Evaluation of Dapagliflozin for Cardiovascular and Renal Outcomes in Post-ICU Patients with Elevated Cardiac or Renal Biomarkers: A Randomized, Double-Blind Study

The primary objective of the DAPA-ICU Trial is to evaluate the benefit of **Dapagliflozin** on cardiovascular, renal, and global outcomes one year after ICU discharge in patients with increased cardiac and/or kidney biomarkers at ICU discharge. This is clinically relevant as it aims to determine the efficacy of Dapagliflozin in improving long-term health outcomes in a vulnerable patient population, potentially reducing morbidity and mortality associated with cardiovascular and renal complications.

Secondary objectives include: - Evaluating the impact of Dapagliflozin on renal outcome, mortality, and new hospitalizations for major cardiovascular events at one year after ICU discharge. - Assessing the safety of Dapagliflozin by examining potential side effects one year post-ICU discharge. - Investigating the possible biological remnant effect of the treatment between 12 months (end of treatment) and 12 months + 6 weeks (end of study). - Evaluating the benefit of Dapagliflozin on cardiovascular, renal, and global outcomes depending on treatment duration. These secondary objectives are crucial for understanding the broader implications of Dapagliflozin therapy, including its safety profile and long-term effects on patient health.

The clinical trial involves **adult patients** who have been discharged alive from the Intensive Care Unit (ICU) with specific medical conditions, including a decreased estimated glomerular filtration rate (**eGFR**), an acute kidney injury (**AKI**) during their ICU stay, and/or elevated NT-proBNP levels at discharge. The study population includes both male and female participants aged 18 years and older. Participants were selected based on their readiness for discharge from the ICU, as determined by the attending physician, and their consent to participate in the study. Key lifestyle factors such as diet and physical activity were not specified. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is a **phase 3**, prospective, randomized, placebo-controlled, double-blinded study designed to evaluate the benefit of **dapagliflozin** on cardiovascular, renal, and global outcomes one year after ICU discharge in patients with increased cardiac and/or kidney biomarkers at ICU discharge. The trial will involve adult patients who have been discharged alive from the ICU with a decreased estimated glomerular filtration rate (**eGFR**), an acute kidney injury (**AKI**) during their ICU stay, and/or an elevated NT-proBNP at discharge. The study will compare the effects of Forxiga 10 mg film-coated tablets against a placebo, both administered orally.

The trial is expected to commence recruitment on December 2, 2024, and conclude by January 16, 2028. Participants will be involved in the study for a maximum treatment period of 12 months, with the overall trial duration extending to 18 months to include follow-up assessments. The primary endpoint is a composite outcome of all-cause mortality, unscheduled hospitalization for heart failure, and significant renal deterioration one year post-ICU discharge. Secondary endpoints include unscheduled hospitalizations for cardiovascular events, the occurrence of severe chronic kidney disease, and other renal and cardiovascular outcomes within the same timeframe.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), mechanical ventilation or vasopressor/inotrope use for more than 24 hours during ICU stay, readiness for ICU discharge, and specific biomarker thresholds. Follow-up visits will occur periodically throughout the treatment phase to monitor safety and efficacy outcomes. The end-of-study visit will assess the long-term effects of the intervention and collect final data on primary and secondary endpoints.

Participants may be withdrawn from the study early if they experience adverse events that compromise their safety, withdraw consent, or if the investigator deems it necessary for medical reasons. The trial's design ensures rigorous monitoring and data collection to provide robust evidence on the efficacy and safety of dapagliflozin in this patient population.

The clinical trial involves the administration of **Forxiga 10 mg film-coated tablets**, which contain the active substance **dapagliflozin**. This medication is provided in the form of film-coated tablets and is administered orally. The dosage is set at 10 mg per day, with a maximum total dose of 3650 mg over a treatment period of 12 months. Dapagliflozin is a chemical substance, and its role in the trial is to evaluate its benefit on cardiovascular, renal, and global outcomes one year after ICU discharge in patients with increased cardiac and/or kidney biomarkers. The product is manufactured by AstraZeneca AB and is authorized under the marketing authorization number EU/1/12/795/009. Participant compliance with the dosing schedule will be monitored throughout the study.

The trial also includes a **placebo** group, which will receive a placebo version of the Forxiga 10 mg film-coated tablets. The placebo is designed to match the experimental medication in appearance and administration route, ensuring the study remains double-blinded. The placebo does not contain the active substance dapagliflozin and serves as a comparator to assess the efficacy and safety of the experimental treatment. The administration schedule for the placebo group mirrors that of the active treatment group, with daily oral administration over the same 12-month period. Compliance with the placebo regimen will be similarly monitored to ensure the integrity of the trial results.

The efficacy of Dapagliflozin in the DAPA-ICU trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is a composite outcome measured one year after ICU discharge, which includes all-cause mortality, unscheduled hospitalization for heart failure, a decrease in estimated glomerular filtration rate (eGFR) by more than 50% from baseline, end-stage kidney disease defined as an eGFR less than 15 ml/min/1.73m², initiation of renal replacement therapy, and kidney transplantation.

Secondary endpoints will evaluate additional parameters over the same period, such as unscheduled hospitalizations for cardiovascular events, the occurrence of severe chronic kidney disease, new episodes of acute kidney injury requiring hospitalization, and variations in NT-proBNP or BNP and eGFR levels. Safety endpoints will also be monitored, including urinary tract infections, necrotizing fasciitis, symptomatic diabetic ketoacidosis, major hypoglycemia, and death from any cause.

These endpoints will be measured using validated clinical criteria and laboratory tests, with data collection scheduled at specific timepoints, including the end of treatment at 12 months and the end of the study at 12 months plus 6 weeks. The trial is designed as a phase 3, prospective, randomized, placebo-controlled, double-blinded study, ensuring rigorous assessment of the efficacy of Dapagliflozin for cardio-renal protection after ICU discharge.