Efficacy and Safety Evaluation of Zibotentan and Dapagliflozin in Patients with Liver Cirrhosis and Portal Hypertension: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the change from baseline in **hepatic venous pressure gradient (HVPG)** in participants with liver cirrhosis and features of portal hypertension. This will be assessed for two treatment regimens: the combination of zibotentan and dapagliflozin versus placebo in Part A, and the combination of zibotentan and dapagliflozin as well as dapagliflozin monotherapy versus placebo in Part B. The clinical relevance of this objective lies in its potential to demonstrate the efficacy of these treatments in reducing portal hypertension, a significant complication of liver cirrhosis that can lead to serious outcomes such as variceal bleeding.

Secondary objectives include:

• Part A: Evaluating the change from baseline in HVPG, the proportion of participants achieving HVPG < 10 mmHg or a reduction in HVPG of ≥ 1.5 mmHg, the effect on change in body weight, total loop-diuretic equivalents use, body water volumes and body fat mass, and changes in office-based systolic and diastolic blood pressure of the combination therapy versus placebo.
• Part B: Evaluating the change from baseline in HVPG, the effect on change in body weight, total loop-diuretic equivalents use, body water volumes and body fat mass, changes in office-based systolic and diastolic blood pressure, and the proportion of participants achieving at least a 20% decrease in HVPG or a reduction to or below 12 mmHg in HVPG of the combination therapy and dapagliflozin monotherapy versus placebo.

The clinical trial involves a total of **106 participants** diagnosed with **liver cirrhosis** with features of portal hypertension. The study population includes both male and female subjects, aged between 18 and 80 years. Participants were selected based on specific criteria, including a clinical and/or histological diagnosis of cirrhosis, with additional considerations such as the Child-Pugh score and MELD score. The trial excludes individuals with significant ascites or recent changes in hepatic function. Participants are required to have a hepatic venous pressure gradient (HVPG) recording of sufficient quality. The study does not involve 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, safety, and tolerability of the combination of **zibotentan** and **dapagliflozin**, as well as **dapagliflozin** monotherapy, in participants with **liver cirrhosis** with features of **portal hypertension**. The trial is divided into two parts, Part A and Part B, each with specific objectives and endpoints. The primary endpoint for both parts is the absolute change in hepatic venous pressure gradient (HVPG) from baseline to Week 6. Secondary endpoints include percent change in HVPG, changes in body weight, total body water, and blood pressure, among others.

The trial is expected to last until March 2025, with recruitment having started in October 2022. Participants will be involved in the study for a maximum treatment period of 16 weeks. The study involves several visits, starting with an inclusion (screening) visit to assess eligibility based on criteria such as age, Child-Pugh score, and HVPG quality. Follow-up visits will occur at regular intervals to monitor the participants' response to treatment and any adverse events. The end-of-study visit will conclude the trial for each participant, assessing the final outcomes and any long-term effects of the treatment.

Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial employs a parallel group design, with participants randomly assigned to receive either the active treatment or placebo, ensuring the reliability and validity of the results. The study drugs, **zibotentan** and **dapagliflozin**, are administered orally in the form of hard capsules and film-coated tablets, respectively, with a maximum daily dose of 15 mg for **zibotentan** and 10 mg for **dapagliflozin**.

The clinical trial involves the administration of **Zibotentan**, a chemical compound provided in the form of a hard capsule. The active substance, **zibotentan**, is manufactured by AstraZeneca AB. Participants will receive a maximum daily dose of 15 mg, administered orally. The treatment period is set for a maximum of 16 weeks. The pharmaceutical form and administration route are consistent across all participants receiving this experimental medication.

In addition to Zibotentan, the trial includes the administration of **Dapagliflozin**, which is also a chemical compound. This medication is provided in the form of a film-coated tablet. The active substance, **dapagliflozin**, is administered orally with a maximum daily dose of 10 mg. The treatment duration for Dapagliflozin is also set for a maximum of 16 weeks. This medication serves as a comparator treatment in the study.

The study also incorporates the use of placebos to maintain the double-blind nature of the trial. **Zibotentan Placebo** and **Dapagliflozin Placebo** are included as non-experimental treatments. These placebos are designed to mimic the appearance and administration route of their respective active medications, ensuring that neither the participants nor the investigators can distinguish between the active treatment and placebo groups. The use of placebos is critical for assessing the efficacy and safety of the experimental treatments.

The efficacy of the investigational treatments in this clinical trial will be assessed primarily through the measurement of **Hepatic Venous Pressure Gradient (HVPG)**. The primary endpoints for both Part A and Part B of the study are the absolute changes in HVPG from baseline to Week 6. Secondary endpoints include the percent change in HVPG, HVPG response rates, and changes in body weight, total body water, extracellular and intracellular water volumes, total body fat mass, and blood pressure from baseline to Week 6 for Part A, and from baseline to both Week 6 and Week 16 for Part B. HVPG response is defined as a reduction in HVPG to less than 10 mmHg or a decrease of at least 1.5 mmHg from baseline for Part A, and a decrease of at least 20% or to 12 mmHg or below for Part B.

Measurements will be conducted using validated methods, with HVPG recordings assessed for quality by a central reader. The study will involve a combination of home-based and office-based assessments for body weight and other parameters. The efficacy assessments are scheduled at baseline, Week 6, and Week 16, where applicable, to evaluate the impact of the combination therapy of Zibotentan and Dapagliflozin, as well as Dapagliflozin monotherapy, compared to placebo in participants with cirrhosis and features of portal hypertension.