Precision Dosing of Beta-lactam Antibiotics in Critically Ill Children (MOMENTUM)

Early Model-Informed Precision Dosing of Beta-lactam Antibiotics in Critically Ill Children: Big Solution for Small People?

The overall objective of this study is to investigate the impact of early model-informed precision dosing (MIPD) on target attainment of three beta-lactam antibiotics (amoxicillin-clavulanic acid, piperacillin-tazobactam and meropenem) in critically ill children. This evaluation includes a comparison with the more standard approach on clinical and patient-oriented measures.

Study Overview

• Status: Not yet recruiting
• Conditions: Amoxicillin-clavulanate; Piperacillin-tazobactam; Meropenem
• Intervention / Treatment: Drug: Beta-lactam antibiotic; Device: Beta-lactam model-informed precision dosing

• Study Type: Interventional
• Enrollment (Estimated): 58
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Pieter De Cock, Prof.; Phone Number: +32 9 332 29 69; Email: pieter.decock@uzgent.be

Study Locations

• Belgium
  • Ghent, Belgium, 9000
    • Ghent University Hospital
    • Contact: Pieter De Cock, Prof.; Phone Number: +32 9 332 29 69; Email: pieter.decock@uzgent.be
    • Principal Investigator: Evelyn Dhont

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subject aged between 0 - 17 years 10 months.
• Subject admitted to a participating ward unit (Neonatal Intensive Care Unit, Pediatric Intensive Care Unit, Pediatric Hematology-Oncology unit).
• Strongly suspected or confirmed systemic infection.
• Subject planned to start on intravenous amoxicillin-clavulanic acid, piperacillin-tazobactam or meropenem treatment at least aimed for a minimum duration of two days at time of inclusion. If the subject was previously treated with the same beta-lactam, the minimum interval to the previous beta-lactam treatment episode is
• 40 hours for amoxicillin-clavulanic acid (based on elimination half-life)
• 8 hours for piperacillin-tazobactam and meropenem (based on elimination half-life) Subject planned to start on intravenous amoxicillin (without clavulanic acid) will not be included.
• Informed consent/assent signed by parents or legal representatives of the subject.
• Not previously enrolled in this trial.

Exclusion Criteria:

• Subject with serum creatinine level ≥ 2 mg/L at inclusion.
• Subject receiving (or planned to receive) haemofiltration, extracorporeal membrane oxygenation, hemodialysis or peritoneal dialysis, molecular adsorbent recirculating system or any other exchange technique.
• Subject receiving (or planned to receive) body cooling.
• Subject death is deemed imminent and inevitable.
• Reporting of first dosing advice (based on blood sampling) is not possible within 28 hours (*) after start treatment.
• The subject is known or suspected to be pregnant.
• The subject has a known allergy to the specific beta-lactam antibiotic.

