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Efficacy, Safety and Pharmacokinetic Study of Intravenous Clonidine Versus Midazolam for Sedation in Paediatric Patients

Information source: University of Erlangen-NĂĽrnberg Medical School
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Sedation in Intensive Care

Intervention: Clonidine (Drug); Midazolam (Drug)

Phase: Phase 3

Status: Not yet recruiting

Sponsored by: University of Erlangen-Nürnberg Medical School

Overall contact:
Antje Neubert, PhD Assoc Prof, Phone: +49 9131 8541203, Email: paed-studienzentrale@uk-erlangen.de


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 tracheal intubation and mechanical ventilation. 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.

Clinical Details

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 design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome: Sedation failure

Secondary outcome:

Pharmacokinetics/Pharmacodynamics (PKPD) modeling (measured by plasma concentrations and sedation score results (COMFORT-B)

Safety assessment (number of patients with adverse events)

Extent of withdrawal effects

Extent of rebound hypertension

Percentage of respiratory depression per group

Neurodevelopment (Bayley Scales of Infant Development, Second Edition (Bayley-II) score)

Pharmacogenomic assessment (measured by plasma concentrations and candidate gene polymorphisms/genotyping)


Minimum age: N/A. Maximum age: 18 Years. Gender(s): Both.


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


- Where applicable, assent obtained from the subject to participate in the clinical

trial Exclusion Criteria:

- Body weight less than 1200 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

- Subjects who have already received clonidine as a sedative agent within the last 7

days prior to admission to PICU

- 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 being treated with forbidden concomitant medications (e. g. continuous

infusion of muscle relaxants; defined in the protocol)

- Subjects less than 24 hours post-resuscitation

- Subjects who have been under sedation for more than 72 hours immediately prior to


- Subjects currently being treated with continuous positive airway pressure (CPAP)

- Subjects currently being treated with Extra Corporeal Membrane Oxygenation (ECMO)

- Subjects with treatment-induced whole body hypothermia

- Subjects with severe organ insufficiencies

- Subjects with traumatic brain injury all grades (due to potential effects on the

level of consciousness)

- Subjects with intracranial pathology (tumour, haemorrhage, infections) with an effect

on level of consciousness

- Subjects with severe mental retardation with or without a well-defined syndrome that

preclude performance of a COMFORT-B Score

- Subjects with Myasthenia gravis, Spinal muscular atrophy, or other rare neurologic

diseases and conditions which that preclude performance of a COMFORT-B Score

- Subjects with major congenital anomalies of the central nervous system

- Subjects with phaeochromocytoma.

- Subjects with severe bradyarrhythmia resulting from either sick-sinus syndrome or

atrioventricular (AV) block of 2nd or 3rd degree

- Subjects with current status epilepticus or active fitting (2 or more seizures

regularly on a daily basis) at admission

- Subjects with acute asthma

- Subjects with paralytic ileus

- 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

- 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, country-specific guidelines are given in the protocol

Locations and Contacts

Antje Neubert, PhD Assoc Prof, Phone: +49 9131 8541203, Email: paed-studienzentrale@uk-erlangen.de

Univerzita Karlova v Praze, Prague 121 09, Czech Republic; Not yet recruiting
Kristýna Matějková, DiS
Pavla Pokorna, MD, Principal Investigator

University of Erlangen-NĂĽrnberg Medical School, Erlangen 91054, Germany; Not yet recruiting
Evelin Muschiol, Phone: +49 9131 85-41203, Email: evelin.muschiol@uk-erlangen.de
Thomas MK Völkl, MD, Principal Investigator

Bambino GesĂą Hospital and Research Institute, Rome 00165, Italy; Not yet recruiting
Piero David, MD, Email: piero.david.md@gmail.com
Alessandra Simonetti, MD, Principal Investigator

Karolinska Institutet, Stockholm 17176, Sweden; Not yet recruiting
Peter Larsson, MD, PhD, Phone: +46851777269, Email: peter.larsson@karolinska.se
Johan Fenhammar, MD, PhD, Phone: +46851773735, Email: johan.fenhammar@karolinska.se
Jonas Berner, MD, PhD, Principal Investigator

Erasmus Medical Center, Rotterdam, Zuid-Holland 3015 CN, Netherlands; Not yet recruiting
Manuel Baarslag, MD, Phone: +31 10 703 75 94, Email: m.baarslag@erasmusmc.nl
Dick Tibboel, MD Prof, Principal Investigator

Additional Information

Starting date: September 2015
Last updated: July 27, 2015

Page last updated: August 20, 2015

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