The CLOSED trial; CLOnidine compared with midazolam for SEDation of paediatric patients in the intensive care unit: study protocol for a multicentre randomised controlled trial

Abstract

IntroductionSedation 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 analysisThe 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.EthicsWritten 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 RegistrationEudraCT: 2014-003582-24; Clinicaltrials.gov: NCT02509273; pre-results.

Optimizing clonidine dosage for sedation in mechanically ventilated children: A pharmacokinetic simulation study

“…The SLEEPs study regimen of a 3 µg/kg/hr loading dose followed by a variable infusion rate of 0‐3 µg/kg/hr achieved the highest median plasma concentrations with most patients above the target level after 5‐10 hours . The CloSed study neonatal regimen achieved below target plasma concentrations while a majority of the children older than 28 days achieved target concentrations after 20 hours …”

“…Three large‐scale clonidine RCTs have been attempted to date or are on‐going, in addition to one pilot RCT . Within these four RCTs, one study used a fixed bolus of 5 µg/kg six hourly via the nasogastric route, one study used a fixed infusion of 1 µg/kg/hr, and two studies used a loading bolus followed by a variable infusion rate up to 2 µg/kg/hr in the CloSed study and 3 µg/kg/hr in the SLEEPs study . The final observational study reflects local practice in PICUs in Ireland with a bolus dosage of 1‐2 µg/kg 6‐8 hourly.…”

“…Eligible studies were identified from a recent systematic review which included three clonidine RCTs . In addition, the ongoing CloSed trial was included . Dosage regimens used in local clinical practice in Ireland were also included …”

“…Evidence to support a particular dosage regimen of clonidine has also been limited. Of the randomized controlled trials (RCTs) previously performed, one previous study (Duffet et al) was a pilot study and not powered for efficacy outcomes, and two studies (SLEEPS and CloSed) encountered recruitment difficulties prohibiting analysis of pre‐planned outcomes. A final study (Hunseler et al) reported efficacy as an opioid‐sparing agent, though this was only observed in one age stratum, that of neonates.…”

“…Recruitment difficulties within the multisite European CloSed trial suggest evidence from RCTs of dosage regimen efficacy might remain elusive for the near future . A recent comparative effectiveness observational study included 692 children in Ireland who received clonidine while mechanically ventilated .…”