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A randomized, open-label study to evaluate the efficacy and safety of esaxerenone compared to trichlormethiazide in patients with essential hypertension.

EXCITE-HT study

600

In the full analysis set (FAS), the baseline patient characteristics by treatment group was 149 (50.5%) in male and 146 (49.5%) in female in the Esaxerenone group (295 patients) and 160 (55.2%) in male and 130 (44.8%) in female in the Trichlormethiazide group (290 patients), respectively. The mean age [standard deviation (SD)], the mean weight, the mean BMI, and the mean duration of hypertension were 65.2 (11.5) years old (range:34-91 years old), 65.66 (14.54) kg, 25.38 (4.32) kg/m2, and 5.33 (5.08) years in the Esaxerenone group, and 64.7 (12.1) years old (range:28-94 years old), 66.63 (13.90) kg, 25.53 (4.20) kg/m2, and 5.46 (5.03) years in the Trichlormethiazide group, respectively. In FAS, the study patients with type 2 diabetes, dyslipidemia, hyperuricemia, and heart failure were 119 (40.3%), 188 (63.7%), 45 (15.3%) and 22 (7.5%) in the Esaxerenone group (295 patients), and 115 (39.7%), 171 (59.0%), 44 (15.2%) and 16 (5.5%) in the Trichlormethiazide group (290 patients), respectively. The background of the study patients in the safety analysis set and PPS was similar to that in FAS. The mean (SD) baseline systolic/diastolic blood pressure at baseline were 140.1 (15.0) / 86.8 (9.6) mmHg for morning home blood pressure, 134.7 (15.8) / 81.5 (10.5) mmHg for bedtime home blood pressure , 143.8(16.5) / 83.5 (11.6) mmHg for office blood pressure in the Esaxerenone group and 139.4 (13.1) / 86.6 (9.4) mmHg for morning home blood pressure, 134.4 (14.0) / 81.3 (10.8) mmHg for bedtime home blood pressure , 142.7 (15.1) / 83.4 (12.2) mmHg for office blood pressure in the Trichlormethiazide group, respectively. In addition, the mean (SD) UACR and NT-proBNP at baseline were 116.27 (482.31) mg/gCr and 109.49 (308.62) pg/mL in the Esaxerenone group, and 101.35 (424.41) mg/gCr and 83.84 (147.38) pg/mL in the Trichlormethiazide group, respectively.

This study started the registration from December 2022, finished the registration in May 2023, and completed the investigation of all patients in September 2023. Of the 736 patients who agree informed consent to participate in the study, 600 patients were enrolled (Esaxerenone group: 302 patients, Trichlormethiazide group: 298 patients, similarly to below). All 600 patients enrolled were included in the safety analysis set. Of these, 585 patients (295 patients, 290 patients) were included in the FAS and 565 patients (275 patients, 290 patients) were included in the PPS. 33 patients (19 patients, 14 patients) discontinued the study after the start of the study, and 567 patients (283 patients, 284 patients) completed the study.

Of the safety analysis set, 158 adverse events occurred in 106 patients (35.1%) in the Esaxerenone group (302 patients) and 176 adverse events occurred in 112 patients (37.6%) in the Trichlormethiazide group (298 patients), of which 22 side effects occurred in 18 patients (6.0%) in the Esaxerenone group and 38 side effects occurred in 28 patients (9.4%) in the Trichlormethiazide group. 3 serious adverse events (1 each of pneumonia, bladder neoplasm, and pulmonary embolism) were reported by 3 patients (1.0%) in the Esaxerenone group and 3 serious adverse events (1 each of retinal detachment, palpitation, and femur fracture) were reported by 3 patients (1.0%) in the Trichlormethiazide group, but all events were considered unrelated to Esaxerenone and Trichlormethiazide, and no serious side effects occurred. Side effects that occurred in 3 or more patients by Preferred Term were blood potassium increased in 5 patients (1.7%) in the Esaxerenone group, while in the Trichlormethiazide group were hyperuricemia in 8 patients (2.7%), blood uric acid increased in 4 patients (1.3%), and each of hypokalemia, dizziness, and blood potassium decreased in 3 patients (1.0%).

