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CS-747S PhaseIII trial -Non-inferiority study of CS-747S versus clopidogrel bisulfate in patients with ischemic cerebrovascular accident.-

CS-747S PhaseIII trial (CVA)

3753

There was no apparent imbalance in background factors between the treatment groups.

3753 subjects were randomized. Of these, 3747 subjects received study drug, 1885 in the CS-747S group and 1862 in the clopidogrel group. The subject group was defined as Full Analysis Set (FAS) and Safety Analysis set. 604 subjects (290 in the CS-747S group, 314 in the clopidogrel group) discontinued from the study.

The incidence rate of adverse events was 89.0% (1677/1885 subjects) in the CS-747S group and 90.2% (1680/1862 subjects) in the clopidogrel sulfate group. The incidence rate of adverse events considered related to the study drug was 32.7% (617/1885 subjects) in the CS-747S group and 31.4% (584/1862 subjects) in the clopidogrel sulfate group. The percentage of deaths was 0.5% (10/1885 subjects) in the CS-747S group and 0.6% (11/1862 subjects) in the clopidogrel sulfate group. Drug-related death was found in 3 subjects (0.2%) in the CS-747S group and 9 subjects (0.5%) in the clopidogrel sulfate group. The incidence rate of serious adverse events was 18.4% (347/1885 subjects) in the CS-747S group and 18.1%(337/1862 subjects) in the clopidogrel sulfate group. The incidence rate of drug-related serious adverse events was 2.4% (45/1885 subjects) in the CS-747S group and 3.3% (62/1862 subjects) in the clopidogrel sulfate group.

The incidence rate of cerebro-cardiovascular events (ischemic stroke, myocardial infarction, and other vascular death) found during the period from the initiation of study treatment to 1 day after completion /discontinuation of study treatment was 3.9% (73/1885 subjects) in the CS-747S group and 3.7% (69/1862 subjects) in the clopidogrel sulfate group (risk ratio [95% CI]: 1.045 [0.757 to 1.443]). The upper limit of 95% CI of the risk ratio for the CS-747S group relative to the clopidogrel sulfate group was 1.443, above the upper limit of noninferiority, 1.35, and therefore the noninferiority of the CS-747S group to the clopidogrel sulfate group failed to be confirmed (hazard ratio [95% CI]: 1.058 [0.753-1.486]).

- The incidence rate of ischemic stroke was 3.7% (69/1885 subjects) in the CS-747S group and 3.4% (64/1862 subjects) in the clopidogrel sulfate group (hazard ratio [95% CI]: 1.058 [(0.753 to 1.486)). - The incidence rate of myocardial infarction was 0.2% (4/1885 subjects) in the CS-747S group and 0.3% (6/1862 subjects) in the clopidogrel sulfate group (hazard ratio [95% CI]: 0.654 [0.184 to 2.316]). - No other vascular death was reported in either treatment group. - The incidence rate of ischemic cerebrovascular events (ischemic stroke, TIA) was 4.4% (82/1885 subjects) in the CS-747S group and 4.0% (74/1862 subjects) in the clopidogrel sulfate group (hazard ratio [95% CI]: 1.087 [0.794 to 1.489]). - The incidence rate of stroke was 3.9% (73/1885 subjects) in the CS-747S group and 3.9% (73/1862 subjects) in the clopidogrel sulfate group (hazard ratio [95% CI]: 0.980 [0.709 to 1.356]). - The incidence rate of life-threatening bleeding, major bleeding, and clinically relevant bleeding was 6.1% (115/1885 subjects) in the CS-747S group and 5.9% (110/1862 subjects) in the clopidogrel sulfate group (hazard ratio [95% CI]: 1.021 [0.786 to 1.327]). - The incidence rate of all bleeding events was 32.4% (610/1885 subjects) in the CS-747S group and 29.5% (549/1862 subjects) in the clopidogrel sulfate group (hazard ratio [95% CI]: 1.110 [0.989 to 1.246]). - The arithmetic mean PRU values at the initiation of study treatment were 226.4 for CS-747S group and 225.3 for clopidogrel sulfate group, and at 4 weeks, 153.6 and 196.2 respectively.

The non-inferiority of CS-747S to clopidogrel for the prevention of ischemic stroke, myocardial infarction, and other vascular death was not confirmed in patients with non-cardioembolic stroke. The incidences rate of cerebro-cardiovascular events and other efficacy events were generally similar to clopidogrel. The incidence rate of adverse events and bleeding events were comparable between CS-747S and clopidogrel, suggesting that there are no significant safety issues with CS-747S.

Feb. 12, 2019

https://doi.org/10.1016/S1474-4422(18)30449-6

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

Sept. 11, 2011

Interventional

Multi-center, randomized, double-blind, double-dummy, parallel group study

treatment purpose

3

-Patients with cerebral infarction that caused the last attack.
-The last attack : between 1 and 26 weeks prior to informed consent.
-Body weight: over 50 kg

-Patients who need the dual antiplatelet therapy.
-History of intracerebral hemorrhage.
-Bleeding disorder or bleeding diathesis.
-Patients with poorly-controlled blood pressure.
-Severe hepatic disorder or kidney disturbance.

Both

Ischemic cerebrovascular accident (except cardiogenic cerebral embolism and asymptomatic cerebral infarction)

investigational material(s)
Generic name etc : prasugrel hydrochloride
INN of investigational material : prasugrel
Therapeutic category code : 339 Other agents relating to blood and body fluides
Dosage and Administration for Investigational material : Once daily orally

control material(s)
Generic name etc : clopidogrel bisulfate
INN of investigational material : clopidogrel
Therapeutic category code : 339 Other agents relating to blood and body fluides
Dosage and Administration for Investigational material : Once daily orally

efficacy
Rate of cerebrovascular and cardiovascular events.
The rate of cerebrovascular and cardiovascular events, and confidence intervals of each groups, which observed from the beginning of the administration of the studying drug to the day after the completion or discontinuation of administration, are to be calculated. Then risk ratio and confidence intervals of CS-747S group against clopidogrel bisulfate group are to be calculated. In addition, cumulative incidence of events is to be estimated by Kaplan-Meier method.

safety
efficacy
pharmacokinetics
pharmacodynamics
pharmacogenomics
Rate of bleeding event, etc.
The rate of bleeding events and their 95% confidence intervals are to be calculated.

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July. 29, 2011