Early Aldo Blockade in Subclinical PA

Official title

Early Aldosterone Blockade to Prevent Hypertension and Cardiorenal Damage in Subclinical Primary Aldosteronism

Overview

This trial aims to evaluate the preventive effect of early intervention with eplerenone, a highly selective nonsteroidal mineralocorticoid receptor antagonist, against new-onset hypertension in normotensive patients with subclinical primary aldosteronism (PA), as well as its cardiorenal target organ protective effects and long-term safety profile. The trial will be conducted across 15 to 20 tertiary hospitals nationwide with established expertise in PA diagnosis and management. A total of 880 eligible patients aged 30 to 55 years with normal blood pressure and biochemically/functionally confirmed subclinical PA will be enrolled and randomly assigned to the eplerenone group or the placebo group at a 1:1 ratio. The eplerenone group will receive a dose titration regimen with a target maintenance dose of 50 mg once daily orally, while the placebo group will follow a matched sham titration protocol. The double-blind treatment period will last 3 years, with an extension to 5 years permitted based on interim analysis findings. The primary endpoint is the incidence of new-onset hypertension within 3 years, adjudicated blindly by an independent Clinical Endpoint Committee (CEC). Secondary endpoints include alterations in biomarkers of cardiorenal target organ damage, improvements in endocrine parameters, changes in adrenal nodule volume, and patient-reported outcomes. Safety endpoints cover the incidence of adverse events such as hyperkalemia, acute kidney injury, and hypotension. This trial will fill a critical gap in evidence-based medicine regarding early intervention for subclinical PA for the first time. Its findings are expected to revise international clinical practice guidelines for PA and deliver a novel precision intervention strategy for the primary prevention of hypertension.

Interventions

• Drug Eplerenone
  Eplerenone tablets, starting dose 25mg once daily orally. At Week 4 visit, titrate to 50mg once daily if serum potassium \<=4.5 mmol/L and eGFR decrease from baseline \<30%; maintain 25mg once daily if serum potassium 4.6-5.0 mmol/L; hold drug if potassium \>5.0 mmol/L or eGFR decrease \>=30%. At Week 8 visit, maintain the stable titrated dose for continuation until the end of the study. Long-term dose adjustment during follow-up will be performed according to the specific protocol Table 1 if po
• Drug Placebo
  Placebo tablets completely matching the appearance, specifications, smell, and packaging of Eplerenone tablets, with no pharmacological activity. A sham titration scheme is adopted that is completely consistent with the Eplerenone group (including dose adjustment processes and follow-up monitoring) to strictly maintain the double-blind design.

Primary outcome measures

• Incidence of New-Onset Hypertension [Time frame: Up to 36 months]

Eligibility criteria

Inclusion criteria

• Age 30 to 55 years old (inclusive), both genders.
• Body Mass Index (BMI) 18.5 to 35.0 kg/m² (inclusive).
• Office blood pressure < 140/90 mmHg, and no use of any antihypertensive drugs. Office blood pressure is measured at 3 visits with 1-week intervals. Patients rest in a seated position for 5 minutes before measurement, measured -times per visit, and the average of the 3 visits must meet the criteria.
• Serum potassium in the low-normal or normal range.
• Meeting diagnostic criteria: (A) ARR ≥ 2.52 ng/dL per pg/mL (chemiluminescence immunoassay), and PAC ≥ 6 ng/dL (blood sample required in the morning, fasting, after resting in a seated position for 30 minutes); OR (B) Renin ≤ 4.0 pg/mL; OR (C) Positive confirmatory test: Saline infusion test (SIT): PAC > 6 ng/dL after 4 hours of isotonic saline infusion; OR Captopril challenge test (CCT): PAC suppression rate < 30% at 2 hours after oral administration of 50mg captopril.
• Adrenal thin-slice CT showing unilateral adrenal nodule (<15 mm in diameter), bilateral adrenal micronodules (<10 mm in diameter), or negative findings.

Exclusion criteria

• History of diagnosed hypertension, including office BP ≥ 140/90 mmHg, previous use of antihypertensive drugs, or previous ABPM meeting hypertension diagnostic criteria.
• Other etiologies of secondary hypertension, including renal artery stenosis, pheochromocytoma, Cushing's syndrome, thyroid dysfunction, glucocorticoid-remediable aldosteronism, etc.
• Severe renal insufficiency: eGFR < 45 mL/min/1.73m² (CKD-EPI formula), or UACR > 300 mg/g.
• Abnormal baseline serum potassium: serum potassium > 5.0 mmol/L, or serum potassium < 3.0 mmol/L.
• Severe hepatic insufficiency: Child-Pugh Class C, or ALT/AST > 3 times the upper limit of normal (ULN).
• History of allergy to eplerenone or any excipients of the study drug.
• Pregnant, lactating women, or subjects planning to become pregnant during the study period.
• History of adrenal surgery.
• Severe cardiovascular diseases, including New York Heart Association (NYHA) Class IV heart failure, previous myocardial infarction, cerebral infarction, transient ischemic attack (TIA), severe arrhythmia, etc.
• Severe comorbidities with an expected life expectancy of <5 years, including malignant tumors, severe autoimmune diseases, end-stage organ failure, etc.
• Use of drugs that cannot be discontinued prior to enrollment: strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, nefazodone, etc.); strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John's wort, etc.); other MRAs, potassium-sparing diuretics (amiloride, triamterene), potassium supplements; systemic glucocorticoids (except physiological replacement), licorice preparations; long-term high-dose NSAIDs.
• History of drug abuse, alcohol dependence, or psychiatric illness that may affect study completion, as judged by the investigator.
• Participation in other clinical trials or use of other investigational drugs within 3 months prior to enrollment.
• Any other conditions that, in the opinion of the investigator, may affect subject safety, trial compliance, or outcome assessment.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Prevention

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07727252 · 260610-06

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