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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Sedation in Intensive Care

Intervention / Treatment
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* Drug: Clonidine
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CLONIDINE HYDROCHLORIDE<br>solution for i.v. infusion (maximum 55 μg/kg per day; maximum 7 day treatment) | Drug: Clonidine<br> <br> |
| Active Comparator: MIDAZOLAM<br>solution for i.v. infusion (maximum 5.5 mg/kg per day; maximum 7 day treatment) | Drug: Midazolam<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics/Pharmacodynamics (PKPD) modeling (measured by plasma concentrations and sedation score results (COMFORT-B) | measured by plasma concentrations and sedation score results (COMFORT-B) | ≤ 7 days treatment period | 
| Safety assessment (number of patients with adverse events) | measured by 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 | measured by score Sophia Observation Withdrawal Symptoms-Paediatric Delirium (SOS-PD) | post dose ≥ 1 day, ≤ 5 days | 
| Extent of rebound hypertension | measured by blood pressure assessment for at least 72 hours after IMP cessation | post dose ≥ 3 days, ≤ 5 days | 
| Percentage of respiratory depression per group | Number of reintubations / number extubation failures ratio % | during re-intubation apnoea in treatment period (≤ 7 days), post dose monitoring every 24 hours up to 10 days | 
| Neurodevelopment (Bayley Scales of Infant Development, Second Edition (Bayley-II) score) | Bayley Scales of Infant Development, Second Edition (Bayley-II) score | 1 year (in neonates only) | 
| Pharmacogenomic assessment (measured by plasma concentrations and candidate gene polymorphisms/genotyping) | measured by plasma concentrations and candidate gene polymorphisms/genotyping | On 1 day of treatment period (≤7 days) only |