Prospective Evaluation of Model-Informed Precision Dosing of Vancomycin Hydrochloride in Critically Ill Adults with Serious Infections

The primary objective of this clinical trial is to prospectively evaluate the performance of a **model-informed precision dosing tool** in achieving desirable intravenous vancomycin exposure targets over 70% of the treatment time in critically ill adults. This is clinically relevant as it aims to optimize vancomycin dosing, ensuring effective treatment of serious infections while minimizing toxicity.

Secondary objectives include:

• Assessing vancomycin treatment AUC24 based target attainment while doses are optimized using the developed model selection and dosing tool.
• Evaluating the safety of the vancomycin model selection and dosing tool.
• Determining whether effective AUC24 can be achieved with concentrations in the lower Ctrough based TDM range of 10-15 mg/kg.

The clinical trial involves participants who are **adults aged 18 years and older** admitted to the tertiary intensive care unit at Tartu University Hospital. The study population includes both male and female subjects, and it is noted that a vulnerable population is selected. Participants are individuals with serious infections requiring treatment with intravenous vancomycin, as determined by the treating physician. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on the necessity for intravenous vancomycin treatment, as assessed by the treating doctor. No specific lifestyle considerations such as diet, physical activity, or habits have been highlighted in the available data.

The clinical trial is designed to evaluate the efficacy of a model-informed precision dosing tool for **vancomycin hydrochloride** in critically ill adults with serious infections requiring intravenous treatment. This is a prospective, low-intervention, phase IV trial, aiming to achieve desirable vancomycin exposure targets over 70% of the treatment duration. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from February 2024 to February 2026, with participant involvement expected to last up to 12 weeks, depending on individual treatment needs.

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) and the necessity for vancomycin treatment as determined by a treating physician. Follow-up visits will be scheduled to monitor the therapeutic target range of vancomycin, defined as an AUC24 of 400-600 µg/mL x hr, and to assess secondary endpoints such as the median proportion of time within the target range, clinical outcomes, and any adverse events. The end-of-study visit will evaluate the attainment of clinical cure and overall treatment success.

Participants may be withdrawn from the study if they experience significant adverse effects, fail to adhere to the study protocol, or if the treating physician deems it necessary for their safety. The primary endpoint is the proportion of patients maintaining the therapeutic target range for 70% of the treatment time, while secondary endpoints include mortality rates, length of hospitalization, and the occurrence of acute kidney injury. The trial's findings will contribute to optimizing vancomycin dosing strategies in critically ill patients, potentially improving clinical outcomes and minimizing adverse effects.

The clinical trial involves the administration of **vancomycin hydrochloride**, an antibiotic used in the treatment of critically ill adults. The experimental medication is provided in the form of a **powder for solution for infusion**. The active substance, **vancomycin hydrochloride**, is of chemical origin. The medication is administered via **infusion**, with a maximum daily dose of 9000 mg and a total maximum dose of 756,000 mg over the course of the study. The treatment period is limited to a maximum of 12 weeks. The study aims to evaluate the performance of a model-informed precision dosing tool to achieve desirable intravenous vancomycin exposure targets over 70% of the treatment time.

Efficacy in this clinical trial will be assessed by evaluating the performance of a model-informed precision dosing tool for **vancomycin hydrochloride** in critically ill adults. The primary endpoint is the proportion of patients who maintain the vancomycin therapeutic target range, defined as an AUC24 of 400-600 µg/mL x hr, for 70% of the treatment time when the dose is optimized using the developed tool. Secondary endpoints include the median proportion of time spent within the therapeutic target range during treatment, the proportion of patients achieving the target AUC24 within the first 24 hours and between 24-48 hours after treatment initiation, and the proportion of patients with an average AUC24 in the target range.

Additional secondary endpoints involve clinical outcomes such as mortality at discharge from the intensive care unit, length of hospitalization, length of vancomycin treatment, and attainment of clinical cure. The study will also assess the cumulative vancomycin dose, corresponding AUC24 and Ctrough levels during the treatment period, and the occurrence and worsening of acute kidney injury according to KDIGO AKI criteria. The percentage of measured vancomycin Ctrough values exceeding 20 mg/L and the proportion of time spent above the recommended AUC24 >600 µg/mL x hr will also be evaluated. The proportion of Ctrough values under, over, or within target ranges will be compared to corresponding AUC24 values.