Clinical trial NCT02509273: Efficacy, Safety and Pharmacokinetic Study of Intravenous Clonidine Versus Midazolam for Sedation in Paediatric Patients
Official title: A Double Blind, Randomised, Multicentre, Active Controlled, Parallel-group, Phase III Trial to Evaluate the Efficacy, Safety and Pharmacokinetics of Intravenous Clonidine (Hydrochloride) Compared to Midazolam for Sedation in Children From Birth to Less Than 18 Years of Age
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Sedation in Intensive Care
Lead sponsor: University of Erlangen-Nürnberg Medical School
Sponsor class: OTHER
Collaborators: name: Erasmus Medical Center
name: University of Tartu
name: Therakind Ltd
name: Gianni Benzi Pharmacological Research Foundation
name: University College, London
name: Karolinska Institutet
name: Univerzita Karlova v Praze
name: Vereniging Samenwerkende Ouder- En Patientenorganisaties
name: Bambino Gesù Hospital and Research Institute
name: European Commission
name: ARNAS Civico Di Cristina Benfratelli Hospital
name: Servicio Madrileño de Salud, Madrid, Spain
First posted: 2015-07-28
Enrollment: 28
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Closed1 aims to compare the efficacy, safety and pharmacokinetics of clonidine (hydrochloride) to midazolam in the sedation of ventilated children and adolescents (0-18 years) admitted to a paediatric intensive care unit (PICU) and requiring mechanical ventilation and sedation for at least 24 hours.

In particular, the proportion of subjects with sedation failure at the maximum possible dose (defined within the study protocol) will be measured. Additionally, the safety and tolerability (including withdrawal effects) of clonidine compared to midazolam will be evaluated. A pharmacokinetic-pharmacodynamic relationship of clonidine for sedation in PICU will be established. Genetic polymorphisms of clinical relevance affecting pharmacokinetics, pharmacodynamics and metabolism will be also identified.

Ad hoc paediatric parenteral formulations of clonidine hydrochloride and midazolam will be manufactured. At least 300 subjects will be enrolled from study centres in five European member countries (Czech Republic, Germany, Italy, the Netherlands, and Sweden).

The clinical study will enrol critically ill paediatric patients who require mechanical ventilation and sedation.

Subjects will be closely followed using standard PICU monitoring of vital functions (continuous assessment of heart rate and peripheral arterial oxygen saturation, intermittent assessment of systolic and diastolic blood pressure), intermittent assessment of pain and depth of sedation, documentation of parameters of mechanical ventilation and intermittent arterial blood gas analysis.

The study will be conducted in compliance with the study protocol, Good Clinical Practice (ICH-GCP) and the applicable regulatory requirement(s). In addition, qualified PICU staff will be monitoring subjects around the clock, thus minimising reaction time in case of alarms or deterioration of clinical parameters.

This project has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement n° 602453.


Eligibility criteria: Inclusion Criteria:

* Male or Female
* Aged from birth (≥34 weeks gestational age \[GA\]) to \<17 years, 11 months, 1 week old
* Admitted or expected to be admitted (post-operatively) to PICU
* Existing or expected indication for invasive or non-invasive ventilation (except Continuous Positive Airway Pressure, CPAP)
* Anticipated need for continuous sedation for at least 24 hours
* Informed consent (or deferred consent) obtained from the subject's parent(s) or legal guardian(s)
* Where applicable, assent obtained from the subject to participate in the clinical trial

Exclusion Criteria:

* Body weight less than 1500 g
* Gestational age \[GA\] of \<34 weeks
* Body weight 3 kg or less AND aged 28 days or older
* Body weight less than 10 kg AND aged 2 years old or older
* Body weight greater than 85 kg
* Subjects who will be 18 years old in less than 3 weeks
* Known hypersensitivity to the IMP (clonidine) or comparator (midazolam), or Non Investigational Medicinal Product (morphine, propofol) or any of their formulation ingredients and their rescue medication
* Subjects anticipated to be treated with forbidden concomitant medications during IMP administration
* Subjects less than 24 hours post-resuscitation
* Subjects who have been under sedation for more than 72 hours immediately prior to assessment
* Subjects currently being treated with Extra Corporeal Membrane Oxygenation (ECMO)
* Subjects with treatment-induced whole body hypothermia
* Subjects with severe organ insufficiencies
* Subjects whose condition is assessed by the investigator to have an effect on the level of consciousness which impairs the assessment of sedation (COMFORT-B/NISS)
* Subjects with phaeochromocytoma
* Subjects with severe bradyarrhythmia resulting from either sick-sinus syndrome or atrioventricular (AV) block of 2nd or 3rd degree
* Known arterial hypertension requiring chronic treatment in medical history
* Females who are pregnant, lactating or planning to become pregnant or who return a positive result to a urine pregnancy test (a dipstick and serum pregnancy test will be performed at the screening visit).
* Employee or direct relative of an employee or any member of the study site staff or the Sponsor/ study management staff (applies to subject and/ or subject's parent(s)
* Participation in a clinical intervention study using drugs within the last 3 weeks
* Previous participation in this clinical study at any time
* Parent(s)/ legal guardian(s) decline to give informed consent. If parent(s)/ legal guardian(s) are not present

Primary outcomes:
measure: Sedation failure
timeFrame: ≤ 7 days
Secondary outcomes:
measure: Pharmacokinetics/Pharmacodynamics (PKPD) modeling (measured by plasma concentrations and sedation score results (COMFORT-B)
timeFrame: ≤ 7 days treatment period
measure: Safety assessment (number of patients with adverse events)
timeFrame: ≤ 21 ± 2 days (treatment period, completion visit, post dose monitoring and follow-up visit) in all subjects
measure: Extent of withdrawal effects
timeFrame: post dose ≥ 1 day, ≤ 5 days
measure: Extent of rebound hypertension
timeFrame: post dose ≥ 3 days, ≤ 5 days
measure: Percentage of respiratory depression per group
timeFrame: during re-intubation apnoea in treatment period (≤ 7 days), post dose monitoring every 24 hours up to 10 days
measure: Neurodevelopment (Bayley Scales of Infant Development, Second Edition (Bayley-II) score)
timeFrame: 1 year (in neonates only)
measure: Pharmacogenomic assessment (measured by plasma concentrations and candidate gene polymorphisms/genotyping)
timeFrame: On 1 day of treatment period (≤7 days) only
Other outcomes:
Locations:
city: Prague
country: Czechia
facility: Univerzita Karlova v Praze
city: Tallinn
country: Estonia
facility: Tallinn Children's Hospital
city: Erlangen
country: Germany
facility: University of Erlangen-Nürnberg Medical School
city: Nürnberg
country: Germany
facility: Diakonie Neuendettelsau - Cnopf'sche Kinderklinik Nürnberg
city: Bari
country: Italy
facility: Azienda Ospedaliero Universitaria Policlinico di Bari
city: Palermo
country: Italy
facility: ARNAS Civico Di Cristina Benfratelli
city: Rome
country: Italy
facility: Bambino Gesù Hospital and Research Institute
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
state: Zuid-Holland
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Stockholm
country: Sweden
facility: Karolinska Institutet
Study officials:
References:
citation: Neubert A, Baarslag MA, Dijk MV, Rosmalen JV, Standing JF, Sheng Y, Rascher W, Roberts D, Winslade J, Rawcliffe L, Hanning SM, Metsvaht T, Giannuzzi V, Larsson P, Pokorna P, Simonetti A, Tibboel D; CLOSED Consortium. 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. BMJ Open. 2017 Jun 21;7(6):e016031. doi: 10.1136/bmjopen-2017-016031.