Efficacy and Safety Evaluation of Baxdrostat in Patients with Uncontrolled and Resistant Hypertension on Multidrug Regimens: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the effect of **baxdrostat** at doses of 2 mg and 1 mg compared to placebo on seated systolic blood pressure (SBP) at Week 12 in participants with uncontrolled hypertension. This is clinically relevant as it aims to determine the efficacy of baxdrostat in reducing SBP, which is a critical factor in managing hypertension and preventing cardiovascular events.

Secondary objectives include:

• Assessing the effect of 2 mg baxdrostat versus placebo on seated SBP at 8 weeks after randomised withdrawal.
• Evaluating the effect of 2 mg baxdrostat versus placebo on seated SBP at Week 12 in the resistant hypertension (rHTN) subpopulation.
• Assessing the effect of 2 mg baxdrostat versus placebo on seated diastolic blood pressure (DBP) at Week 12.
• Evaluating the effect of 2 mg baxdrostat versus placebo on achieving seated SBP < 130 mmHg at Week 12.
• Assessing the effect of 1 mg baxdrostat versus placebo on seated SBP at Week 12 in the rHTN subpopulation.
• Evaluating the effect of 1 mg baxdrostat versus placebo on seated DBP at Week 12.
• Assessing the effect of 1 mg baxdrostat versus placebo on achieving seated SBP < 130 mmHg at Week 12.
• Evaluating the effect of treatment with baxdrostat 2 mg versus placebo on ambulatory 24-hour average SBP at Week 12.
• Assessing the effect of treatment with baxdrostat 1 mg versus placebo on ambulatory 24-hour average SBP at Week 12.

The clinical trial involves a total of **515 participants** diagnosed with either **uncontrolled hypertension** or **resistant hypertension**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including a mean sitting systolic blood pressure of at least 140 mmHg but less than 170 mmHg at screening, and a stable regimen of antihypertensive medications. The trial includes individuals with an estimated glomerular filtration rate of at least 45 mL/min/1.73m² and serum potassium levels between 3.5 and 5.0 mmol/L. The population comprises individuals who are part of a vulnerable group, indicating the need for careful monitoring and ethical considerations. Lifestyle factors such as diet and physical activity were not specified in the selection criteria, focusing instead on the medical management of hypertension.

The clinical trial is designed to evaluate the **efficacy** and safety of **Baxdrostat** in participants with **uncontrolled hypertension** and **resistant hypertension**. This is a randomized, double-blind, placebo-controlled, parallel-group study. The trial will assess the effect of 2 mg and 1 mg doses of Baxdrostat compared to placebo on seated systolic blood pressure over a 12-week period. The trial is expected to commence recruitment on March 15, 2024, and conclude by October 13, 2025.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, blood pressure levels, and current antihypertensive treatment regimen. Eligible participants will be randomized to receive either Baxdrostat or placebo. The primary endpoint is the change from baseline in seated systolic blood pressure at week 12. Secondary endpoints include changes in diastolic blood pressure and achieving target systolic blood pressure levels.

Study visits will include baseline assessments, regular follow-up visits to monitor blood pressure, and safety evaluations through adverse event reporting, vital signs, and laboratory assessments. The end-of-study visit will occur at the conclusion of the 12-week treatment period. Participants are expected to be involved in the study for approximately 12 weeks, with conditions for early termination including significant adverse events or withdrawal of consent.

The trial will ensure that all participants are blinded to the treatment allocation to maintain the integrity of the study results. The use of a placebo control group will help to establish the true efficacy and safety profile of Baxdrostat. The study will adhere to rigorous clinical trial standards to ensure the reliability and validity of the findings.

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 administered **orally**. The trial includes two dosing regimens: a maximum daily dose of 2 mg for a treatment period of up to 52 weeks, and a maximum daily dose of 1 mg for a treatment period of up to 12 weeks. The total maximum dose for the 2 mg regimen is 728 mg, while for the 1 mg regimen, it is 84 mg. The active substance in Baxdrostat is of chemical origin, and the product is manufactured by AstraZeneca AB. Participant compliance with the dosing schedule will be monitored throughout the study.

The study also includes a **placebo** group to serve as a comparator for evaluating the efficacy and safety of Baxdrostat. The placebo is designed to mimic the appearance of the Baxdrostat tablet but does not contain any active pharmaceutical ingredients. The placebo is administered orally, following the same dosing schedule as the experimental medication, to maintain the double-blind nature of the trial. The use of a placebo allows for a controlled assessment of the treatment's effects on seated systolic blood pressure in participants with uncontrolled hypertension.

The efficacy of Baxdrostat in the treatment of **uncontrolled hypertension** will be assessed through a randomized, double-blind, placebo-controlled, parallel-group study. The primary efficacy endpoint is the change from baseline in seated systolic blood pressure (SBP) at week 12 for both 2 mg and 1 mg doses of Baxdrostat compared to placebo. Secondary endpoints include changes from baseline in seated diastolic blood pressure (DBP) and achieving seated SBP of less than 130 mmHg for both dosages. Additionally, the change from baseline in the mean ambulatory 24-hour SBP, as measured by ambulatory blood pressure monitoring (ABPM), will be evaluated for both dosages.

Measurements of blood pressure will be conducted using automated office blood pressure measurement techniques. The schedule for efficacy assessments includes baseline measurements and follow-up assessments at week 12. The analysis will focus on comparing the changes in blood pressure from baseline to week 12 between the Baxdrostat and placebo groups. Safety and tolerability will also be evaluated through adverse events, vital signs, and clinical and laboratory assessments.