Evaluation of Baxdrostat on Ambulatory Blood Pressure in Patients with Resistant Hypertension: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the effect of treatment with **baxdrostat** 2 mg compared to placebo on ambulatory 24-hour average systolic blood pressure (SBP) at Week 12 in participants with resistant hypertension. This is clinically relevant as resistant hypertension is characterized by blood pressure that remains above target levels despite the use of at least three antihypertensive drugs, including a diuretic, at maximum tolerated doses. Effective management of SBP in this population is crucial to reduce the risk of cardiovascular events.

Secondary objectives include assessing the effect of baxdrostat 2 mg versus placebo on:

• Ambulatory night-time average SBP at Week 12
• Ambulatory daytime average SBP at Week 12
• Seated SBP at Week 12
• Achieving ambulatory 24-hour average SBP < 130 mmHg at Week 12
• Ambulatory 24-hour average diastolic blood pressure (DBP) at Week 12
• Ambulatory night-time average DBP at Week 12
• Ambulatory daytime average DBP at Week 12
• Seated DBP at Week 12
• Nocturnal dipping pattern at Week 12

The clinical trial involves a total of **133 participants** diagnosed with **resistant hypertension** (rHTN), characterized by blood pressure that remains above target levels despite the use of at least three antihypertensive drugs of different classes at maximum tolerated doses, including a diuretic. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including a mean seated systolic blood pressure (SBP) of 140 mmHg or higher but less than 170 mmHg at screening, a stable regimen of at least three antihypertensive medications from different therapeutic classes for at least four weeks prior to screening, and an estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m² or higher. Additionally, serum potassium levels must be between 3.5 and 5.0 mmol/L at screening. The trial does not include a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy of **Baxdrostat** in reducing ambulatory blood pressure in participants with **resistant hypertension**. The trial will involve a parallel group design, with participants randomly assigned to receive either Baxdrostat or a placebo. The primary objective is to assess the change from baseline in ambulatory 24-hour average systolic blood pressure (SBP) at Week 12. Secondary endpoints include changes in ambulatory night-time and daytime average SBP, seated SBP, and diastolic blood pressure (DBP) at Week 12, as well as the proportion of participants achieving specific blood pressure targets.

The trial is expected to commence recruitment on April 15, 2024, and conclude by May 23, 2025. Participants will be involved in the study for a total duration of 12 weeks. The study will include several key visits: an initial screening visit to confirm eligibility, a randomization visit, and multiple follow-up visits to monitor blood pressure and assess safety and efficacy. The end-of-study visit will occur at Week 12, where final assessments will be conducted.

Inclusion criteria require participants to be at least 18 years old, with a mean seated SBP of ≥ 140 mmHg and < 170 mmHg at screening, and on a stable regimen of at least three antihypertensive medications, including a diuretic, for at least four weeks prior to screening. Participants must also have an estimated glomerular filtration rate (eGFR) of ≥ 45 mL/min/1.73 m² and serum potassium levels within specified limits. Randomization criteria include a mean ambulatory SBP of ≥ 130 mmHg. Participants may be terminated early from the study if they experience adverse events that compromise safety or if they fail to adhere to the study protocol.

The clinical trial involves the administration of **Baxdrostat**, a synthetic small molecule, as the experimental medication. **Baxdrostat** is provided in a **tablet** form and is intended for **oral use**. The dosage for this trial is set at 2 mg per day, with a maximum treatment period of 14 days. The primary objective is to assess the effect of **Baxdrostat** on ambulatory 24-hour average systolic blood pressure in participants with resistant hypertension. The medication is manufactured by AstraZeneca AB, and its active substance is chemically derived.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The **Baxdrostat Placebo** is also administered in a **tablet** form for **oral use**. The placebo is designed to match the experimental medication in appearance and administration schedule to maintain the study's blinding integrity. Participants will receive either the active medication or the placebo, with compliance monitored throughout the trial to ensure adherence to the dosing schedule.

The efficacy of Baxdrostat in the treatment of **resistant hypertension** will be assessed through a randomized, double-blind, placebo-controlled, parallel-group study. The primary endpoint for evaluating efficacy is the change from baseline in ambulatory 24-hour average systolic blood pressure (SBP) at Week 12. Secondary endpoints include changes from baseline in ambulatory night-time and daytime average SBP, seated SBP, and ambulatory 24-hour average diastolic blood pressure (DBP) at Week 12. Additionally, the study will assess the proportion of participants achieving an ambulatory 24-hour average SBP of less than 130 mmHg and those achieving a nocturnal SBP dipping of 10% or more at Week 12.

Measurements will be collected using ambulatory blood pressure monitoring (ABPM) to ensure accurate and consistent data. The schedule for these assessments is set at baseline and Week 12, with the primary focus on the 24-hour average SBP. The analysis will compare the effects of Baxdrostat 2 mg against a placebo, with the primary objective being the reduction in SBP. The study is designed to provide robust data on the efficacy of Baxdrostat in managing resistant hypertension, with a comprehensive evaluation of both systolic and diastolic blood pressure parameters.