Primary:To assess the non-inferiority of the sedative properties of continuous intravenous (i.v.) clonidine compared to continuous i.v. midazolam in mechanically ventilated children and adolescents (0 -
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
sedatie
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is defined as sedation failure within the study treatment
period (a maximum of seven days).
Sedation failure is defined as:
When a subject*s assessment results are:
Numerical Rating Scale (NRS) score <4 and COMFORT-B score >22
OR
Numerical Rating Scale (NRS) score <4 and COMFORT-B score <=22->=11 AND Nurse*s
Interpretation of Sedation (NISS) score 1
at a point during the study where no further increase in IMP dose is permitted
as described in the dose escalation scheme.
Secondary outcome
* Primary PK parameters estimated will be clearance (CL), volume of
distribution (VD) and inter-compartmental clearance (Q). Additional parameters
include Cmax, AUC, t1/2, Csteadystate, Ctrough. PK measurements will be made
using sparse opportunistic sampling.
* PK-PD modelling will seek to elucidate the relationship between IMP
pharmacokinetics and sedation as measured by COMFORT-B score.
* The PK-PD covariate model will include demographics (e.g. age, weight),
clinical characteristics (e.g. reason for admission) and pharmacogenomics (see
Genetic parameters in Section 4.3.1)
* General safety and tolerability assessments
* Extent of withdrawal effects using the Sophia Observation withdrawal
Symptoms- Paediatric Delirium (SOS-PD) scale measured three times a day in
subjects who receive sedatives and/or opioids for 5 days or more and after
cessation of treatment in all subjects for at least 24 hours after treatment.
* The extent of delirium measured by the SOS-PD scale.
* Rebound hypertension monitored for at least 72 hours post cessation of
treatment.
* Percentage of respiratory depression per group.
* Adverse event reporting of symptoms indicative of post-ICU stress (e.g.
nightmares, confusion, hallucinations).
* Neurodevelopment of subjects recruited in lower age group (from birth to 27
days)
Background summary
Although clonidine is recommended by PICU guidelines as an alternative to
midazolam in critically ill children requiring i.v. sedation, there are limited
clinical data on PK, efficacy and safety available which by no means meet the
criteria for obtaining regulatory approval. Therefore, paediatricians are
forced to use the drug off-label in their patients. Moreover, age- and
weight-adapted parenteral formulations are lacking. Clonidine might have
favourable properties regarding tolerance and withdrawal, however, this has
never been studied.
Study objective
Primary:
To assess the non-inferiority of the sedative properties of continuous
intravenous (i.v.) clonidine compared to continuous i.v. midazolam in
mechanically ventilated children and adolescents (0 - <18 years) admitted to a
paediatric intensive care unit (PICU).
Secondary:
* To evaluate the safety and tolerability (including withdrawal effects) of
clonidine compared with midazolam in ventilated children and adolescents
admitted to PICU.
* To determine clonidine dose-dependent effects on sedation.
* To establish the pharmacokinetics - pharmacodynamics (PK-PD) relationship of
clonidine for sedation in PICU.
* To compare the cumulative total morphine consumption/kg between the two arms
in the first 48 hours of investigational medical product (IMP) administration.
* To determine if candidate genes predict adequate response to clonidine and
midazolam in critically ill paediatric patients.
* To identify polymorphisms of clinical relevance to the sedative action of
clonidine, midazolam and morphine.
* To correlate midazolam pharmacokinetics to polymorphisms of candidate genes.
* To correlate clonidine pharmacokinetics to polymorphisms of candidate genes.
* To correlate morphine pharmacokinetics to polymorphisms of candidate genes.
Study design
This is a double blind, randomised, active-controlled, parallel group,
multicentre, phase III study.
Intervention
Clonidine as sedative with midazolam as active control.
Study burden and risks
Participants are at risk of inadequate sedation, therefore a dose escalation
scheme has been established with frequent assessments of sedation.
There is a risk of cardiovascular side effects of clonidine which are easily
manageable in the PICU setting.
The active control group receivesthe most likely drug to be administered for
this purpose anyway, its use in the framework of the clinical study does not
cause any additional, study-related risk due to its pharmacological properties.
Subjects will have no direct benefits from their participation in the study
other than particularly close monitoring of sedation levels and the application
of a rational IMP dosing regimen based on PK-PD modelling.
Maximiliansplatz 2
Erlangen 91054
DE
Maximiliansplatz 2
Erlangen 91054
DE
Listed location countries
Age
Inclusion criteria
Male or female aged from birth >34 weeks gestational age [GA] to <18 years
Admitted to PICU
Ventilated and anticipated need for sedation for at least 24 hours
Informed consent obtained from the subject*s parent(s) or legal guardian(s).
Exclusion criteria
Body weight less than 1200g and/ or gestational age of less than 34 weeks.
Body weight greater than 85kg.
Subjects under sedation for more than 72 hours
Post-resuscitation less than 24 hours.
Severe organ insufficiency
Abnormalities of the central nervous system impairing the judgement of sedation
Acute asthma
Known hypersensitivity to (non-)investigational medical products
Treatment on ECMO
Relatives to investigators or employees of study site
No informed consent obtained
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-003582-24-NL |
| CCMO | NL51551.078.15 |