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An Exploratory Study of the Efficacy and Safety of Esaxerenone in Uncontrolled Nocturnal Hypertensive Patients : a single-arm, open-label study. (EARLY-NH study)

EARLY-NH study (EARLY-NH study)

101

The baseline characteristics in the 93 patients for the FAS (Full Analysis Set) population were as follows. [ARB combination cohort] Number of patients, 45 Sex, Male 22 (48.9%) / Female 23 (51.1%) Age, 66.5 +- 12.43 years (mean +- SD) Duration of hypertension, 157.4 +- 133.86 months (mean+-SD) [CCB combination cohort] Number of patients, 48 Sex, Male 25 (52.1%) / Female 23 (47.9%) Age, 68.7 +- 10.69 years (mean +- SD) Duration of hypertension, 125.4 +- 110.26 months (mean+-SD)

The number of patients who obtained informed consent was 206. After the observation period, 101 patients (ARB combination cohort: 48, CCB combination cohort: 53) were enrolled in the study and received the esaxerenone. Eighty-two patients (ARB combination cohort: 38, CCB combination cohort: 44) completed the administration period. Of the 101 patients who enrolled the study, the FAS population included 93 patients (ARB combination cohort: 45, CCB combination cohort: 48), and the safety population included 101 patients (ARB combination cohort: 48, CCB combination cohort: 53).

Overall, the mainly reported adverse drug reactions and their incidence were "Hyperkalaemia" 9.9% (10 of 101 patients), "Blood potassium increased" 3.0% (3 of 101 patients), and "Renal disorder" 2.0% (2 of 101 patients). Adverse drug reactions leading to discontinuation of the study were 1.0% each (1/101 cases) of "Blood potassium increased ", "Blood pressure decreased ", and " Hyperkalaemia". No serious adverse drug reactions were reported in this study, the outcomes of the adverse drug reactions were all recovery or relieve, and no new adverse events or adverse drug reactions requiring confirmation were noted. As the serious adverse event, 1 patient of "Pyelonephritis acute" was reported, but the patient recovered by inpatient treatment, and the causal relationship with this study and the study drug were both denied by the investigator.

1. Efficacy results (FAS population) The main results overall were as follows. The changes in nighttime blood pressure using the brachial sphygmomanometer at week 12 of administration period, which are the primary endpoints, were -12.8 mmHg for systolic blood pressure and -5.4 mmHg for diastolic blood pressure. Both were significantly lower than before administration. (P < 0.001) As the Secondary endpoint, the sitting blood pressure at week 12 of administration period and the nocturnal blood pressure using a wrist-type home sphygmomanometer at week 12 were both significantly lower than before administration (P <0.001). The urinary albumin-creatinine ratio (UACR), the serum NT-proBNP, and cardio-ankle vascular index (CAVI) at week 12 were all significantly lower than before administration (UACR: P <0.001, serum NT- proBNP: P = 0.003, CAVI: P = 0.041). The amount of change in plasma renin activity (PRA) was 3.75 +- 9.411 ng/mL/hr and that of in plasma aldosterone concentration (PAC) was 47.28 +- 55.250 pg/mL. 2. Safety results (safety population) The main results overall were as follows. The mean value of eGFRcreat decreased from 68.824 mL/min/1.73 m2 before administration to minimum 63.425 mL/min/1.73 m2, at week 12 of the administration period. The mean serum potassium level increased from 4.07 mEq/L before administration to maximum 4.43 mEq/L, at week 12 of the administration period. The amount of change in pulse rate was -1.0 +- 10.47 bpm when measured in the consultation room, 1.0 +- 4.73 bpm when measured at home in the early morning before medication, and 0.5 +- 4.17 bpm when measured in the upper arm at night.

The amount of change in nocturnal blood pressure using the brachial sphygmomanometer, which is the primary endpoint, shown a statistically significant decrease in both systolic and diastolic blood pressure. A statistically significant decrease was also shown in home blood pressure early morning and before bedtime, and in consultation room blood pressure. No serious adverse reactions were reported and no new adverse events/adverse reactions requiring confirmation were noted in the safety evaluation.

May. 12, 2023

May. 12, 2023

https://pubmed.ncbi.nlm.nih.gov/37173430/

Yes

The datasets generated and/or analyzed during the current study will be available from the corresponding author and the study sponsor on reasonable request.

https://jrct.niph.go.jp/latest-detail/jRCTs031200364

Kario Kazuomi

Jichi Medical University Hospital

3311-1, Yakushiji, Shimotsuke, Tochigi

kkario@jichi.ac.jp

Hoshide Satoshi

Jichi Medical University Hospital

3311-1, Yakushiji, Shimotsuke, Tochigi

+81-285-58-7344

hoshide@jichi.ac.jp

Complete

Feb. 15, 2021

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1) Patients aged 20 years or older at informed consent
2) Patients administered ARB or CCB
3) Patients with a nocturnal systolic BP of at least 120 mmHg

1) Patients diagnosed with secondary hypertension or malignant hypertension
2) Patients with hyperkalemia or serum potassium levels exceeding 5.0 mEq/L
3) Patients with any cerebro-cardiovascular diseases
4) Patients who used prohibited concomitant medications
5) Patients with severely impaired renal function (eGFRcreat < 30 mL/min/1.73 square meter)
6) Patients with seriously impaired hepatic function (e.g., hepatic failure and hepatic cirrhosis)
7) Patients with a life expectancy within 1 year due to some disease
8) Patients with a history of serious drug allergies
9) Pregnant, possibly pregnant, breast-feeding or planning to become pregnant
10) Patients working the night shift at least 3 days a week in a shift-work system
11) Patients deemed otherwise unsuitable for the study by the investigator

Both

Nocturnal hypertension

According to the package insert, esaxerenone is administered orally once a day. Esaxerenone will be started at 2.5 mg and can be titrated up to 5 mg if response is not adequate. In patients with moderately impaired renal function (eGFRcreat of => 30 to < 60 mL/min/1.73 square meter) or diagnosed with albuminuria or proteinuria associated with diabetes mellitus, esaxerenone will be started at 1.25 mg and will generally be titrated up to 2.5 mg after 4 weeks of treatment, depending on the condition of the subject (e.g., serum potassium level). If there is an inadequate response, esaxerenone can be titrated up to 5 mg.

Efficacy Evaluation
Change from baseline in nocturnal BP (systolic BP and diastolic BP)

Efficacy Evaluation
1) Change from baseline in sitting BP (office BP and home BP before early morning medication and bedtime: systolic BP and diastolic BP)
2) Change from baseline in nocturnal BP (systolic BP and diastolic BP) measured with a home wrist BP monitor
3) Time courses of sitting BP and nocturnal BP
4) Achievement ratio of target BP level for sitting BP and nocturnal BP at Week 12
5) Change from baseline in urinary albumin/creatinine ratio
6) Change from baseline in NT-proBNP and normalization rate (=<55 pg/mL) in serum NT-proBNP
7) Change from baseline in vascular function evaluation (CAVI)
8) Change from baseline in plasma renin activity and aldosterone concentration
9) Change from baseline in urinary biomarkers (Na, K, Cr)
Safety Evaluation
1) Incidence of adverse events
2) Time course in eGFRcreat and change from baseline in eGFRcreat
3) Proportion of subjects with the following serum potassium levels
=> 5.5 mEq/L
=> 6.0 mEq/L
4) Time course of serum potassium level
5) Time course in pulse rate and change from baseline in pulse rate

+81-3-3470-3360

Jan. 15, 2021

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