The CLOSED trial; CLOnidine compared with midazolam for SEDation of paediatric patients in the intensive care unit:
Antje Neubert1, Manuel Alberto Baarslag2, Monique van Dijk2
1Department of Children and Adolescents Medicine, Friedrich-Alexander-University Erlangen/Nuremberg, Erlangen, Germany.
Insights
The CLOSED trial investigates clonidine as a sedative for ventilated children, comparing its safety and efficacy against midazolam. This research aims to support off-label use and marketing authorization for clonidine in pediatric critical care.
Area of Science:
- Pediatric Critical Care Medicine
- Clinical Pharmacology
- Anesthesiology
Background:
- Midazolam is the standard sedative in pediatric critical care but has limitations.
- Clonidine is increasingly used off-label for pediatric sedation, necessitating further research.
- Data on clonidine's pharmacokinetics, safety, and efficacy in mechanically ventilated children is limited.
Purpose of the Study:
- To evaluate the efficacy and safety of clonidine compared to midazolam for sedation in mechanically ventilated children.
- To gather data for a potential pediatric-use marketing authorization for clonidine.
- To investigate pharmacokinetic and pharmacodynamic relationships, pharmacogenetics, and clinical outcomes such as delirium and withdrawal.
Main Methods:
- A multicenter, double-blind, randomized, active-controlled non-inferiority trial (CLOSED study).
- 1:1 randomization between clonidine and midazolam in three age strata: <28 days, 28 days to <2 years, and 2-18 years.
- Primary endpoint: sedation failure; Secondary endpoints: PK/PD, pharmacogenetics, delirium, withdrawal, opioid use, neurodevelopment.
Main Results:
- Study is registered and actively recruiting patients (pre-results).
- Data collection is ongoing for primary and secondary endpoints.
- Statistical analysis will involve logistic regression for the primary endpoint.
Conclusions:
- The CLOSED trial is expected to provide crucial data on clonidine's role in pediatric sedation.
- Findings will inform clinical practice and regulatory decisions regarding off-label clonidine use.
- This research addresses a significant gap in evidence for sedatives in critically ill children.
Introduction:
Sedation is an essential part of paediatric critical care. Midazolam, often in combination with opioids, is the current gold standard drug. However, as it is a far-from-ideal agent, clonidine is increasingly being used in children. This drug is prescribed off-label for this indication, as many drugs in paediatrics are. Therefore, the CLOSED trial aims to provide data on the pharmacokinetics, safety and efficacy of clonidine for the sedation of mechanically ventilated patients in order to obtain a paediatric-use marketing authorisation.
Methods And Analysis:
The CLOSED study is a multicentre, double-blind, randomised, active-controlled non-inferiority trial with a 1:1 randomisation between clonidine and midazolam. Both treatment groups are stratified according to age in three groups with the same size: <28 days (n=100), 28 days to <2 years (n=100) and 2-18 years (n=100). The primary end point is defined as the occurrence of sedation failure within the study period. Secondary end points include a pharmacokinetic/pharmacodynamic relationship, pharmacogenetics, occurrence of delirium and withdrawal syndrome, opioid consumption and neurodevelopment in the neonatal age group. Logistic regression will be used for the primary end point, appropriate statistics will be used for the secondary end points.
Ethics:
Written informed consent will be obtained from the parents/caregivers. Verbal or deferred consent will be used in the sites where national legislation allows. The study has institutional review board approval at recruiting sites. The results will be published in a peer-reviewed journal and shared with the worldwide medical community.
Trial Registration:
EudraCT: 2014-003582-24; Clinicaltrials.gov: NCT02509273; pre-results.
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