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An Exploratory Study of CS-3150 to Evaluate the Relation between Antihypertensive Effect and Baseline Factors Compared to Olmesartan Medoxomil in Patients with Essential Hypertension

An Exploratory Study of CS-3150 to Evaluate the Relation between Antihypertensive Effect and Baseline Factors Compared to Olmesartan Medoxomil in Patients with Essential Hypertension

40

There was no apparent imbalance in major background factors between Groups A and B. In the FAS (40 subjects), the mean sitting systolic BP was 152.6 mmHg, and diastolic BP was 96.3 mmHg. 24h mean systolic BP was 157.8 mmHg and diastolic BP was 97.6 mmHg in ABPM.

In this study, 40 subjects (group A: 20 subjects, group B: 20 subjects) were randomized to receive CS-3150 or olmesartan medoxomil during Treatment Period I. All 40 randomized subjects entered Treatment Period II (tertiary enrollment). Thirty-nine of 40 patients enrolled in the tertiary registry (group A: 20 patients, group B: 19 patients) completed the study and 1 patient (group B) discontinued the study. All 40 randomized subjects were included in the FAS and safety population. Two of them were excluded from PPS.

The incidence of adverse events was 20.0% (8/40) after administration of CS-3150 and 32.5% (13/40) after administration of olmesartan medoxomil. The incidence of adverse events considered related to the study drug was 2.5% (1/40) at the term of CS-3150 dos. No study drug-related events were reported with olmesartan medoxomil.

- Related between Changes in 24-hour Blood Pressure by ABPM and Pretreatment Background Factors 1) Correlation between background factors and blood pressure change There were no background factors that correlated with the change in 24-hour blood pressure (systolic blood pressure, diastolic blood pressure, and mean blood pressure) by ABPM at the term of CS-3150 dose. After olmesartan medoxomil dose, the change in 24-hour blood pressure (systolic blood pressure, diastolic blood pressure, mean blood pressure) over ABPM was significantly correlated with baseline urinary K excretion (P = 0.0420, P = 0.0057, P = 0.0137). 2) Investigation of the effect of background factors on the antihypertensive effect of each drug Only the change in systolic blood pressure showed a significant interaction between the drug (CS-3150 and olmesartan medoxomil) and the baseline PRA, which was different from the trend in the olmesartan medoxomil dose, and the lower the baseline PRA, the higher the antihypertensive effect in the CS-3150 administration. Regardless of baseline background factors, the relationships between the change in 24-hour blood pressure due to ABPM and background factors were unchanged for CS-3150 and olmesartan medoxomil regardless of baseline background factors.

1) Changes in 24-hour blood pressure (systolic and diastolic blood pressure) by ABPM (differences before and after treatment in Treatment Period I and Treatment Period II, respectively) In FAS, the mean (SD) of 24-hour BP with ABPM at CS-3150 was 158.3 (14.06) mmHg at baseline and 149.9 (14.30) mmHg at Week 12, with a point estimate of change from baseline (95% confidence interval) of-8.1 (-12.0 to-4.2) mmHg Diastolic blood pressure was 97.5 (8.02) mmHg at baseline and 93.6 (9.45) mmHg at Week 12, with a point estimate of change from baseline (95% confidence interval) of-3.6 (-5.6 to-1.6) mmHg. The mean systolic blood pressure (SD) with olmesartan medoxomil was 159.0 (15.15) mmHg at baseline and 150.4 (19.65) mmHg at Week 12, with a point estimate of change from baseline (95% confidence interval) of-8.5 (-12.3 to-4.7) mmHg. Diastolic blood pressure was 97.7 (8.62) mmHg at baseline and 91.1 (10.68) mmHg at Week 12 , with a point estimate of change from baseline (95% confidence interval) of-6.6 (-8.5 to-4.6) mmHg. 2) Changes in sitting blood pressure (systolic blood pressure, diastolic blood pressure) (difference between baseline and end of treatment in Treatment Period I and Treatment Period II) In the FAS, the mean (SD) of systolic blood pressure at CS-3150 was 149.2 (12.32) mmHg at baseline and 138.4 (14.98) mmHg at Week 12, with a point estimate of change from baseline (95% confidence interval) of-10.7 (-15.1 to-6.4) mmHg. The diastolic blood pressure was 94.1 (5.73) mmHg at baseline and 90.6 (9.17) mmHg at Week 12, and the point estimate of change from baseline (95% confidence interval) was mmHg-3.6 (-6.1 to-1.1). In the FAS, the mean systolic blood pressure (SD) was 150.2 (8.80) mmHg at baseline and 135.6 (16.14) mmHg at Week 12 for sitting blood pressure with olmesartan medoxomil, and the point estimate of change from baseline (95% confidence interval) was-14.5 (-18.8 to-10.2) mmHg. Diastolic blood pressure was 94.6 (6.30) mmHg at baseline and 85.7 (8.24) mmHg at Week 12, with a point estimate of change from baseline (95% confidence interval) of-8.8 (-11.3 to-6.3) mmHg.

An exploratory study of CS-3150 was conducted to investigate the relationship between background factors such as PRA and CS-3150 blood pressure lowering efficacy in patients with essential hypertension for 12 weeks compared with olmesartan medoxomil. As a result, there were no obviously affected background factors in the antihypertensive effects of CS-3150. There were no clinically significant adverse events with CS-3150 administration.

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. 03, 2016

Interventional

Multi-center, randomaized, active control, open label, 2-way crossover, study

treatment purpose

3

1) Male and female subjects aged 20 years or older at informed consent
2) Subjects with essential hypertension during run-in period (mean 24 hr SBP >= 130 and DBP >= 80 mmHg , and Sitting SBP >= 140 mmHg and < 180 mmHg, Sitting DBP >= 90 mmHg and < 110 mmHg)

1) Secondary hypertension or malignant hypertension
2) 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 the study drug once daily after breakfast

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

safety
efficacy
exploratory
- Relationship between the change from baseline in 24 hr blood pressure (systolic, diastolic, and avarage blood pressure) and baseline factors.
- Adverse events

efficacy
- Relationship between the change from baseline in morning, evening, and night blood pressure (systolic, diastolic, and avarage blood pressure) and baseline factors.
- Relationship between the change from baseline in sitting blood pressure (systolic and diastolic blood pressure) and baseline factors.
- Change from baseline in sitting blood pressure (systolic and diastolic blood pressure) and baseline factors.
- Time course of 24 hr blood pressure and sitting blood pressure (systolic, diastolic, and avarage blood pressure)
- Proportion of patients achieving 24 hr and sitting blood pressure control

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July. 07, 2016