Clinical trial NCT04141657: Safety Analysis of Antimicrobial Pharmacotherapy in Intensive Care Unit at Pediatric Hospital
Official title: Observational Prospective Multidirectional Study on the Safety of Antimicrobial Pharmacotherapy in Intensive Care Unit (ICU) Children Aged 0-17
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Drug Therapy
Keywords: neonates
antimicrobial pharmacotherapy
pharmacotherapy adverse events
neonatal Intensive Care Unit
safety
Lead sponsor: National Medical Research Center for Children's Health, Russian Federation
Sponsor class: OTHER_GOV
Collaborators: name: Russian Medical Academy of Continuous Professional Education
name: Morozov Children's Municipal Clinical Hospital of the Moscow City Health Department State-Financed
First posted: 2019-10-28
Enrollment: 100
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The study will enroll the participants from the patients of the Intensive Care Unit at Morozov Children's City Clinical Hospital of the Moscow City Health Department, Moscow, Russian Federation.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Adverse events frequency
timeFrame: From baseline until the date of first documented progression, assessed up to 1 month
measure: ECG QT Interval change
timeFrame: Change from screening QT Interval at 1 month
Secondary outcomes:
Other outcomes:
Locations:
city: Moscow
country: Russian Federation
facility: Morozov Children's City Clinical Hospital
Study officials:
affiliation: Morozov Children's City Clinical Hospital of the Moscow City Health Department
name: Anna Vlasova, PhD, MD
role: PRINCIPAL_INVESTIGATOR
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