Rationale and design of a multicenter randomized study comparing the efficacy and safety of esaxerenone versus trichlormethiazide in patients with uncontrolled essential hypertension: EXCITE‐HT study

Abstract

The next‐generation mineralocorticoid receptor blocker (MRB) esaxerenone has favorable antihypertensive effects in patients who do not respond to treatment with first‐line antihypertensive agents and may be beneficial as a second‐line treatment. However, MRBs are currently considered a fourth‐line treatment as there is no clinical evidence comparing the efficacy of esaxerenone with other classes of antihypertensive agents. The multicenter, randomized, open‐label, parallel‐group EXCITE‐HT study will evaluate the efficacy and safety of esaxerenone as a second‐line agent in the treatment of Japanese patients with uncontrolled essential hypertension. After a 4‐week run‐in period, patients will receive either esaxerenone or trichlormethiazide for 12 weeks per the package insert and the Japanese Society of Hypertension Guidelines for the Management of Hypertension. At Weeks 4 and 8, the dose of esaxerenone or trichlormethiazide may be increased. Blood pressure (home [morning and bedtime] and office), serum biomarkers, and urinary biomarkers will be measured. The primary efficacy endpoint is the change from baseline in morning home systolic blood pressure/diastolic blood pressure to the end of treatment. The EXCITE‐HT study is expected to validate the non‐inferiority of esaxerenone to trichlormethiazide and provide the first evidence for the early use of esaxerenone as a second‐line agent in the treatment of Japanese patients with uncontrolled essential hypertension instead of its current use as a fourth‐line agent.

1. INTRODUCTION

Hypertension is associated with an increased risk of both cerebrovascular and cardiovascular events; however, many hypertensive patients have inadequately controlled blood pressure (BP). ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ Per the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019), angiotensin II receptor blockers (ARBs), angiotensin‐converting enzyme inhibitors, calcium channel blockers (CCBs), and thiazide diuretics are recommended as first‐line treatment of patients with hypertension and no compelling indication. ⁹ For patients who do not respond to first‐line treatment, combination treatment with two or three agents is recommended, and for those who still do not respond, treatment with mineralocorticoid receptor blockers (MRBs) are recommended. Thus, MRBs are considered fourth‐line agents, partly because of the limited evidence supporting their effectiveness as antihypertensive agents as opposed to the evidence in the treatment of heart failure.

The next‐generation MRB esaxerenone has superior selectivity, potency, and a longer half‐life than existing MRBs, such as spironolactone and eplerenone. ¹⁰ , ¹¹ To date, esaxerenone has been shown to have favorable antihypertensive effects in patients with a variety of backgrounds, ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ including as a monotherapy or in combination with renin‐angiotensin system inhibitors (RASi) or CCBs in patients with essential hypertension, ¹² , ¹³ , ²¹ and as a second‐ or third‐line agent with RASi and CCBs in hypertensive patients with type 2 diabetes mellitus and albuminuria. ¹⁶ , ¹⁸ , ¹⁹ , ²⁰ Earlier second‐line treatment with esaxerenone may be a beneficial option for hypertensive patients; however, there is currently no clinical evidence comparing esaxerenone with other classes of antihypertensive agents.

The EXCITE‐HT study is designed to evaluate the efficacy and safety of esaxerenone as a second‐line agent in the treatment of Japanese patients with essential hypertension. The study outcomes are the non‐inferiority of esaxerenone to thiazide diuretics in uncontrolled essential hypertensive patients treated with one ARB or CCB.

2. METHODS

2.1. Study design

The EXCITE‐HT study is a multicenter, randomized, open‐label, parallel‐group study comparing esaxerenone with trichlormethiazide in patients with uncontrolled essential hypertension with one ARB or CCB (Figure 1). The study will be conducted at 54 sites between December 2022 and May 2024 (Supplementary Table). Patients will be randomly assigned in a 1:1 ratio to either the esaxerenone group or the control group, using a block allocation method according to the type of basal antihypertensive medication (ARB or CCB), BP value, and age. The study protocol was approved by the Certified Review Board of Hattori Clinic (CRB3180027), and written informed consent will be obtained from patients before enrollment. The study will be conducted in accordance with the principles of the Declaration of Helsinki and the Clinical Trials Act in Japan, and is registered under the identifier jRCTs031220372 (https://jrct.niph.go.jp/en‐latest‐detail/jRCTs031220372).

