Evaluation of Nicotinamide Efficacy and Tolerance in Patients with Persistent Acute Kidney Injury: A Randomized Double-Blind Controlled Trial

The primary objective of this study is to demonstrate the **superiority** of **nicotinamide** (NAM) in achieving complete renal recovery in patients with persistent **acute kidney injury** (AKI) classified as stage 2 or 3 according to the KDIGO classification, despite 24 hours of standard care. This is clinically relevant as it aims to improve renal outcomes in patients with severe AKI, potentially reducing the need for prolonged renal replacement therapy and improving patient prognosis.

Secondary objectives include assessing the interest of NAM in terms of:

• **Clinical outcomes**: Complete renal recovery from acute kidney disease at days 30, 60, and 90 post-randomization, peak creatinine levels in the first 21 days post-treatment initiation, incidence of new dialysis, duration of renal replacement therapy, dialysis-free survival at days 30, 60, and 90, ICU and hospital length of stay, ICU-free days, and relapse of AKI.
• **Tolerance**: Safety of NAM use during the treatment period.
• **Medico-economic impact**: Efficiency of NAM supplementation compared to standard care in reducing healthcare costs and improving health benefits.
• **Prognosis**: Global and in-hospital mortality, incidence of new chronic kidney disease (CKD), and incidence of new end-stage renal disease (ESRD).
• **Pathophysiology**: Changes in serum and urine concentrations of relevant metabolites of NAD+ and tryptophan, prognosis value of seric and urinary nicotinamide metabolites, and identification of genetic variants associated with AKI recovery and response to NAM supplementation.

The clinical trial focuses on patients with **acute kidney injury**, specifically those classified as stage 2 or 3 according to the KDIGO classification, who have not achieved renal recovery after 24 hours of standard care. The study population includes both male and female participants aged 18 years and older, admitted to an adult intensive care unit of nephrology or a nephrology department. Participants are required to have suspected acute tubular necrosis as the primary cause of their kidney injury and must be free from mechanical ventilation, although hemodynamic support and non-invasive ventilation are permitted. The trial includes individuals affiliated with or beneficiaries of a social security system, and all participants must have provided written informed consent. The sponsor has not provided information regarding the total number of participants. The trial population is considered vulnerable, and the selection criteria ensure that participants are capable of providing informed consent and are not reliant on mechanical ventilation, which may influence the study's outcomes.

The clinical trial is designed to evaluate the **efficacy** and tolerance of **nicotinamide** supplementation in patients with **acute kidney injury**. This is a prospective, randomized, double-blind, controlled trial. Participants will be randomly assigned to receive either nicotinamide or a placebo, with the primary objective being to assess the rate of complete renal recovery at day 21 post-randomization. The trial is expected to commence recruitment on March 31, 2025, and conclude by June 30, 2027.

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 or older), admission to an intensive care unit, and persistent acute kidney injury stage 2 or 3 according to the KDIGO classification. Following randomization, participants will receive the investigational product or placebo orally, with a maximum daily dose of 3 grams and a total dose not exceeding 9 grams over a treatment period of up to 3 days.

Study visits will include follow-up assessments to monitor renal function and overall health status. The primary endpoint is the rate of complete renal recovery, defined by an estimated glomerular filtration rate (eGFR) greater than 60 ml/min or a return to baseline eGFR ± 3, assessed at day 21. Participants will be involved in the study for approximately 21 days, with conditions for early termination including withdrawal of consent or adverse events that compromise safety.

The clinical trial involves the administration of **nicotinamide** as the experimental medication. Nicotinamide is provided in the form of a film-coated tablet. The active substance, nicotinamide, is of chemical origin. The dosage regimen for nicotinamide involves a maximum daily dose of 3 grams, with a total maximum dose of 9 grams over the treatment period. The route of administration is oral, and the treatment duration is limited to a maximum of 3 days. The trial aims to evaluate the efficacy and tolerance of nicotinamide supplementation in patients with persistent acute kidney injury, classified as stage 2 or 3 according to the KDIGO classification, despite 24 hours of standard care.

In addition to the experimental treatment, a non-experimental treatment is utilized in the study as a comparator. This involves the use of **cellulose microcrystalline**, which serves as a placebo. The placebo is designed to match the experimental treatment in appearance but does not contain the active substance. The placebo is administered in a manner consistent with the experimental treatment to maintain the double-blind nature of the trial. The use of a placebo allows for the assessment of the true efficacy of nicotinamide by providing a control for comparison.

The efficacy of nicotinamide supplementation in patients with persistent acute kidney injury will be assessed through a primary endpoint focused on the rate of complete renal recovery. This recovery will be evaluated at day 21 post-randomization. The criteria for complete renal recovery will be based on the estimated glomerular filtration rate (**eGFR**). If the baseline eGFR is unknown, a successful outcome will be defined as an eGFR greater than 60 ml/min at day 21. If the baseline eGFR is available, success will be determined by a return to the baseline eGFR within a margin of plus or minus 3 ml/min.