Rationale and Design of a Randomized, Open‐Label, Parallel‐Group Study of Esaxerenone Versus Angiotensin Receptor Blockers in Older Patients With Uncontrolled Hypertension on Calcium Channel Blocker Monotherapy (ESCORT‐HT)
Background In Japan, the prevalence of hypertension is high and expected to increase further as the population continues to age . The mortality rate for hypertension‐related cerebrovascular disorders remains high, albeit with a decreasing trend . Effective blood pressure (BP) control is essential to prevent cardiovascular and cerebrovascular events , particularly among the older population . Despite the wide availability of various antihypertensive agents, adequate BP control is not always achieved . In the Japanese Society of Hypertension (JSH) 2019 Guidelines for the Management of Hypertension , the choices of BP‐lowering drugs, including combination treatment, are the same for both older and younger patients, with an emphasis on angiotensin II receptor blockers (ARBs), angiotensin‐converting enzyme inhibitors, calcium channel blockers (CCBs), and thiazide diuretics as first‐line treatments. In Japanese clinical practice, ARBs and CCBs are the most commonly prescribed BP‐lowering drugs, with ARBs and CCBs often serving as first‐ and second‐line treatments, respectively, for older Japanese patients with hypertension . However, it has been reported that the antihypertensive effect of ARBs decreases in older patients as renin activity declines . Therefore, effective and safe treatment options are needed to manage hypertension and extend healthy life expectancy among the Japanese older population. Mineralocorticoid receptor blockers (MRBs) have been suggested to be effective for older patients with systolic hypertension and low renin activity . However, the JSH 2019 Guidelines for the Management of Hypertension recommend the use of MRBs as fourth‐line treatment in combination with other antihypertensive agents . The guidelines recommend MRBs for patients with treatment‐resistant hypertension, those unresponsive to first‐line and combination treatments with two or three agents, and those with low‐renin hypertension or secondary hypertension . Esaxerenone is a next‐generation nonsteroidal MRB with higher selectivity and potency, longer half‐life, and more favorable bioavailability compared with other MRBs . The EXCITE‐HT study demonstrated that the morning home BP‐lowering effect of esaxerenone was noninferior to that of trichlormethiazide in patients with uncontrolled essential hypertension receiving an ARB or CCB . Furthermore, a prespecified subanalysis of EXCITE‐HT showed that the morning home BP‐lowering effect of esaxerenone was noninferior to that of trichlormethiazide, regardless of the basal antihypertensive agent used (ARB or CCB) . Another study reported that the ARB/CCB combination was superior to the diuretic/ARB combination in patients with uncontrolled nocturnal hypertension . However, it remains unclear whether esaxerenone is noninferior to ARBs as a second‐line agent with CCBs in terms of its BP‐lowering effect. The present study was designed to evaluate the efficacy of esaxerenone as second‐line treatment for hypertension and to determine whether its BP‐lowering effect is noninferior to that of ARBs in older patients with uncontrolled hypertension on CCB monotherapy. The safety of esaxerenone and ARBs will also be compared. 

