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Efficacy and Safety of Esaxerenone in hypertensive patients with diabetic kidney disease : a single-arm, open-label study. (EX-DKD study)

EX-DKD study (EX-DKD study)

113

Overall in the Full Analysis Set (FAS) (109 subjects), the number of men (59 subjects) and women (50 subjects) was similar, with mean age (SD) was 72.6 (7.0) years (range: 49 to 84 years), mean weight (SD) at the end of observation period was 63.94 (12.25) kg, mean BMI was 25.04 (3.79) kg/m2, mean duration of hypertension (SD) was 10.72 (7.85) years, and mean duration of type 2 diabetes was 11.16 (8.27) years. The majority of subjects (67.0%) had treated with ACEi or ARB + CCB at baseline. Mean baseline SBP/DBP (SD) were 135.6 (12.1)/75.9 (9.3) mmHg for home BP (early morning), 129.3 (13.8)/71.0 (10.0) mmHg for home BP (bedtime), and 144.7 (10.8)/76.1 (9.6) mmHg for office BP. By albuminuria category (albuminuria: negative, 45 subjects; positive, 64 subjects), more men (67.2%) was included in the albuminuria (+) group. Also, subjects in the albuminuria (+) group had higher SBP (home and office BP), higher UACR and so on at baseline.

Enrollment had started since February 2020 and finished in July 2021. The follow-up period for all subjects was finished in October 2021. Disposition of subjects is shown below. Enrolled: 113 subjects (Albuminuria category 1, negative 46 subjects and positive 67 subjects; Albuminuria category 2, normal urine [A1] 46 subjects, microalbuminuria [A2] 43 subjects, and overt albuminuria [A3] 24 subjects). Esaxerenone treated: 112 subjects (Albuminuria category 1, negative 46 subjects and positive 66 subjects; Albuminuria category 2, A1 46 subjects, A2 42 subjects, and A3 24 subjects). Completed: 95 subjects (Albuminuria category 1, negative 39 subjects and positive 56 subjects; Albuminuria category 2, A1 39 subjects, A2 34 subjects, and A3 22 subjects). Safety Analysis Population: 112 subjects Full Analysis Set (FAS): 109 subjects Population following label instructions of esaxerenone: 109 subjects

In the Safety Analysis Population (112 subjects), 26 subjects (23.2%) experienced a total of 41 events, and 8 subjects (7.1%) of them experienced 9 events which related to esaxerenone (ADR). No serious study-related adverse events were reported. The PT of ADRs were hyperkalaemia (2 subjects), eyelid oedema and tinnitus (occurred in a same subject), salivary gland neoplasm (Verbatim term: left parotid tumour), dizziness, palpitations, dermal cyst, and blood potassium increased (1 subject each). All the above events, except for one dizziness, occurred in subjects with normal urine. Three subjects had 5.5 mEq/L or more of serum potassium levels, but no subjects reported 6.0 mEq/L or more.

Primary efficacy endpoint: In the FAS, overall mean (SD) change from baseline at the end of treatment for home BP (early morning) was -11.6 (9.2) mmHg (95% CI: -13.3, -9.8 mmHg, P < 0.001) for SBP and -5.2 (5.4) mmHg (95% CI: -6.2, -4.2 mmHg, P < 0.001) for DBP, which demonstrated statistically significant reduction in both SBP/DBP. By albuminuria category, the mean change from baseline also showed clinically meaningful reductions in SBP with approximately -10 mmHg in either group of subjects with normal urine (A1), microalbuminuria (A2), and overt albuminuria (A3). The change from baseline in DBP was similar to overall results in all A1 to A3 groups. Major secondary efficacy endpoints: Similar to the primary results, statistically significant reduction was observed in both SBP/DBP at the end of treatment for home BP (bedtime) and office BP. The home BP (early morning and bedtime) and office BP were generally decreasing tendency overtime throughout the 12-week treatment period regardless of albuminuria positivity or severity. In addition, substantial reduction in UACR was observed at the end of treatment in subjects with albuminuria (especially in A3), with -327.82 (SD: 267.64) mg/gCr and -63.6% (95% CI: -75.1, -46.7%) for change and percent change from baseline in UACR, respectively.

