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A Double Blind Study of CS-3150 to Evaluate Efficacy and Safety Compared to Eplerenone in Patients With Essential Hypertension (ESAX-HTN study)

A Double Blind Study of CS-3150 to Evaluate Efficacy and Safety Compared to Eplerenone in Patients With Essential Hypertension (ESAX-HTN study)

1001

There were no major differences in background factors between the treatment groups. In FASs (998 patients), the mean sitting blood pressure were 155.3 mmHg in systolic blood pressure and 98.1 mmHg in diastolic blood pressure. Subject characteristics in the safety-analysis set were similar to those in the FAS.

In this study, 1001 subjects were randomized to treatment (331 in the CS-3150 2.5 mg group, 338 in the 5 mg group, 332 in the 50-mg eplerenone group). Forty-nine subjects (21 subjects in the CS-3150 2.5 mg group, 15 subjects in the 5 mg group, 13 subjects in the eplerenone 50-mg group) discontinued the study. All of the 1001 randomized subjects who received the investigational product were included in the safety analysis set. Three subjects were excluded from FAS and 57 from PPS.

The incidence of adverse events was 38.4% (127/331) in the CS-3150 2.5 mg group, 44.1% (149/338) in the 5 mg group, and 37.0% (123/332) in the eplerenone 50 mg group. The incidence of drug related adverse events 7.6% (25/331) in the CS-3150 2.5 mg group, 9.2% (31/338) in the 5 mg group, and 4.8% (16/332) in the eplerenone 50 mg group. Serious adverse events occurred in 4 subjects in the CS-3150 2.5 mg group, 3 subjects in the 5 mg group, and 1 subject in the eplerenone 50-mg group.

- Change in sitting blood pressure (systolic and diastolic) In the PPS nalysis using ANCOVA models, the least-squares mean change in sitting systoric blood pressur (95% confidence interval) was -13.7 (-14.9 to -12.5) mmHg in CS-3150 2.5 mg group, -16.9 (-18.1 to -15.7) mmHg in the CS-3150 5 mg group and-12.1 (-13.3 to-10.9) mmHg in eplerenone 50-mg group, respectively. The least-squares mean change in diastolic blood pressure was-6.8 (-7.6 to-6.1) mmHg in CS-3150 2.5 mg group, -8.4 (-9.1 to -5.4) mmHg in 5 mg and -6.1 (-6.8 to-5.4) mmHg in eplerenone 50-mg group. The point estimate of the difference (95% CI) between the eplerenone 50 mg and CS-3150 2.5 mg groups was-1.6 (-3.3 to 0.1) mmHg in systolic blood pressure and-0.7 (-1.8 to 0.3) mmHg in diastolic blood pressure, both of which were below the upper limit of the two-sided 95% CI (systolic blood pressure: 3.4 mmHg, diastolic blood pressure: 1.5 mmHg), demonstrating non-inferiority of the CS-3150 2.5 mg group to the 50 mg eplerenone group. In a similar analysis using ANCOVA models in FAS, the point estimates (95% confidence interval) of the differences between the CS-3150 2.5 mg and 5 mg groups in the change in sitting blood pressure (systolic and diastolic blood pressure) were-3.4 (-5.1 to-1.7) mmHg in systolic blood pressure and-1.7 (-2.7 to-0.7) mmHg in diastolic blood pressure, both of which had the upper limit of the two-sided 95% confidence interval below 0, demonstrating statistically significantly higher BP lowering effects in the CS-3150 5 mg group than in the 2.5-mg group (P = 0.0001 and P = 0.0011, respectively).

- Twenty-four-hour blood pressure (systolic, diastolic) with ABPM Change in blood pressure The least-squares mean (95% CI) change in 24-hour systolic blood pressure with ABPM was-9.1 (-10.6 to-7.7) in CS-3150 2.5 mg group,-13.1 (-14.5 to-11.7) mmHg in 5 mg group, and-6.6 (-8.0 to-5.3) mmHg in eplerenone 50 mg group. The least-squares mean (95% CI) change in 24-hour diastolic blood pressure with ABPM was -4.1 (-4.8 to-3.4) mmHg in 2.5 mg group, -6.3 (-7.0 to -5.6) mmHg in 5 mg group.The value was-3.2 (-3.9 to-2.5) mmHg in 50 mg eplerenone group.

CS-3150 was administrated once daily for 12 weeks to patients with essential hypertension. The change in sitting blood pressure as the primary efficacy endpoint, was evaluated. The non-inferiority of CS-3150 2.5 mg to eplerenone 50 mg was verified, and the antihypertensive effect of CS-3150 5 mg was statistically significantly superior to that of 2. 5 mg. The incidence of adverse events was similar between 2.5 mg and 5 mg of CS-3150 and 50-mg of eplerenone.

Dec. 02, 2019

https://www.ahajournals.org/doi/abs/10.1161/HYPERTENSIONAHA.119.13569

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. 23, 2016

Interventional

Multi-center, randomized, double-blind, active control, 3- arm, parallel group, comparison study

treatment purpose

3

1) Male and female subjects aged 20 years or older at informed consent
2) Subjects with essential hypertension and satisfied the following blood pressure criteria during run-in period;
- Sitting BP: SBP >= 140 mmHg and < 180 mmHg, DBP >= 90 mmHg and < 110 mmHg
- Mean 24 hr BP: SBP >= 130 and DBP >= 80 mmHg

1) Secondary hypertension or malignant hypertension
2) Diabetic nephropathy or diabetes mellitus with albuminuria
3) Serum potassium level < 3.5 or >= 5.1 mEq/L
4) Reversed day-night life cycle including overnight workers
5) eGFR < 60 mL/min/1.73 m^2.

Both

Essential hypertension

investigational material(s)
Generic name etc : CS-3150
INN of investigational material : Esaxerenone
Therapeutic category code : 214 Antihypertensives
Dosage and Administration for Investigational material : Each subject will orally take study drug once daily after breakfast

control material(s)
Generic name etc : Eplerenone
INN of investigational material : Eplerenone
Therapeutic category code : 214 Antihypertensives
Dosage and Administration for Investigational material : Each subject will orally take study drug once daily after breakfast

efficacy
safety
- Change from baseline in sitting systolic and diastolic blood pressure
- Adverse events

efficacy
Change from baseline in 24 hr systolic and diastolic blood pressure

-

Aug. 17, 2016