Evaluation of Baxdrostat and Dapagliflozin on Chronic Kidney Disease Progression in Hypertensive Patients: A Randomized, Double-Blind, Active-Controlled Phase III Trial

The primary objective of this study is to evaluate whether the combination of **baxdrostat** and dapagliflozin is superior to dapagliflozin alone in slowing the progression of **chronic kidney disease (CKD)**. This is assessed by measuring the change in estimated **glomerular filtration rate (eGFR)** over time. The clinical relevance of this objective lies in its potential to improve renal outcomes in patients with CKD and hypertension, potentially delaying the need for more invasive treatments such as dialysis or transplantation.

Secondary objectives include: - Determining whether baxdrostat/dapagliflozin is superior to dapagliflozin alone in reducing the urine albumin-creatinine ratio (UACR), which is an important marker of kidney damage. - Assessing the combination's efficacy in reducing systolic blood pressure (SBP), a critical factor in managing hypertension and preventing cardiovascular complications. - Evaluating whether the combination slows CKD progression and reduces the risk of end-stage kidney disease (ESKD), which could significantly impact patient morbidity and healthcare costs. - Investigating if the combination slows the rate of kidney function decline after the hemodynamically-mediated acute effect on GFR, providing insights into long-term renal protection. - Determining the combination's effectiveness in reducing the risk of major adverse cardiovascular events (MACE), including cardiovascular death, heart failure, myocardial infarction, and stroke, which are significant contributors to mortality in this patient population.

The clinical trial involves a total of **1825 participants** diagnosed with **chronic kidney disease (CKD)** and **hypertension**. The study population includes individuals of any sex and gender, aged 18 years and older. Participants were selected based on specific health criteria, including an estimated glomerular filtration rate (eGFR) between 30 and 90 mL/min/1.73 m² and a urine albumin creatinine ratio between 200 mg/g and 5000 mg/g at screening. Additionally, participants have a history of hypertension with a systolic blood pressure (SBP) of at least 130 mmHg at screening and at least 120 mmHg at the randomization visit. All participants are required to be on a stable and maximum tolerated dose of an ACE inhibitor or an ARB for at least four weeks prior to the screening visit. The trial includes both male and female subjects and considers vulnerable populations. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, active-controlled study designed to evaluate the efficacy, safety, and tolerability of **Baxdrostat** in combination with **Dapagliflozin** compared to Dapagliflozin alone in participants with **chronic kidney disease (CKD)** and **hypertension**. The primary objective is to determine whether the combination therapy is superior in slowing CKD progression, assessed by changes in estimated glomerular filtration rate (eGFR) over time. The trial is expected to commence recruitment on March 29, 2024, and conclude by April 10, 2028.

Participants will be involved in the study for a maximum treatment period of 24 to 26 months, depending on the specific treatment arm. The study will include several key visits: an initial screening visit to confirm eligibility, randomization, and multiple follow-up visits to monitor safety and efficacy outcomes. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment. Participants must be at least 18 years old, have CKD with an eGFR between 30 and 90 mL/min/1.73 m², and meet specific blood pressure criteria. They must also be on a stable dose of an ACE inhibitor or ARB for at least four weeks prior to the screening visit.

Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The primary endpoint is the change from baseline in eGFR post-treatment. Secondary endpoints include changes in urine albumin creatinine ratio (UACR), systolic blood pressure, and a composite kidney endpoint. The study will also evaluate the time to the first occurrence of cardiovascular events such as death, heart failure, myocardial infarction, or stroke. The trial is not categorized as low intervention and is conducted in accordance with phase III clinical trial standards.

The clinical trial involves the administration of **Baxdrostat**, a synthetic small molecule, as an experimental medication. Baxdrostat is provided in the form of a **tablet** and is intended for **oral use**. The maximum treatment period for Baxdrostat is 24 weeks. The specific dosage and frequency of administration are not detailed in the provided data. The active substance, Baxdrostat, is of chemical origin and is manufactured by AstraZeneca AB. Participant compliance with the medication regimen will be monitored throughout the study.

In addition to Baxdrostat, the trial includes the administration of **Forxiga 10 mg film-coated tablets**, which contain the active substance **dapagliflozin**. This medication is also a synthetic small molecule and is administered orally. The maximum daily dose of Forxiga is 10 mg, with a treatment period extending up to 26 weeks. The clinical product differs from the commercial product in terms of colorant, engraving, and supply chain, but these differences do not affect the active substance or its efficacy. Dapagliflozin is of chemical origin and is also produced by AstraZeneca AB.

The study employs a **placebo** control, referred to as Baxdrostat placebo, which is used to maintain the double-blind nature of the trial. The placebo does not contain any active substance and is not associated with any specific pharmaceutical form or route of administration as per the available data. The placebo is utilized to compare the effects of the experimental treatment with a non-active control, ensuring the reliability of the study outcomes.

The efficacy of the clinical trial will be assessed by evaluating the impact of the combination therapy of **baxdrostat** and dapagliflozin compared to dapagliflozin alone on the progression of Chronic Kidney Disease (CKD) in participants with CKD and high blood pressure. The primary endpoint for efficacy assessment is the change from baseline in the estimated Glomerular Filtration Rate (eGFR) to post-treatment. This will be measured to determine the effect of the treatment on slowing CKD progression.

Secondary endpoints include several parameters: change from baseline in Urine Albumin Creatinine Ratio (UACR), change from baseline in systolic blood pressure, and a kidney hierarchical composite endpoint. The composite endpoint is defined by the most severe outcome among death, chronic dialysis or kidney transplant, sustained GFR decline, and individual change in eGFR. Additionally, the time to the first occurrence of cardiovascular events such as cardiovascular death, heart failure, myocardial infarction, and stroke will be evaluated.

These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial, with the primary focus on changes from baseline to post-treatment. The trial is designed to provide a comprehensive assessment of the treatment's impact on CKD progression and associated health outcomes.