A multicenter, randomized, controlled clinical trial is being conducted to evaluate the impact of model-informed precision dosing (MIPD) on vancomycin therapy in critically ill children. The study aims to determine if MIPD, guided by the InsightRX Nova web application, can improve vancomycin dosing accuracy and clinical outcomes compared to standard-of-care (SoC) practices.
Trial Design and Objectives
The trial is designed to assess the clinical utility of MIPD in pediatric intensive care units (PICUs). Participants are randomized to either the MIPD intervention arm or the SoC control arm. The primary objective is to compare the proportion of patients in each arm who achieve the target vancomycin area under the concentration-time curve (AUC24h) of 400–600 mg*h/L between 24 and 48 hours after the start of treatment. This AUC range is considered optimal for efficacy against methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcal bacteremia while minimizing the risk of nephrotoxicity.
Intervention: Model-Informed Precision Dosing (MIPD)
In the MIPD arm, vancomycin dosing is guided by the InsightRX Nova web application, which incorporates the vancomycin pharmacokinetic (PK) model developed by Colin et al. This model uses patient-specific data, including weight, age, and serum creatinine, to predict vancomycin concentrations and calculate optimal doses. The software also incorporates real-time checks and warnings to prevent dosing errors. Extra blood samples are taken in the interventional arm to allow for early and accurate AUC-based dose adjustment on subsequent doses.
The target AUC24h/MIC is defined between 400 and 600, assuming an MIC of 1 mg/L. In case of severe infections, typically the higher end of the target range is used.
Control Arm: Standard-of-Care (SoC) Dosing
Patients in the SoC arm receive vancomycin dosing according to institutional guidelines and dose adjustment nomograms, prescribed by the attending physician. Therapeutic drug monitoring (TDM) of vancomycin concentrations is performed as per standard practice, with trough samples taken before the second, third, fourth, or fifth dose for intermittent dosing regimens and around 24 hours after the start of loading dose for continuous dosing regimens. Dosing regimens are prescribed by the attending physician. Maintenance doses are based on the patient’s weight and estimated kidney function.
Key Endpoints and Outcome Measures
The primary endpoint is the proportion of patients reaching target 24 h AUC (400–600) between 24 and 48 h after the start. Secondary endpoints include:
- Proportion of patients with (worsening) AKI during vancomycin treatment, defined using neonatal and pediatric RIFLE criteria.
- Proportion of patients reaching target 24 h AUC (400–600) between 48 and 72 h after the start of treatment.
- Time to clinical cure, defined as the duration of vancomycin treatment without recommencement of antibiotics for the same indication within 48 hours after stopping.
- Ward unit and hospital length-of-stay.
- Thirty-day mortality.
Tertiary endpoints include the number of blood samples required to achieve the first target attainment, cumulative vancomycin dose, and the number of dose adjustments needed.
Sample Size and Statistical Analysis
The trial aims to enroll 332 patients, accounting for an estimated 15% dropout rate. This sample size is calculated to provide 80% power to detect a significant difference in the primary outcome, assuming a 70% target attainment rate in the MIPD group versus 50% in the SoC group, with adjustments for potential contamination between the study arms.
Safety Considerations and Discontinuation Criteria
Patients may be discontinued from the intervention if they require extracorporeal treatment (renal replacement therapy, extracorporeal membrane oxygenation, body cooling) or develop acute kidney injury RIFLE class failure. The treating physician can also discontinue the intervention for other safety reasons. The patient and/or parent/legal guardian of the patient may withdraw consent at any time during the study.
Significance
This trial has the potential to optimize vancomycin dosing in critically ill children, potentially improving clinical outcomes and reducing the risk of nephrotoxicity. The results will provide valuable evidence for the implementation of MIPD strategies in pediatric intensive care settings.