FIGURE 1.

Design of the multicenter, open‐label, parallel‐group, interventional EXCITE‐HT study. ^aDosage and administration should be in accordance with the instructions in the package insert and the Japanese Society of Hypertension 2019 guidelines. ⁹ , ^{23 b}Includes serum potassium, sodium, calcium, chloride, creatinine, and uric acid. ^cIncludes triglycerides, total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, blood glucose levels, hemoglobin A1c, and NT‐proBNP. ^dSerum biomarker measurements will be taken either at the beginning or at the end of the run‐in period.

2.2. Eligibility criteria

Key eligibility criteria are age of ≥20 years, having received prior basal antihypertensive agents (either one ARB or one CCB) at the same dose for ≥4 weeks prior to registration, and having a mean morning home systolic BP (SBP) of ≥125 mmHg and/or a diastolic BP (DBP) of ≥75 mmHg as measured by a brachial sphygmomanometer in the 5 days prior to registration. Patients aged ≥75 years, and those with cerebrovascular disease or proteinuria‐negative chronic kidney disease have different BP eligibility criteria and will be eligible if they have a mean morning home SBP of ≥135 mmHg and/or a DBP of ≥85 mmHg. If tolerated, patients aged ≥75 years with a morning home SBP of ≥125 mmHg and/or a DBP of ≥75 mmHg may be eligible.

Patients with either secondary hypertension (including endocrine hypertension), hyperkalemia, or serum potassium level of >5.0 mEq/L, hyponatremia or hypokalemia, severe renal dysfunction (estimated glomerular filtration rate [eGFR] of <30 mL/min/1.73 m²), and acute renal failure or anuria will be excluded.

2.3. Study schedule and interventions

Following a 4‐week run‐in period, patients will receive esaxerenone at a starting dose of 2.5 mg/day per the Japanese package insert. ²² After a 4‐week observation period, the dose can be increased to 5 mg/day at either 4 or 8 weeks, as shown in Figure 1. Patients with an eGFR of 30−59 mL/min/1.73 m² or those with diabetes mellitus and albuminuria or proteinuria at baseline will receive a starting esaxerenone dose of 1.25 mg/day. The dose can be increased to 2.5 mg/day at 4 weeks and 5 mg/day at 8 weeks. At Weeks 4 and 8, the physician will determine whether to increase the dose of esaxerenone based on achievement of target BP, serum potassium levels, and occurrence of any adverse events.

Patients in the control group will receive trichlormethiazide at the physician's discretion per the Japanese package insert and the JSH 2019. The package insert recommends that dosage should be started at a small dose and gradually increased for hypertension. The detail of the small dose is described in the JSH 2019, which recommends a daily dose of 1 mg/day or less. ⁹ , ²³ At Weeks 4 and 8, the physician will determine whether to increase or decrease the dose of trichlormethiazide based on achievement of target BP, maximum recommended dose reached of trichlormethiazide per the JSH 2019, serum potassium and sodium levels, and occurrence of any adverse events.

Patients will continue to receive basal antihypertensives (ARBs or CCBs) at a constant dose until the end of treatment (EOT). The dose determination information, criteria for concomitant drug use, and key discontinuation criteria are provided in the Supplementary Methods.

2.4. Study measurements

Home BP will be measured by the patients twice daily in the morning and at bedtime using an HCR‐7501T digital upper arm sphygmomanometer (OMRON Healthcare Co., Ltd., Japan) throughout the study period. Home BP will be automatically measured after 1−2 min of rest while sitting, and all data will be collected electronically. The average of two measurements at each timepoint within the last 5 days before the patient's visit will be recorded. Morning home BP will be measured after urination and within 1 h after waking up, before breakfast, medication, and caffeine intake. Bedtime home BP will be measured before sleeping and at least 1 h after bathing, drinking, and smoking.

