Evaluation of Irbesartan on Cardiovascular and Global Outcomes Post-Acute Kidney Injury in ICU-Discharged Patients: A Randomized, Double-Blind, Multicenter Trial

The primary objective of this study is to evaluate the impact of **RAASi** (Renin-Angiotensin-Aldosterone System inhibitors) on cardiovascular and global outcomes during the year following discharge from the Intensive Care Unit (ICU) or Transitional Care Unit (TCU) in patients who developed **acute kidney injury** (AKI) and have either fully or partially recovered. This is clinically relevant as it aims to determine the potential benefits of RAASi in improving long-term health outcomes in this patient population, which could influence post-discharge treatment strategies.

Secondary objectives include:

• Evaluating the impact of RAASi initiation on renal outcomes after ICU or TCU discharge.
• Assessing the impact of RAASi initiation on new hospitalizations for major cardiovascular events.
• Evaluating the impact of RAASi initiation on potential side effects of the treatment, focusing on safety.
• Identifying patient characteristics that influence response to treatment, utilizing biological samples collected at inclusion and at the end of the study.

The clinical trial focuses on patients who have experienced **acute kidney injury** and have either fully or partially recovered. The study population includes both male and female participants aged 18 years and older. Participants must have met the criteria for acute kidney injury during their stay in the Intensive Care Unit (ICU) or Transitional Care Unit (TCU), as defined by the KDIGO criteria. Their renal function should have stabilized for at least 48 hours, with serum creatinine levels either decreasing or not increasing by more than 26 micromol/L or 25%, among those ready for discharge from the ICU or TCU, and within 30 days post-discharge. All participants are required to be affiliated with a Social Security System. Additionally, women of childbearing potential and men must agree to use adequate and highly effective contraception until the end of the research. The sponsor has not provided information regarding the total number of participants in the trial. The trial does not include a vulnerable population, and lifestyle considerations such as diet and physical activity are not specified.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the impact of treatment with an angiotensin receptor blocker on outcomes following **acute kidney injury** in patients discharged from the Intensive Care Unit (ICU) or Transitional Care Unit (TCU). The trial will involve the administration of **Irbesartan** EG 150 mg film-coated tablets and a placebo, both administered orally. The primary objective is to assess the effect of the treatment on cardiovascular and global outcomes within one year post-discharge. The trial is expected to run from November 2022 to June 2027, with a maximum treatment period of 380 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), history of acute kidney injury during ICU stay, and stabilized renal function. Follow-up visits will be scheduled to monitor the primary endpoint, which is the time to major adverse cardiovascular events (MACE), including all-cause mortality and unscheduled hospital readmissions for cardiovascular events. Secondary endpoints include albuminuria, occurrence of chronic kidney disease, changes in estimated glomerular filtration rate, and new episodes of acute kidney injury requiring hospitalization.

The expected length of participant involvement is approximately one year, with conditions for early termination including significant adverse events or withdrawal of consent. Participants must agree to use effective contraception throughout the study. The end-of-study visit will involve a final assessment of the primary and secondary endpoints, as well as the collection of biological samples. The trial is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants.

The clinical trial involves the administration of **Irbesartan EG 150 mg** in the form of film-coated tablets. The active substance in this experimental medication is **irbesartan**, a chemical compound classified under the ATC code C09CA04. The tablets are intended for **oral use** and are manufactured by EUROGENERICS N.V./S.A. The maximum daily dose of irbesartan is 300 mg, with a total maximum dose of 113 grams over the course of the study. The treatment period is set to a maximum of 380 days. The tablets undergo a process of deblistering and reblistering to ensure the same level of protection as the original packaging. Participant compliance with the dosing schedule will be monitored throughout the trial.

The study also includes a **Placebo IRBESARTAN EG 150 mg**, which serves as the comparator treatment. The placebo is designed to mimic the appearance and administration route of the active medication, ensuring the double-blind nature of the trial. The placebo is administered orally, in the same frequency and dosage form as the active treatment, to maintain consistency across the study groups. The placebo is utilized to assess the efficacy and safety of the experimental medication by providing a baseline for comparison.

Efficacy in the clinical trial titled "Impact of a treatment with angiotensin receptor blocker on outcome after acute kidney injury in patients discharged from the ICU 'START-or-NOT' trial" will be assessed using both primary and secondary endpoints. The primary endpoint is the time to **MACE** (major adverse cardiovascular events), which is a composite outcome consisting of all-cause mortality and all unscheduled hospital readmissions for cardiovascular events, such as acute heart failure, stroke, and acute coronary syndrome, during the year following ICU or Transitional Care Unit (TCU) discharge.

Secondary endpoints include several parameters: albuminuria greater than 0.3 g/day one year after ICU or TCU discharge, the occurrence of chronic kidney disease one year after discharge defined as an estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73m², a decrease in estimated glomerular filtration from baseline to one year after enrollment, changes in chronic kidney disease staging one year after enrollment, new episodes of acute kidney injury requiring hospitalization, hyperkalemia greater than 6 mmol/L, death, and the collection of biological samples at inclusion and at the end of the study.