Phase 2b Multicenter, Randomized, Double-Blind, Placebo-Controlled Study on TIN816 Efficacy and Safety in Sepsis-Associated Acute Kidney Injury

The primary objective of this study is to evaluate the **dose response relationship** of TIN816 on renal function, specifically measured by creatinine clearance (CrCl), in participants with **Sepsis-associated Acute Kidney Injury** (SA-AKI). This is clinically relevant as it aims to determine the optimal dosing of TIN816 to improve renal function in this patient population, potentially leading to better management and outcomes in SA-AKI.

Secondary objectives include:

• Evaluating the effect of TIN816 versus placebo in reducing major adverse kidney events (MAKE).
• Assessing the effect of TIN816 versus placebo in improving renal function.
• Investigating the effect of TIN816 versus placebo in improving overall health condition.
• Evaluating the safety and tolerability of TIN816 versus placebo.

These secondary objectives are important for understanding the broader impact of TIN816 on kidney health and overall patient well-being, as well as ensuring the treatment's safety profile.

The clinical trial involves a total of **201 participants** diagnosed with **sepsis-associated acute kidney injury**. The study population includes both male and female subjects, aged between **18 to 85 years**. Participants are selected based on their admission to an ICU or intermediate care unit, with a diagnosis of sepsis as per the Sepsis-3 criteria, and acute kidney injury (AKI) Stage 1 or greater. The trial population is characterized by a vulnerable group, given the critical nature of their health status. Lifestyle considerations such as diet and physical activity are not specified, but the inclusion criteria emphasize the acute medical condition of the participants. The selection process ensures that individuals have a confirmed or suspected infection with an acute increase in the SOFA score, excluding the renal component, and a significant rise in serum or plasma creatinine levels. This trial aims to evaluate the dose-response relationship of TIN816 on renal function, specifically measured by creatinine clearance in this specific patient group.

The clinical trial is a **randomized**, **double-blind**, placebo-controlled, four-arm, parallel-group, dose-finding phase 2b study designed to evaluate the efficacy and safety of TIN816 in the treatment of patients with **sepsis-associated acute kidney injury** (SA-AKI). The primary objective is to assess the dose-response relationship of TIN816 on renal function, specifically measured by creatinine clearance (CrCl). The trial is expected to commence recruitment on June 3, 2024, and conclude by November 28, 2025. Participants will be randomly assigned to receive either TIN816 or a placebo, with the placebo being a sterile 0.9% sodium chloride solution administered intravenously.

The study will involve several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 to 85 years), admission to an ICU or high dependency care unit, and a diagnosis of sepsis and acute kidney injury (AKI) stage 1 or greater. Following randomization, participants will undergo regular follow-up visits to monitor renal function and other health parameters. The primary endpoint is the weighted average of the area under the time-corrected endogenous creatinine clearance curve from Day 1 to Day 8. Secondary endpoints include major adverse kidney events, changes in renal function, and adverse events up to Day 90.

The expected duration of participant involvement is approximately 90 days, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The study will also assess the composite endpoint of major adverse kidney events, including death, use of renal replacement therapy (RRT), and a significant reduction in estimated glomerular filtration rate (eGFR) at Day 90. The trial will ensure rigorous monitoring of safety and efficacy through scheduled assessments and data collection throughout the study period.

The clinical trial involves the administration of **TIN816**, an investigational medication, which is provided in the form of a **powder for solution for injection/infusion**. The active substance, TIN816, is a protein of other origin, developed by Novartis Pharma AG. The medication is administered intravenously, with a maximum daily dose of 4.0 mg/kg. The treatment period is limited to a maximum of one day. The study aims to evaluate the dose-response relationship of TIN816 on renal function, specifically measuring creatinine clearance in participants with sepsis-associated acute kidney injury (SA-AKI). Compliance with the dosing schedule is monitored throughout the trial to ensure accurate assessment of the medication's efficacy and safety.

In addition to the experimental treatment, a **sterile 0.9% sodium chloride solution** is used as a placebo. This solution is administered to participants randomized to the placebo group. The placebo is provided in a ready-to-use 100 mL infusion bag and is also administered intravenously. The use of a placebo allows for a controlled comparison to assess the true effects of TIN816 on the study's primary endpoints. The administration of the placebo follows the same schedule as the experimental treatment to maintain the study's double-blind design.

The efficacy of TIN816 in the treatment of patients with **Sepsis-associated Acute Kidney Injury (SA-AKI)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the weighted average of the area under the time-corrected endogenous creatinine clearance curve from Day 1 to Day 8 (AUC1-8). This measurement will provide insight into the renal function improvement over the initial treatment period.

Secondary endpoints include a composite endpoint of major adverse kidney events (MAKE), which encompasses death, the use of renal replacement therapy (RRT), and a ≥25% reduction in estimated glomerular filtration rate (eGFR) at Day 90. Additional renal function endpoints will be evaluated, such as the area under the time-corrected endogenous serum creatinine and serum cystatin C curves from Day 1 to Day 14 and Day 1 to Day 30, and the weighted average of the area under the time-corrected endogenous creatinine clearance curve from Day 5 to Day 14 (AUC5-14). The study will also monitor any use of RRT during the trial, RRT dependency at Day 90, days alive and free of RRT at Day 90, the proportion of participants with an eGFR decline of ≥25% at Day 90, and changes in the KDIGO AKI stage at Day 14.

Furthermore, changes in the sequential organ failure assessment (SOFA) score from baseline to Day 30 will be recorded, alongside adverse events and serious adverse events. These efficacy parameters will be collected and analyzed at specified timepoints to determine the therapeutic impact of TIN816 on renal function in the context of SA-AKI.