Safety Analysis of Antimicrobial Pharmacotherapy in Intensive Care Unit at Pediatric Hospital

Completed

• Conditions: Drug Therapy
• Interventions: Other: Pharmacogenetic test

• Registration Number: NCT04141657
• Lead Sponsor: Anna Vlasova

Brief Summary

Changes in the metabolic ability of cytochrome P-450 during child development can affect both bioavailability and elimination depending on the involvement of intestinal and hepatic metabolic processes. The age-related variability of cytochrome P-450 isoenzymes in children has been described since 2010. The variability in the development of the activity of specific cytochrome P-450 isoenzymes illustrates why the pharmacogenetic features of the medicine use at different age periods should be studied for individual drugs. This will provide an understanding of the mechanisms for preventing adverse events appearing in pediatric intensive care units while more common antimicrobial pharmacotherapy is administered. Improved knowledge of the pharmacogenetic characteristics of cytochrome P-450 and the unintended consequences of modulation of its isoenzymes could provide an understanding of the susceptibility to adverse events in children in critical conditions staying at Intensive Care unit (ICU).

Detailed Description

An observational prospective multidirectional study on the safety of antimicrobial pharmacotherapy in ICU children aged 0-17. The endpoints of the safety assessment are the frequency of adverse events with antimicrobial agents (AMA); electrocardiography (ECG), fibrinogen concentration, international normalized ratio (INR) and prothrombin index (IPT) at screening and at the end of the treatment course, and pharmacogenetic indicators (a more detailed study of the safety profile). A demonstration of the effectiveness of each of these comparisons of inequality will be based on the hypothesis testing approach, according to which the null hypothesis concludes that there is no difference between groups receiving different AMA combinations for the endpoint of interest; and an alternative hypothesis supposes a difference between treatment groups receiving different AMA combinations. Changes in the sequential organ failure assessment (SOFA) scale in dynamics compared to the baseline will be analyzed using the Mixed-Effect Model Repeated Measure (MMRM) model which assume the baseline, gender, age, AMA combination, and the duration of the AMA course. For a population of subjects aged 0-3 months, the analysis will be performed using the analysis of covariance (ANCOVA) model with the effects of INR, fibrinogen, and IPT values at the initial level for gender, age, and AMA combination in the treatment groups.

To assess the secondary endpoint for the general population - the frequency and timing of the transition to de-escalation at ICU, cluster analysis will be conducted to identify the relationship of specific AMA combinations with the possibility of de-escalation in ICU children.

Studies will be conducted to reveal the relationship in gene polymorphism encoding isoenzymes of the cytochrome P-450 biotransformation, and the relationship between the activity of transport proteins with the indicators of effectiveness and safety of antimicrobial pharmacotherapy. The lack of pharmacological safety studies in children administered medicine combinations to overcome pan-resistant gram-negative infection provides relevant prerequisites for this study.

Study Timeline

• Study First Submitted: 2019-10-09
• Study First Submitted QC: 2019-10-24
• Study First Posted: 2019-10-28
• Study Start: 2020-02-01
• Primary Completion: 2021-08-28
• Study Completion: 2021-10-15
• Status Verified: 2022-03
• Last Update Submitted: 2022-03-04
• Last Update Posted: 2022-03-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

1. Intensive Care Unit (ICU) patient;

2. Community-acquired infections with risk factors for multidrug-resistant pathogens (risk factors for extended-spectrum β-lactamase (ESBL) - type II;

3. Nosocomial infections - type III:

   • IIIa: hospitalized during the period of 90 days, without prior antimicrobial agent (AMA) therapy outside the ICU (risk factors for ESBL);
   • IIIb: prolonged hospitalization (> 7 days) and/or stay at ICU for more than 3 days and/or previous AMA therapy (risk factors for ESBL, carbenicillin-resistant (CARB-R), nonfermenting Gram-negative bacteria (NFGNB), methicillin-resistant Staphylococcus aureus (MRSA));

4. Nosocomial infections with a risk of invasive candidiasis - type IV (candida score ≥2 points);

5. Written informed consent for medical intervention signed by at least one parent or caregiver (legal guardian) or informed consent of a patient under 15 years of age;

6. Written informed consent for pharmacogenetic research signed by at least one parent or caregiver (legal guardian) or informed consent of a patient under 15 years of age.

Exclusion Criteria

1. Type I: patients with community-acquired infections and without risk factors for multidrug-resistant pathogens, without hospitalization during the previous 90 days;
2. Previous/concomitant therapy is not significant;
3. Children in the ward: children under guardianship are not eligible.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Group 1 (0-17 years)	Pharmacogenetic test	We will observe the treatment course in ICU pediatric patients, register adverse events (AEs) and serious adverse events (SAEs) if occur, and assess patient health status at the end of the performed therapy.

Primary Outcome Measures

Name	Time	Method
Adverse events frequency	From baseline until the date of first documented progression, assessed up to 1 month	Registered adverse events in participants during the treatment course
ECG QT Interval change	Change from screening QT Interval at 1 month	Assessment of QT Interval change at the end of the AMA course comparing with screening measurement

Trial Locations

Locations (1)

Morozov Children's City Clinical Hospital; 🇷🇺 Moscow, Russian Federation