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.

Clinic of Anaesthesiology and Intensive Care Tartu University Hospital Tartu Estonia

Clinical Trial Center Bambino Gesù Children's Hospital Rome Italy

Department of Biostatistics Erasmus MC Rotterdam The Netherlands

Department of Children and Adolescents Medicine Friedrich Alexander University Erlangen Nuremberg Erlangen Germany

Department of Pediatric Anesthesia and Intensive Care Astrid Lindgrens Childrens Hospital Karolinska University Hospital Stockholm Sweden

Department of Pediatrics 1st Faculty of Medicine Charles University Prague Prague Czech Republic

Fondazione per la Ricerca Farmacologica Gianni Benzi onlus Valenzano Italy

Institute of Child Health University College London London United Kingdom

Intensive Care and Department of Pediatric Surgery Erasmus MC Sophia Children’s Hospital Rotterdam The Netherlands

Therakind Ltd London United Kingdom

UCL School of Pharmacy University College London London United Kingdom

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ClinicalTrials.gov
NCT02509273

EudraCT
2014-003582-24