The office BP will be measured twice per the JSH 2019 at baseline, Weeks 2, 4, 8, 12, and at discontinuation; the average of the two measurements at each timepoint will be recorded. ⁹ Office BP will be measured following at least 5 min of rest while sitting. Measurements will also be taken at Weeks 6 and 10 if the dose of esaxerenone is increased at Weeks 4 and 8, respectively.

Serum and urinary biomarkers including serum N‐terminal pro brain natriuretic peptide (NT‐proBNP) and urinary albumin‐to‐creatinine ratio (UACR) will be measured. Detailed information is provided in Supplementary Methods.

2.5. Study endpoints

The primary efficacy endpoint is the change from baseline in morning home SBP/DBP to the EOT. The secondary endpoints include the change from baseline in bedtime home and office SBP/DBP to EOT; time‐course change in morning home, bedtime home, and office BP; achievement rate of target BP levels (detailed information is provided in Supplementary Methods) ⁹ ; change and percentage change from baseline in UACR and NT‐proBNP at Week 12; and time‐course change and change from baseline in urinary biomarkers (sodium, potassium, and sodium/potassium ratio [Na/K ratio]) at Week 12. Safety endpoints are treatment‐emergent adverse events (TEAEs); time‐course change and change from baseline in eGFR, uric acid (UA), and blood electrolytes (sodium, potassium, calcium, chloride); change from baseline in clinical laboratory test values (hemoglobin A1c, blood glucose, triglycerides, total cholesterol, low‐density lipoprotein cholesterol, and high‐density lipoprotein cholesterol); the proportion of patients with a serum potassium level of ≤3.5 mEq/L, ≥5.5 mEq/L, and ≥6.0 mEq/L; and the proportion of patients with a UA level of >7.0 mg/dL.

2.6. Sample size and statistical analyses

The target sample size was set to provide sufficient statistical power (≥80% power, 2.5% one‐sided type 1 error probability) to verify that the change in morning home SBP/DBP from baseline to EOT for esaxerenone is non‐inferior to that for trichlormethiazide. We set the target sample size at 270 per treatment group, and the rationale for the sample size is shown in Supplemental methods.

Multiplicity adjustments will be made only for the primary endpoint, and superiority of esaxerenone to trichlormethiazide will be tested only if non‐inferiority has first been verified. The BP‐lowering effect of esaxerenone will be considered non‐inferior if the upper limit of the two‐sided 95% confidence interval (CI) for the difference in both SBP and DBP change between esaxerenone and trichlormethiazide is below 3.9 and 2.1 mmHg, respectively. If the upper limit of the two‐sided 95% CI is below 0, patients treated with esaxerenone will be considered to have a significantly greater reduction in BP than patients treated with trichlormethiazide.

The full analysis set (FAS) will comprise all enrolled patients who have received at least one dose of study drug and have efficacy endpoint measurements recorded for at least one timepoint. The per protocol set (PPS) is defined as FAS patients who adhered to the package insert of study drugs. For the primary objective (non‐inferiority validation of the primary efficacy endpoint), the main analysis will be performed on the FAS, with an ancillary analysis on the PPS. For other efficacy analyses, the FAS will be the primary analysis set, and analyses of the PPS will also be conducted. The safety analysis set will comprise all enrolled patients who have received at least one dose of study drug; TEAEs will be coded by System Organ Class and Preferred Term per the Medical Dictionary for Regulatory Activities, version J.25.1.

Continuous data will be summarized using mean and standard deviation; categorical data will be summarized by number and percentage. For the primary endpoint, the least mean squares and 95% CI of the change in morning home BP will be calculated using an analysis of covariance (ANCOVA) model, with morning home SBP/DBP change from baseline as the objective variable; treatment group as the explanatory variable; and baseline BP, baseline antihypertensive medication, and baseline age as covariates. The same ANCOVA model will determine the point estimate of the between‐group difference in morning home BP and the 95% CIs. The 95% CIs for change and geometric percentage change from baseline for each secondary efficacy endpoint will be calculated and compared using paired t‐tests. The Clopper–Pearson method will calculate 95% CIs for the achievement rate of target BP levels. For BP, the missing values at EOT will be imputed by the last observation carried forward method using data from Week 4 onward. Missing measurements of patients with no data before Week 4 will not be inferred. All statistical analyses will have a two‐sided significance level of 5% (unless otherwise noted) and will be conducted using SAS version 9.4 or higher (SAS Institute Inc., USA).

