Validation of Betalactam ML Prediction Models - TDMAide (TDMAide)

Validation of Uncertainty Quantifying Machine Learning Models to Predict Beta-lactam Antimicrobial Concentrations in ICU Patients

The goal of this study is to learn about the real wold behavior of developed machine learning models that predict the plasma concentration of piperacillin-tazobactam and meropenem in critically ill patients admitted to the intensive care unit (ICU).

The main aim of the study is to validate the performance of these machine learning models. To this end, daily measured plasma concentrations of the investigated antimicrobials will be compared with the predicted concentration by the machine learning algorithms.

Additional goals of the study include:

• To describe the total plasma concentration over time of piperacillin-tazobactam and meropenem in patients admitted to the ICU.
• To quantify the correlation between plasma concentrations of piperacillin-tazobactam and meropenem and the development of side effects.
• To evaluate the perceived necessity of therapeutic drug monitoring (TDM) of consultants and physicians in training working in the ICU.
• To evaluate the perceived added value of daily TDM.

Samples (where possible taken routinely) from participating patients will be analyzed for meropenem and piperacillin-tazobactam plasma concentration. Participating physicians will be asked to fill in a short daily questionnaire during the time a patient under their care is treated with the antimicrobial under investigation.

Study Overview

• Status: Not yet recruiting
• Conditions: Infections
• Intervention / Treatment: Device: Prediction of plasma concentration of piperacillin-tazobactam or meropenem; Diagnostic test: Determination of plasma concentration of piperacillin-tazobactam or meropenem; Other: Daily short questionnaire

• Study Type: Interventional
• Enrollment (Estimated): 600
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Thomas De Corte, MD; Phone Number: 0032093324134; Email: thomas.decorte@uzgent.be

Study Locations

• Belgium
  • Ghent, Belgium, 9000
    • University Hospital, Ghent
    • Principal Investigator: Jan De Waele, MD, PhD
    • Contact: Jan De Waele, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Patients

Inclusion Criteria:

• Admission to the ICU.
• Age above 18 years old.
• Treatment with piperacillin-tazobactam or meropenem for less than 48 hours.

Exclusion Criteria:

• Pregnant or lactating patients.
• Limitation of therapy beyond "Do not resuscitate".
• Expected demise within 48 hours after inclusion.
• Haemoglobin < 7 g/dL.
• Previous inclusion in this study for a treatment course with the same antimicrobial.

Consultants and physicians in training

Inclusion Criteria:

• Consultant or physician in training working in the ICU.

Exclusion Criteria:

• None

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Patients; Patients admitted to the ICU who are treated with piperacillin-tazobactam or meropenem.	Device: Prediction of plasma concentration of piperacillin-tazobactam or meropenem; For included patients, a prediction will be made by developed machine learning models about the expected plasma concentration of piperacillin-tazobactam or meropenem by using routinely collected health care data.; Diagnostic test: Determination of plasma concentration of piperacillin-tazobactam or meropenem; For included patients, the total plasma concentration of piperacillin-tazobactam or meropenem will be determined. Were possible, this will be done using a blood sample that was collected during routine daily bloodwork which is performed in the morning. If no routine sample is available, a study specific sample will be drawn at approximately the same time as a routine sample would be drawn.
Other: Physicians; Physicians in training or consultants who care for patients that are included in the study.	Other: Daily short questionnaire; Physicians who care for patients included in the study will be asked to fill in a short daily questionnaire that evaluates the perceived necessity and added value of daily therapeutic drug monitoring.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference between predicted (TDMAIde) and measured (via HPLC-MS/MS method) plasma concentrations	The difference between the predicted concentration (from the TDMAide software) and the concentration range based on the measured concentration (measured from the blood sample from the patient and analyzed using a HPLC-MS/MS method, with and without taking into account intra- and inter measurement variabilities of the HPLC-MS/MS method.	Through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma concentration (determined via HPLC-MS/MS) trends	Trends in total plasma concentration over time of piperacillin-tazobactam and meropenem in patients admitted to the ICU	Through study completion, an average of 1 year
Correlation between plasma concentrations (measured by HPLC-MS/MS) and side effects as percentage of patients experiencing the side effect	The correlation between plasma concentrations of piperacillin-tazobactam and meropenem and the development of renal (decline in urinary output, rise in serum creatinin), gastro-intestinal (C. difficile infections, stool consistency, elevation of ALT/AST/gamma GT/Alkalic fosfatase/INR/APTT/bilirubin), neurological (delirium as measured by Intensice Care Delirium Screening Checklist - ICDSC) or hematological (Rise or fall of thrombocytes, development of leucopenia/agranulocytosis/eosinophelia/hemolytic anemia) side effects.	Through study completion, an average of 1 year
Perceived necessity of therapeutic drug monitoring	The perceived necessity of therapeutic drug monitoring of consultants and physicians in training working in the ICU by evaluating the perceived necessity collected during the surveys with the measured plasma concentrations.	Through study completion, an average of 1 year
Perceived added value of therapeutic drug monitoring	The perceived added value of daily therapeutic drug monitoring from the responses to the survey	Through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: University Hospital, Ghent
• Collaborators: Imec; Research Foundation Flanders
• Investigators: Principal Investigator: Jan De Waele, MD, PhD, University Hospital, Ghent

Study record dates

Study Major Dates

• Study Start (Estimated): April 26, 2024
• Primary Completion (Estimated): May 31, 2025
• Study Completion (Estimated): May 31, 2025

Study Registration Dates

• First Submitted: June 9, 2023
• First Submitted That Met QC Criteria: September 4, 2023
• First Posted (Actual): September 7, 2023

Study Record Updates

• Last Update Posted (Actual): April 12, 2024
• Last Update Submitted That Met QC Criteria: April 11, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Intensive Care Unit; Artificial Intelligence; Machine Learning; Meropenem; PK/PD; Piperacillin-tazobactam
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Meropenem; Piperacillin; Tazobactam; Piperacillin, Tazobactam Drug Combination
• Other Study ID Numbers: CIV-23-04-042892

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data will be made available upon reasonable request and after approval by the appropriate ethical and regulatory bodies.
• IPD Sharing Time Frame: At publication of the results
• IPD Sharing Access Criteria: Individual participant data will be made available upon reasonable request and after approval by the appropriate ethical and regulatory bodies.
• IPD Sharing Supporting Information Type: ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No