1.Primary endpoints Change from baseline in morning home blood pressure (systolic and diastolic blood pressure): Mean change (SD) from baseline at the end of treatment for systolic blood pressure was -12.0 (10.6) mmHg and -9.5 (9.2) mmHg in the Esaxerenone and Trichlormethiazide groups (similarly to below), and for diastolic blood pressure was -6.3 (5.8) mmHg and -5.6 (5.3) mmHg. The difference between groups (Esaxerenone group - Trichlormethiazide group) in change from baseline in blood pressure at the end of treatment was -2.2 (95% CI: -3.6, -0.8) mmHg for systolic blood pressure (SBP) and -0.6 (95% CI: -1.4, 0.2) mmHg for diastolic blood pressure (DBP), and the upper limit of the two-sided 95% CI was below the non-inferiority margin (systolic blood pressure/diastolic blood pressure = 3.9 mmHg/2.1 mmHg). The result showed the non-inferiority of Esaxerenone to Trichlormethiazide for both SBP and DBP, and superiority for SBP but not for DBP. Similar results showed in the PPS. Therefore, Esaxerenone demonstrated non-inferiority to Trichlormethiazide in its antihypertensive effects based on morning home blood pressure in both FAS and PPS. 2. Main secondary endpoints Change from baseline in bedtime home blood pressure (systolic and diastolic blood pressure): Mean changes (SD) from baseline in bedtime home blood pressure at the end of treatment were -11.1 (10.5) mmHg (95% CI: -12.4, -9.9 mmHg, P<0.0001) and -8.9 (10.1) mmHg (95% CI: -10.1, -7.7 mmHg, P<0.0001) for systolic blood pressure, and -6.2 (6.1) mmHg (95% CI: -6.9, -5.5 mmHg, P<0.0001) and -5.3 (6.4) mmHg (95% CI: -6.1, -4.6 mmHg, P<0.0001) for diastolic blood pressure, all with statistically significant reductions. The PPS had similar results for morning home blood pressure. Change from baseline in office blood pressure (systolic and diastolic blood pressure): Mean change (SD) from baseline in office blood pressure at the end of treatment was -13.0 (13.1) mmHg (95% CI: -14.6,-11.5 mmHg, P<0.0001) and -9.6 (12.7) mmHg (95% CI: - 11.1, - 8.1 mmHg, P<0.0001) for systolic blood pressure in the Esaxerenone and Trichlormethiazide groups (similarly to below) , and -6.4 (8.8) mmHg (95% CI: -7.4, -5.4 mmHg, P<0.0001) and -4.9 (8.6) mmHg (95% CI: -5.9, -3.9 mmHg, P<0.0001) for diastolic blood pressure, that showed significantly reductions. The PPS had similar results for morning home blood pressure. Time course and change rate of UACR: UACR in the Esaxerenone group decreased from Week 4 of the treatment period, and the decreased value was maintained until the end of treatment compared with the baseline value. The mean (SD) baseline value was 116.27(482.31)mg/gCr, the percentage change in geometric mean was -38.9% (95% CI: -45.1, -32.0%, P < 0.0001). The results for the Trichlormethiazide group were generally similar to those for the Esaxerenone group, with the mean (SD) baseline value of 101.35(424.41)mg/gCr, the percentage change in geometric mean of -41.9% (95% CI: -46.9, -36.4%, P < 0.0001). Change and change rate of NT-proBNP: The mean (SD) NT-proBNP at baseline was 109.49(308.62) pg/mL in the Esaxerenone group. Mean changes(SD) from baseline at Week 12 was -33.09(243.79)pg/mL and change rate from baseline at Week 12 was -18.08%(95% CI: -30.00, -4.14%, p value=0.0131),which showed significantly reductions. The mean (SD) NT-proBNP at baseline was 83.84(147.38) pg/mL in the Trichlormethiazide group. Mean changes(SD) from baseline at week 12 was -9.53(91.34)pg/mL and change rate from baseline at Week 12 was -22.66% (95% CI: -33.29, -10.34%, p value=0.0007), which showed significantly reductions. Change in serum potassium levels, uric acid levels and eGFRcreat: Serum K levels increased over the first 2 weeks after starting Esaxerenone treatment, then gradually decreased up to Week 12. Serum K levels gradually decreased up to Week 12 in the Trichlormethiazide group. The percentages of patients with serum K levels <3.5 mEq/L, >=5.5 mEq/L, and>=6.0 mEq/L were 3.1%, 2.0%, and 0% in the Esaxerenone group and 11.5%, 0.7%, and 0% in the Trichlormethiazide group, respectively. Uric acid levels increased over the first 2 weeks, then remained constant until Week 12 in both groups. The percentages of patients with uric acid levels >7.0 mg/dL were 27.5% and 34.6% in the Esaxerenone and the Trichlormethiazide groups, respectively. eGFRcreat decreased over the first 2 weeks and remained constant until Week 12 in both groups. Mean changes (SD) from baseline at Week 12 was -7.08(8.61)mL/min/1.73 m2 in the Esaxerenone group and -4.67(9.84)mL/min/1.73 m2 in the Trichlormethiazide group, respectively.