3. DISCUSSION

In the JSH 2019, MRBs, including esaxerenone, are listed as the fourth‐line antihypertensive agent. ⁹ However, previous phase 3 clinical trials have demonstrated that esaxerenone administered as a second‐line agent exerted a reliable office BP‐lowering effect in uncontrolled hypertensive patients with a variety of backgrounds who have insufficient responses to first‐line antihypertensive agents. ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ Furthermore, the recent post‐marketing clinical studies have also shown that esaxerenone administered as a second‐ or third‐line agent reduced morning home and nighttime BPs in patients with uncontrolled hypertension, achieving 24‐hour BP control. ²⁰ , ²¹ These phase 3 and post‐marketing studies have confirmed not only the antihypertensive effect, but also the organ‐protective effect of esaxerenone, including albuminuria, NT‐proBNP, and cardio‐ankle vascular index‐lowering effects. ¹³ , ¹⁵ , ¹⁶ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²⁴ These findings suggest that esaxerenone has the potential to be an antihypertensive option that can be used earlier than fourth‐line therapy. However, the current evidence is insufficient, with only four randomized controlled studies comparing eplerenone or placebo, ¹² , ¹⁸ , ²⁵ , ²⁶ and without any direct comparisons with first‐line antihypertensive agents. The EXCITE‐HT study has been initiated with the aim of evaluating the non‐inferiority of esaxerenone to thiazide diuretics in uncontrolled essential hypertension treated with ARBs or CCBs. This study will provide the first evidence to further inform the early use of esaxerenone as a second‐line agent in the treatment of Japanese patients with essential hypertension.

Of the first‐line agents in the JSH 2019, ⁹ thiazide diuretics were chosen as the comparator drug in this study based on the actual use of antihypertensive agents in Japan. From many randomized clinical trials and meta‐analyses, thiazide diuretics have been shown to be effective for preventing all types of cardiovascular morbidities and mortality, ²⁷ , ²⁸ and are recommended as one of the first‐line antihypertensive agents in both the United States and European guidelines. ²⁹ , ³⁰ However, thiazide diuretics increase the risk of adverse effects in a dose‐dependent manner, including effects on glucose and lipid metabolism due to worsening insulin resistance, and metabolic effects such as hypokalemia and hyperuricemia. ²⁷ , ³¹ , ³² , ³³ Therefore, the use of “low‐dose” thiazide diuretics is recommended in the JSH 2019. ⁹ Even at low doses, thiazide diuretics have sufficient antihypertensive effect and prevent the occurrence of cerebrovascular and cardiovascular events. ³⁴ However, due to concerns about their adverse effects, CCBs and ARBs are often prescribed as first‐ and second‐line agents in Japan, and diuretics are used as the third and subsequent agents. ³⁵ , ³⁶ , ³⁷ In the study, we employed a design in which esaxerenone and trichlormethiazide were added as a second‐line agent to ARBs or CCBs. The reason for this is that a study design matched to the actual use of antihypertensive medications in Japan could facilitate extrapolation of the study results to clinical practice.

By comparing the antihypertensive effects of esaxerenone and thiazide diuretics against eplerenone, it is possible to predict whether the non‐inferiority of the antihypertensive effect of esaxerenone against trichlormethiazide can be verified. In the ESAX‐HTN study, the non‐inferiority of the antihypertensive effect of 2.5 mg esaxerenone to 50 mg eplerenone was verified, and the study has also shown that the BP change for 5 mg esaxerenone was significantly greater than the change for 50 mg eplerenone. ¹² In contrast, the study comparing 50 mg eplerenone with thiazide diuretics (12.5 mg hydrochlorothiazide or 1 mg trichlormethiazide) in hypertensive patients with albuminuria treated with ARBs found comparable reductions in BP. ³⁸ Another study in hypertensive patients with obesity found that eplerenone was more effective at lowering BP than trichlormethiazide. ³⁹ Although patient background and the number of concomitant antihypertensive agents are different in the ESAX‐HTN study and these diuretics studies, ¹² , ³⁸ , ³⁹ these results suggest that the non‐inferiority in the antihypertensive effect of esaxerenone to thiazide diuretics will be verified in this study.