Methods 2.1 Study Design ESCORT‐HT is a multicenter, randomized, ARB‐controlled, open‐label, parallel‐group study. The study design is illustrated in Figure . The study will be conducted at 48 sites between November 2024 and August 2026 (planned) (Table ). Patients will be randomly assigned in a 1:1 ratio to receive either esaxerenone or an ARB (control), using a block allocation method according to BP measurement and age. The study protocol was approved by the Certified Review Board of Hattori Clinic (CRB3180027). 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 was registered at the Japan Registry of Clinical Trials on August 27th, 2024, under the identifier jRCTs031240300 ( https://jrct.niph.go.jp/en‐latest‐detail/jRCTs031240300 ). 2.2 Study Participants Full inclusion and exclusion criteria are shown in Table . Patients aged ≥65 years, with previous treatment with a CCB (amlodipine 2.5 or 5 mg) as a basal BP‐lowering drug at the same dose for ≥4 weeks before registration, and with a mean morning home systolic BP (SBP) ≥135 mmHg as measured by brachial sphygmomanometer 5 days before registration will be included. Key exclusion criteria are as follows: patients with secondary hypertension (including endocrine hypertension); hyperkalemia or serum potassium >4.8 mmol/L; renal dysfunction (estimated glomerular filtration rate [eGFR] <45 mL/min/1.73 m 2 ); very poor bile secretion or severe hepatic impairment; and/or history of serious adverse reactions to esaxerenone or ARBs. 2.3 Study Schedule and Interventions After a 4‐week run‐in period, esaxerenone or an ARB will be additionally administered to patients receiving treatment with a CCB (Figure ). In accordance with the Japanese package insert , after a 4‐week treatment period, patients with an eGFR 45–<60 mL/min/1.73 m 2 or those with diabetes mellitus and albuminuria at baseline will receive a starting esaxerenone dose of 1.25 mg/day, as shown in Figure . The dose can be increased to 2.5 mg/day at 4 and 8 weeks, as judged by the attending physician based on the achievement of target BP and serum potassium level (<5.0 mmol/L). Patients other than the above will receive an esaxerenone starting dose of 2.5 mg/day. After increasing to the standard dose, patients will not be allowed to decrease the dose below the standard dose or to receive the maximum dose. The Guidelines for the Treatment of Hypertension in the Elderly state that the BP‐lowering effect should be gradual, taking into account safety considerations for older people, and this was used as a reference for the doses in this study . In the ARB group, patients will receive one ARB at the standard dose (azilsartan, irbesartan, olmesartan medoxomil, candesartan cilexetil, telmisartan, valsartan, or losartan potassium) once daily in accordance with the corresponding Japanese package insert. An overview of the dosing regimen is shown in Figure . Patients will continue to receive their basal BP‐lowering drug (CCB; amlodipine) at a constant dose until the end of treatment (EOT). Details regarding concomitant treatment and discontinuation criteria are included in the Supporting Information. 2.4 Study Measurements Study participants will measure their home BP twice daily (in the morning and at bedtime) using an HCR‐7501T digital upper arm sphygmomanometer (OMRON Healthcare Co., Ltd., Kyoto, Japan). Further details are provided in the Supporting Information. Office BP measurements will be taken twice per the JSH 2019 Guidelines at baseline; 2, 4, 8, and 12 weeks; and discontinuation . The average of both measurements taken at each timepoint will be recorded. Additional measurements will be taken at 6 and 10 weeks if the esaxerenone dose is increased at 4 and 8 weeks, respectively. Blood and urine samples will be taken to measure serum and urinary biomarkers such as serum N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) and urinary albumin‐to‐creatinine ratio (UACR). Additional details of biomarker measurements and target BP levels are provided in the Supporting Information. 2.5 Study Endpoints The primary efficacy endpoint will be the change from baseline in morning home SBP at EOT. Secondary endpoints will include the change from baseline at EOT and time‐course change in morning home, bedtime home, and office SBP/diastolic BP (DBP); achievement rate of target BP levels; change and percentage change from baseline in UACR and NT‐proBNP; change from baseline in plasma aldosterone concentration, plasma renin activity, and aldosterone–renin ratio; and change from baseline and time‐course change in urinary biomarkers (sodium, potassium, creatinine, and sodium/potassium ratio). Safety endpoints will include treatment‐emergent adverse events (TEAEs); change from baseline and time‐course change in eGFR and serum potassium levels; time‐course change in hemoglobin A1c; and the proportion of patients with a serum potassium level ≥5.5 and ≥6.0 mmol/L. 2.6 Sample Size and Statistical Analyses The target sample size is set at 380, which will provide sufficient statistical power (≥80% power, 2.5% one‐sided type 1 error probability) to determine if the morning home SBP‐lowering effect of esaxerenone from baseline to EOT is noninferior to that of ARBs. In a clinical study of ARB/CCB combination treatment (irbesartan/amlodipine besilate) , the difference in the change in SBP from baseline to 8 weeks (amlodipine 5 mg plus irbesartan group − amlodipine alone group) was −7.65 mmHg. The noninferiority margin was set to 3.8 mmHg, which corresponds to the absolute value of one half of the effect, considering it the smallest difference that could be considered clinically noninferior. Based on these assumptions, a minimum of 174 patients are required to adequately power a noninferiority trial. Considering an estimated drop‐out rate of 10%, the target sample size was set at 190 per treatment group. The full analysis set (FAS) is defined as all enrolled patients receiving at least one dose of the study drug and with efficacy endpoint measurements recorded for at least one timepoint. The per‐protocol set (PPS) is defined as the FAS population with full adherence to the study protocol. The safety analysis set is defined as all enrolled patients receiving at least one dose of the study drug. For the primary objective of evaluating the noninferiority of esaxerenone to ARBs in the primary efficacy endpoint, the FAS will be used for the main analysis and the PPS will be used for an ancillary analysis. The BP‐lowering effect of esaxerenone will be considered noninferior to that of ARBs if the upper limit of the two‐sided 95% confidence interval (CI) for the difference in SBP change between esaxerenone and ARB is <3.8 mmHg. If the upper limit of the two‐sided 95% CI is <0, the BP‐lowering effect of esaxerenone will be considered superior. For the primary endpoint, the least squares mean change (95% CI) in morning home BP and the point estimate of the between‐group difference (95% CI) will be calculated using an analysis of covariance model with baseline BP, SBP (≥145 and <145 mmHg), and baseline age (≥75 and <75 years) as covariates. Multiplicity adjustments will only be made for the primary endpoint, and the superiority of esaxerenone to ARBs will only be tested after confirming the noninferiority. Paired t ‐tests will be used to compare the 95% CIs for change and geometric percentage change from baseline for each secondary efficacy endpoint. The proportion of patients who achieve the target BP levels and their 95% CIs will be calculated. Missing BP values at EOT will be imputed by the last observation carried forward method using data from 4 weeks onward. Data will not be imputed for patients with missing data before 4 weeks of treatment. TEAEs will be coded by System Organ Class and Preferred Term using the Medical Dictionary for Regulatory Activities, Japanese version J 27.0. 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., Cary, NC, USA). 

