Evaluation of Dapagliflozin for Safety in Patients with Decompensated Liver Cirrhosis: A Phase IIb Randomized Controlled Trial

The primary objective of this study is to evaluate the **safety** of dapagliflozin compared to standard medical therapy in patients with decompensated liver cirrhosis. This is clinically relevant as ensuring the safety of dapagliflozin in this patient population is crucial for its potential therapeutic use, given the complex nature of liver cirrhosis and the associated risks of treatment-related adverse effects.

Secondary objectives include:

• Evaluating signs of clinical effectiveness of dapagliflozin versus standard medical therapy treatment.
• Assessing the effect of dapagliflozin on patients' quality of life compared to standard therapy.
• Evaluating the effect of the intervention on biomarkers of systemic inflammation.
• Assessing the effect of the intervention on biomarkers of circulatory dysfunction.
• Evaluating the effect of the intervention on biomarkers of oxidative stress.

The clinical trial involves participants diagnosed with **decompensated liver cirrhosis**, with an age range between 18 and 85 years. Both male and female subjects are included in the study, and the trial does not specifically target a vulnerable population. The study population was selected based on a documented diagnosis of liver cirrhosis, confirmed through histological examination or clinical and instrumental assessments such as ultrasonography, CT scan, or liver elastography with a measurement greater than 15 kPa. Participants must have experienced liver cirrhosis decompensation, characterized by overt hepatic encephalopathy, clinically significant ascites, or hemorrhage from esophageal varices, within the past 12 months. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits have not been specified in the available data.

The clinical trial is a **randomized, controlled** study designed to evaluate the safety of **dapagliflozin** in patients with **decompensated liver cirrhosis**. The trial is set to commence recruitment on June 1, 2024, and is expected to conclude by May 30, 2026. Participants will be randomly assigned to receive either dapagliflozin or standard medical therapy. The trial will be conducted in a **double-blind** manner to ensure unbiased results. The primary endpoint is the incidence of global adverse events and serious adverse events, while secondary endpoints include various measures of liver function and quality of life.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age between 18 and 85 years, documented diagnosis of liver cirrhosis, and recent decompensation. Follow-up visits will occur at regular intervals, specifically on days 28, 56, 84, 112, 140, and 168, with a margin of ±7 days. These visits will assess the incidence of further decompensation events, changes in liver function scores, and other health parameters. The end-of-study visit will coincide with the final follow-up visit, marking the completion of the participant's involvement in the trial.

The expected duration of participant involvement is approximately 168 days, aligning with the maximum treatment period. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or withdrawal of consent by the participant. The trial's design and procedures are structured to ensure the collection of comprehensive safety and efficacy data, contributing to the understanding of dapagliflozin's role in managing decompensated liver cirrhosis.

The clinical trial involves the administration of **dapagliflozin**, marketed under the name Forxiga, as the experimental medication. Forxiga is provided in the form of film-coated tablets, each containing 10 mg of the active substance dapagliflozin. The tablets are intended for **oral use**. The maximum daily dose is 10 mg, with a total maximum dose of 1680 mg over the course of the treatment period, which spans 168 days. The administration schedule requires participants to take the medication once daily. Compliance with the dosing regimen will be monitored throughout the trial to ensure adherence to the prescribed treatment protocol.

In addition to the experimental treatment, the study includes a comparator group receiving standard medical therapy for decompensated liver cirrhosis. This standard-of-care therapy serves as the control treatment against which the safety and efficacy of dapagliflozin will be evaluated. The specific components of the standard medical therapy are not detailed in the provided data. The trial aims to assess the safety profile of dapagliflozin in comparison to this established treatment regimen.

The efficacy of dapagliflozin in the treatment of decompensated liver cirrhosis will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the incidence of global adverse events and serious adverse events. Secondary endpoints include a composite of further decompensation of cirrhosis, such as the occurrence of variceal bleeding, **hepatic encephalopathy**, new-onset or recurrent ascites, hepatorenal syndrome, spontaneous bacterial peritonitis, and death. These will be assessed at multiple timepoints: day 28 (±7), 56 (±7), 84 (±7), 112 (±7), 140 (±7), and 168 (±7).

Additional secondary endpoints involve changes from baseline in various clinical scores and biomarkers. These include the MELD score, MELD-Na score, Child-Pugh score, EQ-5D quality of life questionnaire score, and the Liver Frailty index. Changes in creatinine, estimated glomerular filtrate values, 24-hour sodiuria, body weight, and proinflammatory cytokines will also be measured. Furthermore, markers of circulatory dysfunction, oxidative stress, endothelial dysfunction, liver fibrosis, bacterial translocation, and "DAMPs" biomarkers will be evaluated. Metabolites measured by untargeted metabolomics will be assessed at day 84 (±7) and 168 (±7).