The present study will also examine the UACR‐lowering effect as well as safety, including effects on glucose, lipid, and UA metabolism. Esaxerenone and thiazide diuretics have a similar mechanism for UACR‐lowering effects, whereby circulating and renal blood flow are reduced by lowering BP; however, esaxerenone is suggested to have another mechanism that involves direct inhibitory action against mineralocorticoid receptors in the kidney. ⁴⁰ Therefore, a comparison of the UACR‐lowering effect may also provide insight into this different mechanism of UACR reduction.

The limitations of this study include the potential bias between the two treatment groups, as patients will be allocated only by basal antihypertensive, BP, and age. Additionally, only one type of diuretic will be evaluated in this study.

4. CONCLUSIONS

The EXCITE‐HT study will provide the first evidence to inform the early use of esaxerenone as a second‐line drug in the treatment of Japanese patients with essential hypertension.

CONFLICTS OF INTEREST STATEMENT

Kazuomi Kario received research grants from A&D Co., Ltd., MSD K.K., Astellas Pharma Inc., OMRON Healthcare, Inc., CureApp, Inc., Taisho Pharma Co., Ltd., Mitsubishi Tanabe Pharma Corp., Nippon Boehringer Ingelheim Co., Ltd., Fukuda Denshi Co., Ltd., Mochida Pharmaceutical Co., Ltd., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Otsuka Holdings Co., Ltd., Sanwa Chemical Co., Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Fukuda Life Tech Tokyo Co., Ltd., Bristol‐Myers Squibb K.K., and Roche Diagnostics K.K.; consulting fees from A&D Co., Ltd., Jimro Co., Ltd., OMRON Healthcare, Inc., CureApp, Inc., Mochida Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Sanwa Chemical Co., Ltd., Terumo Corporation, and Fukuda Denshi Co., Ltd.; honoraria from Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Medtronic Japan Co., Ltd., OMRON Healthcare, Inc., Novartis Pharma K.K., Viatris Inc.; participation on a data safety monitoring board/advisory board from Novartis Pharma K.K., Fukuda Denshi Co., Ltd., Daiichi Sankyo Co., Ltd. Mitsuru Ohishi received honoraria from Daiichi Sankyo Co., Ltd. Tomohiro Katsuya received lecture fees from Daiichi Sankyo Co., Ltd.; honoraria from Novartis Pharma K.K., Takeda Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd.; payment for expert testimony from Takeda Pharmaceutical Co., Ltd., Novartis Pharma K.K.; support for travel expenses from Takeda Pharmaceutical Co., Ltd., Novartis Pharma K.K., AstraZeneca K.K. Takashi Taguchi, Ayumi Tanabe, and Kotaro Sugimoto are employees of Daiichi Sankyo Co., Ltd. Tatsuo Shimosawa received honoraria from Novartis Pharma K.K., Taisho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd.

PATIENT CONSENT

Written informed consent will be obtained from patients before enrollment.

CLINICAL TRIAL REGISTRATION

The study was registered on October 7, 2022 under the identifier jRCTs031220372 (https://jrct.niph.go.jp/en‐latest‐detail/jRCTs031220372).

Supporting information

Supporting Information

Kario K, Ohishi M, Katsuya T, et al. Rationale and design of a multicenter randomized study comparing the efficacy and safety of esaxerenone versus trichlormethiazide in patients with uncontrolled essential hypertension: EXCITE‐HT study. J Clin Hypertens. 2023;25:861–867. 10.1111/jch.14705

DATA AVAILABILITY STATEMENT

The anonymized data underlying the results presented in this manuscript may be made available to researchers upon submission of a reasonable request to the corresponding author. The decision to disclose the data will be made by the corresponding author and the funder, Daiichi Sankyo Co., Ltd. Data disclosure can be requested for 36 months from article publication.