In hypertensive patients with DKD inadequately controlled by RASi or RASi plus CCB, esaxerenone demonstrated a BP-lowering effect and improvement in albuminuria. The beneficial effects were consistent regardless of the severity of albuminuria. Additionaly, esaxerenone can be used safely without clinically relevant serum potassium elevation and eGFR reduction. Esaxerenone may be a suitable antihypertensive treatment option for hypertensive patients with DKD with moderately renal impairment.

May. 10, 2022

Sept. 07, 2022

https://pubmed.ncbi.nlm.nih.gov/36070133/

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/jRCTs061190027

Wada Jun

Okayama University Hospital

2-5-1 Shikata-cho, Kita-ku, Okayama

junwada@okayama-u.ac.jp

Uchida Haruhito

Okayama University Hospital

2-5-1 Shikata-cho, Kita-ku, Okayama

+81-86-235-7234

hauchida@okayama-u.ac.jp

Complete

Dec. 27, 2019

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1) Subjects aged 20 to 85 years at informed consent
2) Patients with type 2 diabetes and HbA1c < 9.0%
3) UACR < 30 mg/gCr, or 30 =< UACR < 1,000 mg/gCr
4) Patients with 30 mL/min/1.73 m2 =< eGFRcreat < 60 mL/min/1.73 m2
5) Patients treated with ACEi or ARB, or, ACEi or ARB + CCB
6) Subjects with hypertension (Office blood pressure: 130 mmHg =< Sitting SBP < 180 mmHg and/or 80 mmHg =< Sitting DBP < 110 mmHg
7) Patients who are able to measure home BP

1) Secondary hypertension or malignant hypertension
2) Patients with type 1 diabetes
3) Patients with diabetes due to other specific mechanisms or diseases (Pancreatic exocrine disease, endocrine disease, etc.)
4) Patients diagnosed with non-diabetic nephropathy, AND, whose prescription for steroid or immunosuppressive medication had been modified within 3 months prior to obtaining the signed informed consent, OR, will have their medication adjusted within the next 4 months (e.g. glomerulonephritis, lupus nephritis).
5) Patients with nephrotic syndrome and active nephritis
6) Patients with rapid exacerbation of kidney disease (serum Cr level increased by 50% or more)
7) Patients with comorbidity or history of orthostatic hypotension
8) Patients with a history of serious adverse events to esaxerenone, spironolactone, eplerenone, RA inhibitors or Ca antagonists
9) Hyperkalemia patients, patients whose serum potassium level exceeds 5.0 mEq/L, etc.
10) Patients who are or will be participating in clinical trials with intervention
11) Pregnant, possibly pregnant, breast-feeding or planning to become pregnant during the study
12) Patients whose Ankle-Brachial-Index is =< 0.9 and with symptoms caused by Arteriosclerosis obliterans
13) Patients with cerebrocardiovascular disease
14) Patients with severe liver dysfunction (liver failure, cirrhosis, etc.)
15) Patients diagnosed with life expectancy within one year due to some disease
16) Patients with a history of serious drug allergies
17) Patients who are inappropriate for this study judged by their primary physicians because of some reasons

Both

Hypertensive patients with diabetic kidney disease

Esaxerenone is given orally once daily. The initial daily doses will be started at 1.25 mg and titrated to 2.5 mg or 5 mg depending on the patient's condition.

DKD, Hypertension

Esaxerenone

Change from baseline in blood pressure (home BP [early morning]: systolic BP, diastolic BP) in the sitting position

1. Efficacy
1) Change from baseline in blood pressure (office BP and home BP[bedtime]: SBP, DBP) in the sitting position
2) Trend of change from baseline in blood pressure (office BP and home BP [before early morning medication and bedtime ]: systolic BP, diastolic BP and mean BP) in the sitting position
3) Achievement ratio of target BP levels
4) Change from baseline in UACR
5) Change from baseline in CAVI
6) PD markers (PAC, PRA), blood and urine markers (Na,K,Creatinine,protein/creatinine ratio, NT-proBNP, L-FABP, NAG, beta2-MG, AGT, 8-OHdG)
2. Safety
1) Adverse ebents, Laboratory Assessment, Vital Signs, 12-lead ECG
2) Ratio of change of eGFR
3) Percentage of study subjects with serum potassium levels:5.5 mEq/L or more, 6.0 mEq/L or more

+81-86-235-7133

Dec. 13, 2019

None