Study Design ESCORT‐HT is a multicenter, randomized, ARB‐controlled, open‐label, parallel‐group study. The study design is illustrated in Figure . The study will be conducted at 48 sites between November 2024 and August 2026 (planned) (Table ). Patients will be randomly assigned in a 1:1 ratio to receive either esaxerenone or an ARB (control), using a block allocation method according to BP measurement and age. The study protocol was approved by the Certified Review Board of Hattori Clinic (CRB3180027). 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 was registered at the Japan Registry of Clinical Trials on August 27th, 2024, under the identifier jRCTs031240300 ( https://jrct.niph.go.jp/en‐latest‐detail/jRCTs031240300 ). 

Study Participants Full inclusion and exclusion criteria are shown in Table . Patients aged ≥65 years, with previous treatment with a CCB (amlodipine 2.5 or 5 mg) as a basal BP‐lowering drug at the same dose for ≥4 weeks before registration, and with a mean morning home systolic BP (SBP) ≥135 mmHg as measured by brachial sphygmomanometer 5 days before registration will be included. Key exclusion criteria are as follows: patients with secondary hypertension (including endocrine hypertension); hyperkalemia or serum potassium >4.8 mmol/L; renal dysfunction (estimated glomerular filtration rate [eGFR] <45 mL/min/1.73 m 2 ); very poor bile secretion or severe hepatic impairment; and/or history of serious adverse reactions to esaxerenone or ARBs. 

Study Schedule and Interventions After a 4‐week run‐in period, esaxerenone or an ARB will be additionally administered to patients receiving treatment with a CCB (Figure ). In accordance with the Japanese package insert , after a 4‐week treatment period, patients with an eGFR 45–<60 mL/min/1.73 m 2 or those with diabetes mellitus and albuminuria at baseline will receive a starting esaxerenone dose of 1.25 mg/day, as shown in Figure . The dose can be increased to 2.5 mg/day at 4 and 8 weeks, as judged by the attending physician based on the achievement of target BP and serum potassium level (<5.0 mmol/L). Patients other than the above will receive an esaxerenone starting dose of 2.5 mg/day. After increasing to the standard dose, patients will not be allowed to decrease the dose below the standard dose or to receive the maximum dose. The Guidelines for the Treatment of Hypertension in the Elderly state that the BP‐lowering effect should be gradual, taking into account safety considerations for older people, and this was used as a reference for the doses in this study . In the ARB group, patients will receive one ARB at the standard dose (azilsartan, irbesartan, olmesartan medoxomil, candesartan cilexetil, telmisartan, valsartan, or losartan potassium) once daily in accordance with the corresponding Japanese package insert. An overview of the dosing regimen is shown in Figure . Patients will continue to receive their basal BP‐lowering drug (CCB; amlodipine) at a constant dose until the end of treatment (EOT). Details regarding concomitant treatment and discontinuation criteria are included in the Supporting Information. 

Study Measurements Study participants will measure their home BP twice daily (in the morning and at bedtime) using an HCR‐7501T digital upper arm sphygmomanometer (OMRON Healthcare Co., Ltd., Kyoto, Japan). Further details are provided in the Supporting Information. Office BP measurements will be taken twice per the JSH 2019 Guidelines at baseline; 2, 4, 8, and 12 weeks; and discontinuation . The average of both measurements taken at each timepoint will be recorded. Additional measurements will be taken at 6 and 10 weeks if the esaxerenone dose is increased at 4 and 8 weeks, respectively. Blood and urine samples will be taken to measure serum and urinary biomarkers such as serum N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) and urinary albumin‐to‐creatinine ratio (UACR). Additional details of biomarker measurements and target BP levels are provided in the Supporting Information. 

