Evaluation of Nicotinamide Supplementation in Preventing Major Adverse Kidney Events in Septic Shock: A Multicenter Randomized Controlled Trial

The primary objective of this study is to demonstrate the superiority of **Nicotinamide** supplementation compared to a placebo in patients experiencing septic shock who are admitted to intensive care. This is clinically relevant as septic shock is associated with high morbidity and mortality, and improving outcomes in this patient population could significantly impact clinical practice.

Secondary objectives include: - Increasing the number of days patients live without extra-renal treatment by day 30. - Reducing the incidence of major renal adverse events at day 90 (MAKE 90). - Decreasing the length of hospital stay in intensive care. - Assessing the tolerance of Nicotinamide at the doses used in the study. - Evaluating the efficacy of Nicotinamide supplementation based on the urinary quinolonate/tryptophan ratio on day 0 and day 1.

The clinical trial focuses on patients experiencing **adverse kidney events during septic shock**. The study population includes both male and female adults, specifically those aged 18 years and older. Participants are required to have septic shock, characterized by sepsis with persistent hypotension necessitating vasopressors to maintain a mean arterial pressure (MAP) of at least 65 mm Hg, along with a serum lactate level greater than 2 mmol/L despite adequate volume resuscitation. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **nicotinamide** supplementation in preventing major adverse kidney events during septic shock. This study is a multicenter, randomized, controlled trial with a double-blind design to ensure unbiased results. The trial aims to demonstrate the superiority of nicotinamide compared to a placebo in patients admitted to intensive care with septic shock. The trial is expected to run from June 14, 2021, to September 14, 2024, with a maximum treatment period of three 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 adult patients with septic shock requiring vasopressors and elevated serum lactate levels. Follow-up visits will occur on days 1, 2, 3, and 7 to monitor primary and secondary endpoints, including the incidence of acute kidney injury, days without renal replacement therapy, and liver toxicity. The end-of-study visit will assess the primary endpoint, which is the proportion of patients meeting criteria for MAKE30, including in-hospital mortality and renal dysfunction.

The expected length of participant involvement is approximately 30 days, with conditions for early termination including withdrawal of consent or adverse events that compromise patient safety. The trial will utilize **sodium chloride** solutions for infusion and injection as part of the placebo group, ensuring a controlled environment for evaluating the effects of nicotinamide. The study's primary and secondary endpoints will provide comprehensive data on the potential benefits of high-dose vitamin B3 supplementation in this critical patient population.

The clinical trial involves the administration of **nicotinamide** as the experimental medication. The product, marketed as VITAMINE PP AGUETTANT 500 mg/5 ml, is a **solution for injection**. The active substance, nicotinamide, is of chemical origin. The maximum daily dose is 1000 mg, with a total maximum dose of 3000 mg over a treatment period of up to 3 days. The administration route is intravenous, and the formulation is not pediatric. The trial aims to evaluate the efficacy of nicotinamide in preventing major adverse kidney events during septic shock.

Two non-experimental treatments are used as comparators in the study. The first is CHLORURE DE SODIUM 0,9 % AGUETTANT, a **solution for infusion** containing **sodium chloride**. This product is administered via intravenous perfusion. The maximum daily dose is 500 ml, with a total maximum dose of 1500 ml over a 3-day period. The second comparator is CHLORURE DE SODIUM FRESENIUS 0,9 %, a **solution for injection** also containing sodium chloride. This product is administered intravenously, with the same dosing schedule as the first comparator. Both sodium chloride solutions serve as placebos in the trial.

Participant compliance with the dosing schedule is monitored throughout the trial. The trial is designed to assess the superiority of nicotinamide supplementation compared to the placebo group in patients with septic shock admitted to intensive care. The study is conducted under strict adherence to clinical trial protocols to ensure the reliability and validity of the results.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of patients meeting one or more criteria for MAKE30, which includes in-hospital mortality, receipt of new renal replacement therapy (RRT), or persistent renal dysfunction defined as a final inpatient serum creatinine value that is at least two times the baseline serum creatinine on day 30. Secondary endpoints include the reduction in the incidence of moderate to severe acute kidney injury (AKI) as defined by stages 2 and 3 of the KDIGO 2012 classification, the increase in the number of days living without RRT (censored at death or at day 30), and the length of hospital stay for subjects discharged alive from resuscitation. Additional secondary endpoints involve the reduction of major renal adverse events at day 90 (MAKE 90), reduction of intensive care unit length of stay, and assessment of liver toxicity on days 1, 2, 3, and 7 through measurements of transaminases, bilirubin, alkaline phosphatase, and gamma-glutamyltransferase. Other secondary endpoints include the evaluation of nausea, vomiting, headache, flushing, and facial erythema, as well as the effectiveness of **Nicotinamide** supplementation according to the urinary quinolonate/tryptophan ratio on days 0 and 1.