A Phase IIa, Randomised, Double-blind, Placebo-controlled, Multicentre Study to Assess the Efficacy, Safety, and Tolerability of AZD4144 in Participants with Sepsis-associated Acute Kidney Injury (SERENIA)

The primary objective of this study is to evaluate the effect of AZD4144 on creatinine clearance in patients with sepsis-associated acute kidney injury. Creatinine clearance serves as a key indicator of renal function and glomerular filtration capacity, making it clinically relevant for assessing therapeutic efficacy in acute kidney injury management.

The secondary objectives include:

• To evaluate the effect of AZD4144 on additional measures of kidney function

• To evaluate the effect of AZD4144 on inflammatory biomarkers

• To assess the pharmacokinetics of AZD4144 in patients with sepsis-associated acute kidney injury

• To evaluate the effect of AZD4144 on MAKE30 (major adverse kidney events at 30 days)

• To evaluate the effect of AZD4144 on other clinical observations

This clinical trial enrolled a total of **58 participants** diagnosed with **sepsis-associated acute kidney injury (AKI)**. The study population comprised **adults aged 18 to 80 years**, including both **male and female subjects**. Participants were hospitalized individuals with a diagnosis of **sepsis** (suspected or confirmed) within 7 days of admission, who subsequently developed **acute kidney injury** classified as KDIGO Stage 1 or higher within 72 hours of sepsis diagnosis. The trial population was selected based on specific clinical criteria, including the presence of sepsis-induced hypotension requiring **vasopressor** and/or **inotrope therapy** for at least 4 hours following appropriate volume resuscitation. Eligible participants demonstrated persistent AKI after initial fluid resuscitation and had adequate baseline renal function, with pre-AKI **eGFR** of at least 30 mL/min/1.73 m² measured prior to hospital admission or at least 45 mL/min/1.73 m² measured at admission. The study included a **vulnerable population** and required that participants or their legally authorized representatives provide informed consent. All participants were able to receive the investigational drug within 36 hours of SA-AKI diagnosis.

This is a Phase IIa, randomized, double-blind, placebo-controlled, multicentre clinical trial designed to evaluate the efficacy, safety, and tolerability of AZD4144 in participants with sepsis-associated acute kidney injury. The study investigates a synthetic small molecule administered as a solution for infusion via intravenous infusion, compared against a matching placebo. The primary objective is to evaluate the effect of AZD4144 on Creatinine Clearance. The trial is expected to commence recruitment in January 2026 and conclude in January 2027.

Eligible participants include adults aged 18 to 80 years who are hospitalized with a diagnosis of sepsis (suspected or confirmed) within 7 days of admission and have developed acute kidney injury (KDIGO Stage ≥ 1) within 72 hours of sepsis diagnosis. Participants must be able to receive the study drug within 36 hours of SA-AKI diagnosis. Sepsis diagnosis must meet The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria, including suspected or confirmed bacterial infection and an acute increase of mSOFA score of 2 or more excluding the renal component. Participants must require vasopressor and/or inotrope therapy for sepsis-induced hypotension for at least 4 hours after appropriate volume resuscitation prior to randomization. The diagnosis of AKI with modified KDIGO Stage ≥ 1 must persist after initial volume resuscitation. Additionally, participants must have an outpatient pre-AKI reference eGFR ≥ 30 mL/min/1.73 m² or admission pre-AKI reference eGFR ≥ 45 mL/min/1.73 m². Informed consent must be provided by the participant or legally authorized representative.

The primary endpoint is the Area Under the Curve of 24-hour Creatinine Clearance. Secondary endpoints include days alive and free of kidney replacement therapy (KRT), days alive and free of modified KDIGO AKI Stage 2 or 3, and AUC measurements of serum creatinine, serum cystatin C, and measured glomerular filtration rate. Additional secondary endpoints assess Cmax/Cbaseline ratios for serum creatinine and serum cystatin C, AUC of plasma and urine IL-18 and IL-6, and plasma concentrations of AZD4144. The study also evaluates the occurrence of MAKE30 components, which include a decrease from pre-AKI reference eGFR of ≥ 25%, initiation of KRT at any time, or death from any cause. Further secondary endpoints include days alive and free of mechanical ventilation, days alive and outside of the ICU, rehospitalization rates, days alive and free of hospitalization, days alive and free of vasopressor and/or inotrope use, and AUC mSOFA score.

The trial involves a screening visit to assess eligibility and confirm the diagnosis of sepsis-associated acute kidney injury according to specified criteria. Following enrollment and randomization, participants receive either AZD4144 or placebo via intravenous infusion. The study includes follow-up visits to monitor efficacy parameters, safety assessments, and collection of biological samples for pharmacokinetic and biomarker analyses. The end-of-study visit evaluates long-term outcomes and safety. Participant involvement extends through the treatment period and follow-up phase as defined by the protocol. Early termination from the study may occur due to withdrawal of consent, adverse events requiring discontinuation, protocol violations, loss to follow-up, or investigator decision based on participant safety considerations.

The experimental treatment investigated in this clinical trial is **AZD4144**, a synthetic small molecule developed by AstraZeneca AB. AZD4144 is administered as a **solution for infusion** via **intravenous infusion**. The active substance is AZD4144, which is of chemical origin. The maximum treatment period is 999 days. This investigational medicinal product serves as the test intervention in this randomised, double-blind, placebo-controlled study evaluating efficacy, safety, and tolerability in participants with **sepsis-associated acute kidney injury**.

The comparator treatment consists of a **placebo** matched to AZD4144. The placebo is administered to maintain blinding in this controlled trial design. The placebo formulation is specifically designed for AZD4144 to ensure appropriate blinding of both investigators and participants throughout the study duration.

Efficacy will be assessed through the evaluation of renal function parameters and clinical outcomes in participants with sepsis-associated acute kidney injury. The primary efficacy endpoint is the Area Under the Curve (AUC) of 24-hour Creatinine Clearance (CrCl). Secondary efficacy endpoints include days alive and free of kidney replacement therapy (KRT), days alive and free of modified KDIGO AKI Stage 2 or 3, and AUC measurements of serum creatinine, serum cystatin C, and measured glomerular filtration rate (mGFR). Additional secondary endpoints encompass the ratio of maximum concentration to baseline (Cmax/Cbaseline) for serum creatinine and serum cystatin C, as well as AUC measurements of plasma and urine interleukin-18 (IL-18) and plasma and urine interleukin-6 (IL-6). Plasma concentrations of AZD4144 will be measured to support efficacy assessments. The occurrence of any of the following MAKE30 components will be evaluated: decrease from pre-AKI reference estimated glomerular filtration rate (eGFR) of 25% or greater, initiation of KRT at any time, and death from any cause. Other secondary endpoints include days alive and free of mechanical ventilation, days alive and outside of the intensive care unit (ICU), rehospitalisation, days alive and free of hospitalisation, days alive and free of vasopressor and/or inotrope use, and AUC of the modified Sequential Organ Failure Assessment (mSOFA) score.