analysis Set, SEE occurred in 3 subjects in the edoxaban group (0.4%/yr) and 6 subjects in the placebo group (0.9%/yr) during the overall study period. Fewer SEE events were reported in the edoxaban group than in the placebo group, with the point estimate of a hazard ratio of less than 1.0 (HR, 0.503; 95% CI, 0.126 to 2.011). In ITT Analysis Set, ischemic stroke occurred in 12 subjects in the edoxaban group (1.8%/yr) and 39 subjects in the placebo group (5.9%/yr) during the overall study period. Fewer ischemic stroke events were reported in edoxaban group than in the placebo group, with the point estimate of a hazard ratio of less than 1.0 (HR, 0.306; 95% CI, 0.160 to 0.585). In ITT Analysis Set, no hemorrhagic stroke occurred in the edoxaban group (0.0%/yr), whereas hemorrhagic stroke occurred in 2 subjects in the placebo group (0.3%/yr) during the overall study period.

In ITT Analysis Set, the annual incidence of composite events of stroke, SEE, and death due to CV were 7.8%/yr for the edoxaban group and 10.9%/yr for the placebo group during the overall study period. The annual incidence of composite events of stroke, SEE, and death due to CV was lower in the edoxaban group than in the placebo group (HR, 0.720; 95% CI, 0.504 to 1.028). In ITT Analysis Set, the annual incidence of MACE was 7.7%/yr for the edoxaban group and 11.0%/yr for the placebo group during the overall study period. The annual incidence of MACE was lower in the edoxaban group than in the placebo group (HR, 0.704; 95% CI, 0.492 to 1.007). In ITT Analysis Set, annual incidences of composite event of stroke, SEE, and all-cause mortality were 11.1%/yr for the edoxaban group and 14.8%/yr for the placebo group during the overall study period. The annual incidence of composite event of stroke, SEE, and all-cause mortality was lower in the edoxaban group than in the placebo group (HR, 0.753; 95% CI, 0.557 to 1.019). In ITT Analysis Set, annual incidences of net clinical benefit: stroke, SEE, major bleeding, and all-cause mortality were 13.5%/yr for the edoxaban group and 15.6%/yr for the placebo group during the overall study period. The annual incidence was lower in the edoxaban group than in the placebo group (HR, 0.863; 95% CI, 0.648 to 1.147). In ITT Analysis Set, annual all-cause mortality was 9.9%/yr for the edoxaban group and 10.2%/yr for the placebo group during the overall study period. The annual all-cause mortality was comparable between the treatment groups (HR, 0.972; 95% CI, 0.694 to 1.363).

In very elderly Japanese patients with nonvalvular atrial fibrillation who were not appropriate candidates for standard doses of oral anticoagulants, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding than placebo.

Aug. 30, 2020

https://www.nejm.org/doi/10.1056/NEJMoa2012883

Yes

Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/ Supporting Documents: - Study Protocol - Statistical Analysis Plan - Clinical Study Report Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication. Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent. URL: https://vivli.org/ourmember/daiichi-sankyo/

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

completed

Aug. 05, 2016

Interventional

A phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven study

treatment purpose

3

Patients with NVAF aged 80 years or older who are ineligible for available oral anticoagulation therapy

Patients with active bleeding
Patients who have poorly controlled hypertension
Patients who have liver dysfunction accompanied with disorder of blood coagulation

Both

Non-valvular atrial fibrillation

investigational material(s)
Generic name etc : DU-176b
INN of investigational material : edoxaban
Therapeutic category code : 333 Anticoagulants
Dosage and Administration for Investigational material : once daily,Edoxaban 15 mg

control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : once daily,Placebo

efficacy
Efficacy outcome (eg, stroke events)

safety
efficacy
Safety outcome (eg, bleeding events)

May. 24, 2016