Evaluation of Zibotentan and Dapagliflozin Combination Versus Dapagliflozin Monotherapy in Chronic Kidney Disease with High Proteinuria: A Phase III Randomized Study

The primary objective of this Phase III, randomized, multicenter, double-blind study is to evaluate whether a fixed-dose combination of **zibotentan** and **dapagliflozin** is superior to dapagliflozin alone in slowing the decline in kidney function in participants with **chronic kidney disease** and high proteinuria. This is clinically relevant as it addresses the progression of kidney disease, which is a significant concern in patients with high proteinuria, potentially leading to end-stage kidney disease (ESKD) or renal death.

Secondary objectives include:

• Determining the superiority of the fixed-dose combination over dapagliflozin alone in reducing proteinuria and albuminuria.
• Assessing the reduction in the incidence of the renal composite endpoint, which includes a 40% sustained decline in estimated glomerular filtration rate (eGFR), ESKD, or renal death.
• Evaluating the reduction in systolic blood pressure.
• Measuring the proportion of participants achieving a urine protein-to-creatinine ratio (UPCR) of less than 1g/g and a greater than 30% reduction from baseline in proteinuria.
• Assessing the safety and tolerability of the fixed-dose combination compared to dapagliflozin alone.

The clinical trial involves a total of **1180 participants** diagnosed with **Chronic Kidney Disease and High Proteinuria**. The study population includes both male and female subjects, aged 18 years and older, who are capable of providing informed consent. Participants are required to have an estimated glomerular filtration rate (eGFR) between 20 and 90 mL/min/1.73 m² and a urine albumin-to-creatinine ratio (UACR) greater than 700 mg/g or a urine protein-to-creatinine ratio (UPCR) greater than 1000 mg/g. All female participants must have a negative serum pregnancy test unless they are not of childbearing potential. The trial population was selected based on their diagnosis and stability on RAASi therapy, which includes ACE inhibitors or ARBs, for at least four weeks. The study does not specify any particular lifestyle considerations such as diet or physical activity. Participants are considered a vulnerable population, and the trial includes both genders without any specific exclusion based on gender. The selection criteria ensure that participants are receiving the maximum tolerated labeled daily dose of RAASi therapy, which has been stable for at least four weeks prior to the study.

The clinical trial is a **Phase III**, randomized, double-blind, controlled study designed to evaluate the efficacy, safety, and tolerability of a fixed-dose combination of **zibotentan** and **dapagliflozin** compared to dapagliflozin alone in participants with **chronic kidney disease** and high proteinuria. The trial aims to determine whether the combination therapy is superior in slowing the decline in kidney function. The study will involve oral administration of the investigational products in the form of film-coated tablets. The trial is expected to last for approximately 24 months, with an estimated end date in July 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis of chronic kidney disease, and stable RAASi therapy. Following successful screening, participants will be randomized to receive either the combination therapy or dapagliflozin alone. Regular follow-up visits will occur from Day 15 up to Month 24 to monitor changes in key endpoints, including estimated glomerular filtration rate (eGFR), urinary protein-to-creatinine ratio (UPCR), and urinary albumin-to-creatinine ratio (UACR). The end-of-study visit will conclude the participant's involvement, assessing the primary endpoint of change in eGFR from baseline to Month 24.

Participant involvement is expected to last the full duration of the trial, approximately 24 months, unless early termination is warranted. Conditions for early termination include adverse events, withdrawal of consent, or non-compliance with study procedures. The trial will adhere to rigorous scientific and ethical standards to ensure the integrity and reliability of the data collected.

The clinical trial involves the evaluation of a **fixed-dose combination** of **Zibotentan** and **Dapagliflozin**. This experimental medication is administered in the form of a **film-coated tablet**. The route of administration is **oral**, and the treatment period is set for a maximum of 24 weeks. The combination tablet is designed to be taken once daily, although the specific dosage in milligrams is not specified in the provided data. The active substances, **Dapagliflozin** and **Zibotentan**, are both of chemical origin and are manufactured by AstraZeneca AB. The combination aims to assess its efficacy in slowing the decline of kidney function in participants with chronic kidney disease and high proteinuria.

In addition to the experimental treatment, the study includes a comparator treatment with **Dapagliflozin** alone. This comparator is also provided as a **film-coated tablet** and is administered orally. The treatment duration for the comparator is consistent with the experimental treatment, extending up to 24 weeks. The role of Dapagliflozin in the trial is to serve as a standard-of-care therapy, allowing for a direct comparison of its effects against the combination therapy. The dosing schedule for Dapagliflozin alone mirrors that of the combination therapy, with daily administration, although specific dosage details are not provided.

Participant compliance with the medication regimen is monitored throughout the trial to ensure adherence to the dosing schedule. The trial is designed to maintain a double-blind methodology, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias in the assessment of the treatment outcomes. The primary objective of the trial is to determine the superiority of the fixed-dose combination over Dapagliflozin alone in terms of efficacy, safety, and tolerability.

Efficacy in this clinical trial will be assessed by evaluating the impact of the fixed-dose combination of zibotentan and dapagliflozin compared to dapagliflozin alone in participants with **Chronic Kidney Disease** (CKD) and high proteinuria. The primary endpoint for efficacy evaluation is the change in estimated glomerular filtration rate (eGFR) from baseline to Month 24. This will be measured to determine the effect of the treatment on slowing the decline in kidney function.

Secondary endpoints include several parameters: the change in urine protein-to-creatinine ratio (UPCR) and urine albumin-to-creatinine ratio (UACR) from baseline to each participant's mean level across visits from Day 15 up to Month 24, the time to the first occurrence of any components of the renal composite endpoint (40% sustained decline in eGFR, end-stage kidney disease (ESKD), or renal death), the change in systolic blood pressure from baseline to each participant's mean level across the visits from Day 15 up to Month 24, and the proportion of participants achieving UPCR < 1000 mg and > 30% reduction from baseline for each participant's mean level across the visits from Day 15 up to Month 24.