Evaluation of Eplerenone, Spironolactone, and Torasemide in the Management of Resistant Hypertension in Patients with Uncontrolled Blood Pressure

The primary objective of the study is to evaluate the efficacy of treatment strategies for **hypertension** across three phases. In Phase A, the focus is on determining the percentage of patients with uncontrolled blood pressure (BP) confirmed by ambulatory blood pressure monitoring (ABPM), with a 24-hour mean systolic blood pressure (SBP) of ≥125 mm Hg or diastolic blood pressure (DBP) of ≥80 mm Hg. Phase B aims to assess the percentage of patients achieving controlled BP after 12 weeks of treatment with a triple single-pill combination (SPC), confirmed by ABPM, with a 24-hour mean SBP of <125 mm Hg and DBP of <80 mm Hg. This phase evaluates the efficacy of switching from ineffective treatment to a triple SPC in the entire cohort and separately in P+I+A and E+H+A groups. Phase C investigates the magnitude of SBP reduction on ABPM after 12 weeks of treatment, comparing eplerenone versus spironolactone and torasemide versus spironolactone.

The secondary objectives include: Phase A - assessing the percentage of patients with BP controlled as confirmed by home blood pressure monitoring (HBPM) and the consistency of uncontrolled BP rates between ABPM and HBPM. Phase B - evaluating the percentage of patients with controlled BP after 12 weeks of treatment, confirmed by office blood pressure monitoring (OBPM) and HBPM. Phase C - examining changes in SBP on ABPM after 12 weeks of treatment in patients receiving spironolactone, eplerenone, or torasemide compared to baseline.

The clinical trial focuses on participants diagnosed with **hypertension**, specifically targeting individuals with a documented history of the condition. The study population comprises both women and men aged between 18 and 69 years. Participants are required to have been undergoing treatment for hypertension for at least six months, with a stable antihypertensive treatment regimen maintained for a minimum of four weeks prior to the study. The trial does not include a vulnerable population. Participants are expected to have an office blood pressure of at least 130/80 mm Hg and must be on a regimen of three or more antihypertensive drugs, including an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, and a thiazide or loop diuretic. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of treatment strategies for **hypertension**. The study is structured as a randomized, double-blind, controlled trial, with an estimated duration extending until December 31, 2025. The trial is divided into three phases: Phase A, Phase B, and Phase C, each with specific objectives and endpoints. Participants will be involved in the study for a maximum treatment period of 30 days, with the possibility of early termination if they do not comply with study procedures or experience adverse effects.

Study visits are sequenced to ensure comprehensive data collection and participant monitoring. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, documented history of hypertension, and current antihypertensive treatment regimen. Follow-up visits will occur at regular intervals to assess blood pressure control and treatment efficacy. The end-of-study visit will conclude the participant's involvement, with final assessments and data collection.

Participants are expected to attend all scheduled visits and adhere to the study protocol. The primary endpoints include the percentage of patients with uncontrolled blood pressure in Phase A, the efficacy of switching to a triple single-pill combination (SPC) in Phase B, and the magnitude of systolic blood pressure reduction in Phase C. Secondary endpoints focus on blood pressure control consistency between ambulatory and home measurements. The trial aims to provide insights into optimal treatment regimens for managing difficult-to-treat hypertension.

The clinical trial involves several treatments, including both experimental and non-experimental medications. **Elestar HCT** is an experimental medication used in the trial, available in two formulations: 40 mg + 10 mg + 25 mg and 40 mg + 5 mg + 12.5 mg. These are **film-coated tablets** containing **olmesartan medoxomil**, **amlodipine**, and **hydrochlorothiazide**. The medication is administered orally, with a maximum daily dose of 40 mg, and the treatment period is up to 30 days. The combination acts as an angiotensin II receptor antagonist, calcium antagonist, and diuretic.

Another experimental treatment is **Triplixam**, available in two formulations: 10 mg + 2.5 mg + 5 mg and 5 mg + 1.25 mg + 5 mg. These are also **film-coated tablets** containing **indapamide**, **amlodipine besilate**, and **perindopril arginine**. The medication is administered orally, with a maximum daily dose of 10 mg, and the treatment period is up to 30 days. This combination preparation includes a calcium antagonist, diuretic, and angiotensin-converting enzyme inhibitor.

**Spironol** is a non-experimental treatment used as a comparator in the study. It is available as a 25 mg **tablet** containing **spironolactone**. The medication is administered orally, with a maximum daily dose of 50 mg, and the treatment period is up to 24 days. Spironolactone acts as a diuretic.

**Toramide** is another non-experimental treatment, available as a 10 mg **tablet** containing **torasemide**. It is administered orally, with a maximum daily dose of 20 mg, and the treatment period is up to 24 days. Torasemide is classified as a diuretic.

**Espiro** is also included in the trial as a non-experimental treatment. It is available as a 25 mg **film-coated tablet** containing **eplerenone**. The medication is administered orally, with a maximum daily dose of 100 mg, and the treatment period is up to 24 days. Eplerenone functions as an aldosterone antagonist.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial aims to evaluate the efficacy of these treatments in managing uncontrolled hypertension, with specific objectives outlined for each phase of the study.

The efficacy of the clinical trial titled "Optimal medical treatment of uncontrolled hypertension. OPTIMAL-HT" will be assessed through a series of phases, each with specific endpoints. In **Phase A**, the primary endpoint is the percentage of patients with uncontrolled blood pressure (BP), defined as a 24-hour mean systolic blood pressure (SBP) of ≥125 mm Hg or diastolic blood pressure (DBP) of ≥80 mm Hg, as measured by ambulatory blood pressure monitoring (ABPM). This will quantify the efficacy of the current antihypertensive treatment. Secondary endpoints include the percentage of patients with BP controlled as confirmed by home blood pressure monitoring (HBPM) and the consistency of uncontrolled BP rates between ABPM and HBPM.

**Phase B** focuses on the efficacy of switching to a triple single-pill combination (SPC) treatment. The primary endpoint is the percentage of patients achieving BP control, defined as a 24-hour mean SBP of <125 mm Hg and DBP of <80 mm Hg, after 12 weeks of treatment. This will be assessed at Visit 5 in the intention-to-treat (ITT-B) data set. The efficacy of each triple SPC drug will also be evaluated separately for the P+I+A and O+H+A groups.

In **Phase C**, the primary endpoint is the magnitude of reduction in SBP on ABPM after 12 weeks of treatment, comparing eplerenone, torasemide, and spironolactone groups. The main analysis will focus on the change from baseline (Visit 6) to week 12 (Visit 8) in mean 24-hour SBP, conducted on the per-protocol (PP) set. ABPM measurements obtained after premature discontinuation of treatment will be excluded from this analysis.