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

NCT02509273 | Terminated Phase 3 DMC

• 2 other identifiers: CLON012014-003582-24
• Study Type: interventional
• Target: 28
• Locations: 6 countries
• Sites: 9

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.

Conditions

Sedation in Intensive Care

Outcome Measures

Primary Outcomes (1)

• Sedation failure

  measured by pain score Numerical Rating Scale (NRS), sedation score COMFORT-B and sedation score Nurse's Interpretation of Sedation (NISS)

  ≤ 7 days

Secondary Outcomes (7)

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

  ≤ 7 days treatment period

• Safety assessment (number of patients with adverse events)

  ≤ 21 ± 2 days (treatment period, completion visit, post dose monitoring and follow-up visit) in all subjects

• Extent of withdrawal effects

  post dose ≥ 1 day, ≤ 5 days

• Extent of rebound hypertension

  post dose ≥ 3 days, ≤ 5 days

• Percentage of respiratory depression per group

  during re-intubation apnoea in treatment period (≤ 7 days), post dose monitoring every 24 hours up to 10 days

Study Arms (2)

CLONIDINE HYDROCHLORIDE

EXPERIMENTAL

solution for i.v. infusion (maximum 55 μg/kg per day; maximum 7 day treatment)

Drug: Clonidine

MIDAZOLAM

ACTIVE COMPARATOR

solution for i.v. infusion (maximum 5.5 mg/kg per day; maximum 7 day treatment)

Drug: Midazolam

Interventions

Clonidine DRUG

CLONIDINE HYDROCHLORIDE

Midazolam DRUG

MIDAZOLAM

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Erlangen-Nürnberg Medical School: lead
• Erasmus Medical Center: collaborator
• University of Tartu: collaborator
• Therakind Ltd: collaborator
• Gianni Benzi Pharmacological Research Foundation: collaborator
• University College, London: collaborator
• Karolinska Institutet: collaborator
• Univerzita Karlova v Praze: collaborator
• Vereniging Samenwerkende Ouder- En Patientenorganisaties: collaborator
• Bambino Gesù Hospital and Research Institute: collaborator
• European Commission: collaborator
• ARNAS Civico Di Cristina Benfratelli Hospital: collaborator
• Servicio Madrileño de Salud, Madrid, Spain: collaborator

Study Sites (10)

Univerzita Karlova v Praze

Prague, 121 09, Czechia

Location

Tallinn Children's Hospital

Tallinn, Estonia

Location

University of Erlangen-Nürnberg Medical School

Erlangen, 91054, Germany

Location

Diakonie Neuendettelsau - Cnopf'sche Kinderklinik Nürnberg

Nuremberg, Germany

Location

Azienda Ospedaliero Universitaria Policlinico di Bari

Bari, 70124, Italy

Location

ARNAS Civico Di Cristina Benfratelli

Palermo, 90127, Italy

Location

Bambino Gesù Hospital and Research Institute

Rome, 00165, Italy

Location

Erasmus Medical Center

Rotterdam, South Holland, 3015 CN, Netherlands

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Karolinska Institutet

Stockholm, 17176, Sweden

Location

Related Publications (1)

• 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.

  PMID: 28637741 DERIVED

MeSH Terms

Interventions

Clonidine; Midazolam

Intervention Hierarchy (Ancestors)

Imidazolines; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 27, 2015
• First Posted: July 28, 2015
• Study Start: May 1, 2016
• Primary Completion: October 1, 2018
• Study Completion: October 22, 2018
• Last Updated: January 9, 2019

Record last verified: 2019-01

Locations

DE (2); CZ (1); ES (1); IT (3); SE (1); NL (1)