Study Endpoints The primary efficacy endpoint will be the change from baseline in morning home SBP at EOT. Secondary endpoints will include the change from baseline at EOT and time‐course change in morning home, bedtime home, and office SBP/diastolic BP (DBP); achievement rate of target BP levels; change and percentage change from baseline in UACR and NT‐proBNP; change from baseline in plasma aldosterone concentration, plasma renin activity, and aldosterone–renin ratio; and change from baseline and time‐course change in urinary biomarkers (sodium, potassium, creatinine, and sodium/potassium ratio). Safety endpoints will include treatment‐emergent adverse events (TEAEs); change from baseline and time‐course change in eGFR and serum potassium levels; time‐course change in hemoglobin A1c; and the proportion of patients with a serum potassium level ≥5.5 and ≥6.0 mmol/L. 

Sample Size and Statistical Analyses The target sample size is set at 380, which will provide sufficient statistical power (≥80% power, 2.5% one‐sided type 1 error probability) to determine if the morning home SBP‐lowering effect of esaxerenone from baseline to EOT is noninferior to that of ARBs. In a clinical study of ARB/CCB combination treatment (irbesartan/amlodipine besilate) , the difference in the change in SBP from baseline to 8 weeks (amlodipine 5 mg plus irbesartan group − amlodipine alone group) was −7.65 mmHg. The noninferiority margin was set to 3.8 mmHg, which corresponds to the absolute value of one half of the effect, considering it the smallest difference that could be considered clinically noninferior. Based on these assumptions, a minimum of 174 patients are required to adequately power a noninferiority trial. Considering an estimated drop‐out rate of 10%, the target sample size was set at 190 per treatment group. The full analysis set (FAS) is defined as all enrolled patients receiving at least one dose of the study drug and with efficacy endpoint measurements recorded for at least one timepoint. The per‐protocol set (PPS) is defined as the FAS population with full adherence to the study protocol. The safety analysis set is defined as all enrolled patients receiving at least one dose of the study drug. For the primary objective of evaluating the noninferiority of esaxerenone to ARBs in the primary efficacy endpoint, the FAS will be used for the main analysis and the PPS will be used for an ancillary analysis. The BP‐lowering effect of esaxerenone will be considered noninferior to that of ARBs if the upper limit of the two‐sided 95% confidence interval (CI) for the difference in SBP change between esaxerenone and ARB is <3.8 mmHg. If the upper limit of the two‐sided 95% CI is <0, the BP‐lowering effect of esaxerenone will be considered superior. For the primary endpoint, the least squares mean change (95% CI) in morning home BP and the point estimate of the between‐group difference (95% CI) will be calculated using an analysis of covariance model with baseline BP, SBP (≥145 and <145 mmHg), and baseline age (≥75 and <75 years) as covariates. Multiplicity adjustments will only be made for the primary endpoint, and the superiority of esaxerenone to ARBs will only be tested after confirming the noninferiority. Paired t ‐tests will be used to compare the 95% CIs for change and geometric percentage change from baseline for each secondary efficacy endpoint. The proportion of patients who achieve the target BP levels and their 95% CIs will be calculated. Missing BP values at EOT will be imputed by the last observation carried forward method using data from 4 weeks onward. Data will not be imputed for patients with missing data before 4 weeks of treatment. TEAEs will be coded by System Organ Class and Preferred Term using the Medical Dictionary for Regulatory Activities, Japanese version J 27.0. 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., Cary, NC, USA). 