Compared with the treatment of Trichlormethiazide, morning home blood pressure showed superiority for systolic blood pressure and non-inferiority for diastolic blood pressure, when Esaxerenone was administered to patients with essential hypertension inadequately controlled with an ARB or a CCB, and finally, the non-inferiority of Antihypertensive efficacy for morning home blood pressure was confirmed.

Nov. 01, 2024

July. 23, 2024

https://pubmed.ncbi.nlm.nih.gov/39039285/ https://pubmed.ncbi.nlm.nih.gov/39394512/

Yes

The datasets generated and/or analyzed during the current study will be available from the corresponding author and Daiichi Sankyo.Co.,Ltd. on reasonable request.

https://jrct.mhlw.go.jp/latest-detail/jRCTs031220372

Kario Kazuomi

Jichi Medical University (Jichi Medical University Hospital)

3311-1, Yakushiji, Shimotsuke City, Tochigi

kkario@jichi.ac.jp

Kario Kazuomi

Jichi Medical University

3311-1, Yakushiji, Shimotsuke City, Tochigi

+81-285-44-2111

kkario@jichi.ac.jp

Complete

Oct. 07, 2022

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

Patients will be included if they meet all of the following inclusion criteria:
1) Patients (=> 20 year of age) at the time of informed consent
2) Hypertensive patients treated with an antihypertensive drug (ARB or CCB) *1
3) Patients with a mean systolic blood pressure =>125 mmHg and/or diastolic blood pressure =>75mmHg in the last 5 days of early morning home blood pressure measured by a brachial phygmomanometer.
However, elderly people aged 75 years or older*2, patients with cerebrovascular disease, and patients with CKD (proteinuria negative) can be registered with systolic blood pressure =>135 mm Hg and/or diastolic blood pressure =>85 mm Hg.

*1:In principle, hypertensive patients who are taking an antihypertensive drug (ARB or CCB) for at least 4 weeks prior to the start of the observation period are eligible.
*2: if tolerated, registration with criteria of systolic blood pressure greater than 125 mmHg and/or diastolic blood pressure greater than 75 mmHg is acceptable.

Patients who meet any of the following criteria will be excluded:
1) Patients diagnosed with secondary hypertension (endocrine hypertension, etc.)
2) Hyperkalemia patients or patients with serum potassium level over 5.0 mEq/L
3) Patients with hyponatremia or hypokalemia
4) Patients with severe renal impairment (eGFRcreat< 30 mL/min/1.73m2)
5) Patients with acute renal failure or anuria
6) Patients with a history of hypersensitivity to esaxerenone or thiazide diuretics
7) Pregnant, possibly pregnant, breast-feeding or planning to become pregnant
8) Patients who are inappropriate for this study judged by primary investigators

Both

Patients with essential hypertension inadequately controlled with ARB or CCB

[Dosage and administration of the research drug]
Esaxerenone is given orally once daily. The initial daily doses will be started at 2.5 mg and titrated to 5 mg if the effect is insufficient.
Patients with moderate renal dysfunction (eGFRcreat is 30 or more and less than 60 mL.min/1,73m2) and diabetic patients with albuminuria or proteinuria should start with 1.25mg of esaxerenone, and the dose is increased to 2.5 mg after 4 week of the administration period, depending on the patient's condition including serum potassium level. If the effect is insufficient, the dose can be increased to 5 mg.

[Dosage and administration of the research drug (Comparator drug)]
Trichlormethiazide is given orally, 2-8 mg per day divided into 1-2 doses. The dosage may be adjusted depending on patient's age and symptoms.
However, when used for hypertension, start with a small dose and gradually increase the dose.

Hypertension

Change from baseline in morning home blood pressure (systolic and diastolic blood pressure)

1.Efficacy
1) Change from baseline in office blood pressure and bedtime home blood pressure (systolic and diastolic blood pressure)
2) Changes in each blood pressure (office, morning home and bedtime home(systolic and diastolic blood pressure))
3) Achieving rate of target blood pressure (office, morning home and bedtime home(systolic and diastolic blood pressure))
4) Change, %change from baseline and change from baseline in UACR
5) Change and change from baseline in urinary biomarkers (Na,K,Cr and Na/K)

2.Safety
1) Adverse events (event name, number of events and incidence rate)
2) Change and Change from baseline in eGFRcreat,uric acid and blood electrolytes (Na,K,Ca,and Cl)
3) Change in laboratory test values(HbA1c,blood glucose,triglycerides,T-Cho,LDL-C and HDL-C)
4) Percentage of study subjects with serum potassium levels:less than 3.5 mEq/L ,5.5 mEq/L or more,6.0 mEq/L or more
5) Percentage of study subjects with uric acid level:exceeds 7.0mg/dL

+81-3-3470-3360

Sept. 12, 2022

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