(*) The first (a posteriori) dose calculation and dose adjustment if necessary, is performed within a maximum timeframe of 28 hours after start of treatment (i.e. maximum timeframe to first dose adjustment).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of Care beta-lactam treatment; Beta-lactam standard-of-care dosing regimen, as currently used at participating wards, during 28 day study period	Drug: Beta-lactam antibiotic; amoxicillin-clavulanic acid, piperacillin-tazobactam, meropenem treatment; Other Names: piperacillin-tazobactam; meropenem; amoxicillin-clavulanic acid
Experimental: Beta-lactam model-informed precision dosing; fT>MIC-based model-informed precision dosing of beta-lactam antibiotics using a dosing calculator during 28 day study period.	Drug: Beta-lactam antibiotic; amoxicillin-clavulanic acid, piperacillin-tazobactam, meropenem treatment; Other Names: piperacillin-tazobactam; meropenem; amoxicillin-clavulanic acid; Device: Beta-lactam model-informed precision dosing; A dosing calculator is used for the prediction of starting doses (a priori dose predictions) and follow-up doses (a posteriori calculations), using a target 100% fT>MIC.; Other Names: Dosing calculator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects reaching the therapeutic target 100% fT>MIC	fT>MIC refers to the percentage of the dosing interval during which the beta-lactam concentration remains above the Minimum Inhibitory Concentration (MIC). A target lower boundary for trough concentrations is set to achieve 100% fT>MIC. A conservative upper threshold for trough concentrations of 100% fT>4xMIC is used. Therefore, the therapeutic target range is 10-40 mg/L for amoxicillin (*), 18-72 mg/L for piperacillin (**) and 2-8 mg/L for meropenem (***). (*) 10 mg/L for amoxicillin: taking into account a EUCAST breakpoint (for Escherichia coli infections) of 8 mg/L and a plasma protein binding of 18%. (**) 18 mg/L for piperacillin: taking into account a EUCAST breakpoint (for wild-type Pseudomonas spp. infections) of 16 mg/L and a plasma protein binding of 9%. (***) 2 mg/L for meropenem: taking into account a EUCAST breakpoint of 2 mg/L (for wild-type Enterobacterales species) and a plasma protein binding of 2%.	At 48 hours after start of beta-lactam treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects reaching the therapeutic target 100% fT>MIC	The therapeutic target range is 10-40 mg/L for amoxicillin, 18-72 mg/L for piperacillin and 2-8 mg/L for meropenem.	At 120 hours after start of beta-lactam treatment
Proportion of subjects reaching the therapeutic target 100% fT>MIC	The therapeutic target range is 10-40 mg/L for amoxicillin, 18-72 mg/L for piperacillin and 2-8 mg/L for meropenem.	Within the interval 48 to 72 hours after start of beta-treatment
Hospital length-of-stay	Number of days from randomization to hospital discharge. Patients who are not discharged from hospital within 28 days will be censored at 28 days, the maximum follow up time. Patients who die before hospital discharge will also be censored at 28 days.	From date of randomization until date of hospital discharge, with a maximum of 28 days.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects with supratherapeutic beta-lactam concentration	A supratherapeutic concentration is defined as > 40 mg/L for amoxicillin, > 72 mg/L for piperacillin and > 8 mg/L for meropenem.	At 48 hours and at 120 hours after start of beta-lactam treatment
Mean percentage of time above the therapeutic target 100% fT>MIC	Above the therapeutic target is defined as > 10 mg/L for amoxicillin, > 18 mg/L for piperacillin and > 2 mg/L for meropenem.	Within the interval 0 hours (baseline) to 120 hours (Day 5) after start of beta-treatment.
Proportion of subjects with clinical cure	Clinical cure will be defined as the completion of the beta-lactam treatment course (on or prior to test-of-cure day 14) without recommencement of antibiotic therapy within 48 hours of cessation. Change of antibiotic therapy (i.e. either escalation or de-escalation) for the same indication for which the beta-lactam antibiotic was commenced is considered part of the antibiotic treatment course. Participants discharged from the hospital within 14 days after start of beta-lactam antibiotic will be considered to meet the definition of clinical cure.	At day 14 after start of beta-lactam treatment
Number and type of adverse events and serious adverse events, considered to be related to study assigned dosing method (possibly, probably or definitely)		From start date of beta-lactam treatment until stop date of beta-lactam treatment (up to 28 days)
Feasibility and compliance endpoint: time elapsed from blood collection to TDM concentration result availability	Blood samples will be collected within the first five days (120 hours) after starting beta-lactam treatment. A maximum of 8 blood samples will be taken from subjects in both the control and intervention group.	Blood samples taken within 120 hours of starting beta-lactam treatment (0-120 hours)
Feasibility and compliance endpoint: time elapsed from first dose of antimicrobial to TDM concentration result availability		The first two blood samples are collected within a maximum timeframe of 24 hours after start of beta-lactam treatment. TDM concentration is measured once a day and only on weekdays.
Feasibility and compliance endpoint: number of possible dose adjustments	Number of times a dose could be adjusted based on the TDM concentration result. Three blood samples are taken within 48 hours after start of beta-lactam treatment: The first two blood samples are collected within a maximum timeframe of 24 hours after start of treatment. One random sample is taken between 24 and 48 hours after start of treatment.	At 48 hours after start of beta-lactam treatment
Feasibility and compliance endpoint: Proportion of dosing advices implemented (before the next planned dose) by the prescriber		From start date of beta-lactam treatment until stop date of beta-lactam treatment (up to 28 days).

Collaborators and Investigators

• Sponsor: University Hospital, Ghent
• Investigators: Principal Investigator: Evelyn Dhont, Dr., Ghent University Hospital, Princess Elisabeth Children's Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): April 22, 2025
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: January 13, 2025
• First Submitted That Met QC Criteria: April 8, 2025
• First Posted (Actual): April 16, 2025

Study Record Updates

• Last Update Posted (Actual): April 16, 2025
• Last Update Submitted That Met QC Criteria: April 8, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: meropenem; critically ill children; amoxicillin-clavulanate; model-informed precision dosing; dose calculator; piperacillint-tazobactam
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; beta-Lactamase Inhibitors; Meropenem; Tazobactam; Piperacillin, Tazobactam Drug Combination; Beta Lactam Antibiotics; Amoxicillin; Anti-Bacterial Agents; Lactams; beta-Lactams; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination; Piperacillin
• Other Study ID Numbers: ONZ-2024-0295; 2024-516447-12-00 (Ctis)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No