Discussion MRBs, including esaxerenone, are currently recommended as a fourth‐line treatment for hypertension based on the JSH 2019 Guidelines . Previous clinical studies have demonstrated the BP‐lowering and organ‐protective effects of esaxerenone when administered as second‐ or third‐line treatment in patients with uncontrolled hypertension [ , , , , , , ]. The recent EXCITE‐HT study demonstrated the noninferiority of esaxerenone to trichlormethiazide in lowering morning home BP as a second‐line treatment in patients with uncontrolled essential hypertension receiving an ARB or CCB , regardless of the basal antihypertensive agent used . Notably, the EXCITE‐HT study also showed that the morning home SBP‐lowering effect of esaxerenone was superior to that of trichlormethiazide , same as for ARBs , although it did not show superiority for lowering morning home DBP. The ESCORT‐HT study is designed to evaluate the effectiveness of esaxerenone as a second‐line antihypertensive treatment by verifying its noninferiority to ARBs in older patients with uncontrolled hypertension on CCB monotherapy. The prevalence of hypertension in older people is high, and hypertension significantly contributes to the development of cerebrovascular disease in this population. The antihypertensive treatment options for older patients are generally the same as those for younger patients. In Japan, CCBs are often administered as first‐line treatment for older patients with hypertension, due to their low metabolic effect, reliable antihypertensive effects regardless of demographic factors, and ease of use for older patients . However, only approximately 40% of patients achieve target BP levels with CCB monotherapy . ARBs are assumed to provide organ‐protective effects in addition to lowering BP , but they are also associated with adverse effects, including aldosterone breakthrough after long‐term use and serum potassium elevation . Aldosterone breakthrough was observed in 30%–50% of patients with hypertension undergoing long‐term treatment with renin–angiotensin system inhibitors, in whom the production of aldosterone increased as a compensatory mechanism leading to higher plasma aldosterone levels . Furthermore, renin activity decreases in older patients , sometimes attenuating the antihypertensive effect of ARBs and leading to insufficient BP control. This highlights the need for another antihypertensive drug to be used in combination with CCBs to replace ARBs. A pooled analysis of seven Phase 3 clinical trials suggested that esaxerenone has a stronger antihypertensive effect (office DBP‐lowering) in older patients (≥65 years) compared with younger patients (<65 years) . In another pooled analysis, esaxerenone showed a consistent home BP‐lowering effect regardless of older age with no increased risk of hyperkalemia . Change in UACR was also reduced in both esaxerenone and trichlormethiazide groups regardless of age but was numerically greater in patients aged ≥65 years. Therefore, the noninferiority of esaxerenone to ARBs in its BP‐lowering effect will be verified in the ESCORT‐HT study. In the ESCORT‐HT study, morning home BP will be used as an index for the primary endpoint. Morning home BP, rather than office BP, is more closely associated with cardiovascular events [ , , , , ]. Furthermore, the JSH 2019 Guidelines recommend the use of home BP measurements to evaluate the efficacy of antihypertensive drugs . Home BP measurements are considered more variable than office BP measurements. Therefore, in the ESCORT‐HT study, morning home BP will be measured twice daily, and the average of the last 5 days will be used. 3.1 Limitations Patients previously treated with CCBs other than amlodipine will not be included. ARBs will be prescribed by physicians under real‐world clinical conditions based on the most appropriate drug for each patient, potentially leading to bias. 

Limitations Patients previously treated with CCBs other than amlodipine will not be included. ARBs will be prescribed by physicians under real‐world clinical conditions based on the most appropriate drug for each patient, potentially leading to bias. 

Conclusion The ESCORT‐HT study will assess the noninferiority of esaxerenone to ARBs as a second‐line antihypertensive treatment in older patients with uncontrolled hypertension on CCB monotherapy. The safety profile of esaxerenone will also be evaluated. The findings may contribute to the further development of antihypertensive treatment strategies by clarifying the possible benefits of earlier use of MRBs in hypertension treatment, thus increasing the number of available treatment options for these patients. 

All authors contributed to the study design, drafted the manuscript, and approved the submitted version of the manuscript. Takashi Taguchi and Ayumi Tanabe contributed to planning the statistical analysis. 

The study protocol was approved by the Certified Review Board of Hattori Clinic (CRB3180027). The study will be conducted in accordance with the principles of the Declaration of Helsinki and the Clinical Trials Act in Japan and was registered at the Japan Registry of Clinical Trials on August 27, 2024, under the identifier jRCTs031240300 ( https://jrct.niph.go.jp/en‐latest‐detail/jRCTs031240300 ). 

All participants will be required to provide written informed consent before enrollment. 

Kazuomi Kario received research advisory fees from Daiichi Sankyo Co., Ltd.; grants from Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., MSD K.K., Sumitomo Pharma Co., Ltd., and Nippon Boehringer Ingelheim Co., Ltd.; consulting fees from Sanwa Kagaku Kenkyusho Co., Ltd.; honoraria from Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Novartis Pharma K.K., and Viatris Inc.; and is an advisory board member of Daiichi Sankyo Co., Ltd., and Novartis Pharma K.K. Tomohiro Katsuya received lecture fees from Daiichi Sankyo Co., Ltd., Novartis Pharma K.K., and CureApp Inc. Tatsuo Shimosawa received consultant fees from EPS Corporation, Sekisui Medical Co., Ltd., and EP Mediate Co., Ltd. and lecture fees from Daiichi Sankyo Co., Ltd., Novartis Pharma K.K., and Otsuka Pharmaceutical Co., Ltd. Takashi Taguchi and Ayumi Tanabe are employees of Daiichi Sankyo Co., Ltd. Mitsuru Ohishi received lecture fees from Daiichi Sankyo Co., Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., and Kowa Co., Ltd. 

Supporting Information 

