Effect & Safety of Inhaled Isoflurane vs IV Midazolam for Sedation in Mechanically Ventilated Children 3-17 Years Old

Study Overview
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Brief Summary
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This is a study to compare safety and efficacy of inhaled isoflurane delivered by the AnaConDa-S versus intravenous midazolam for sedation in mechanically ventilated children admitted to an intensive care unit.

Detailed Description
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This is a phase III, multi-centre, prospective, randomized, active-controlled, assessor-blind study. Primary endpoint: percentage of time of adequately maintained sedation, in absence of rescue sedation, within the COMFORT-B interval (light, moderate, or deep sedation) prescribed at randomization, monitored every 2 hours for an expected minimum of 12 hours (up to 48 hours).

Official Title
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A Randomised Active-controlled Study to Compare Efficacy & Safety of Inhaled Isoflurane Delivered by the AnaConDa-S (Anaesthetic Conserving Device) vs IV Midazolam for Sedation in Mechanically Ventilated Paediatric Patients 3-17 Years Old

Conditions
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Sedation

Intervention / Treatment
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* Drug: Midazolam
* Drug: Isoflurane


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients at least 3 years to 17 (less than 18) years at the time of randomization, admitted to an ICU/with planned ICU admission. Expected mechanical (invasive) ventilation and sedation for at least 12 hours. Informed consent obtained from the patient, patient's legal guardian(s) Exclusion Criteria: Ongoing seizures requiring acute treatment. Continuous sedation for more than 72 hours at time of randomization. Less than 24 hours post cardiopulmonary resuscitation. Uncompensated circulatory shock. Known or suspected genetic susceptibility to malignant hyperthermia. Patients with acute asthma or obstructive lung disease symptoms requiring treatment at inclusion. Patient with tidal volume below 30 mL or above 800 mL. Inability to perform reliable COMFORT-B assessment in the opinion of the Investigator Patients with intracranial pressure (ICP) monitoring or with suspected increase in ICP Patients with treatment-induced whole-body hypothermia. Patients with pheochromocytoma. Patients with prolonged QT interval or with significant risk for prolonged QT interval. Patient not expected to survive next 48 hours or not committed to full medical care.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 17 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Drug: Midazolam<br>Midazolam for sedation in the ICU | Drug: Midazolam<br>* Solution for Injection/Infusion<br>|
| Experimental: Drug: Isoflurane<br>Volatile for sedation in the ICU | Drug: Isoflurane<br>* Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of time adequate sedation depth | To compare the percentage of time adequate sedation depth is maintained within the individually prescribed target range in absence of rescue sedation as assessed according to the COMFORT-B scale, in isoflurane vs midazolam treated paediatric patients for an expected minimum of 12 hours. | Minimum of 12 hours up to 48 hours (± 6 hours). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare the use of opiates | Compare the use of opiates, and the development of tolerance to the sedative regimen as measured by the change in dose of study drug,opiates and other analgesics, over time in isoflurane- vs midazolam treated patients. | Minimum of 12 hours up to 48 hours (± 6 hours). | 
| Compare the need for rescue sedatives | Compare the need for rescue sedatives and other sedatives in isoflurane- vs midazolam-treated patients. | Minimum of 12 hours up to 48 hours (± 6 hours). | 
| Compare time from sedation termination to extubation | Compare time from sedation termination to extubation in isoflurane- vs midazolam-treated patients. | Time from end of study drug administration to extubation | 
| Compare the proportion of time with spontaneous breathing | Compare the proportion of time with spontaneous breathing in isoflurane- vs midazolam treated patients. | During study treatment | 
| Evaluate haemodynamic effect as indicated by inotropic/vasopressor agent | Evaluate haemodynamic effect as indicated by inotropic/vasopressor agent administration in patients sedated with isoflurane compared with midazolam. | During study treatment period compared to baseline | 
| Evaluate the frequency of withdrawal symptom | Evaluate the frequency of withdrawal symptoms in isoflurane- vs midazolam-treated patients. | Patients exposed > 96 hours sedation (including pre-study sedation period) until the end of the 48-hour post study treatment monitoring or ICU discharge, whichever comes first. | 
| Evaluate the frequency of delirium | Evaluate the frequency of delirium in isoflurane- vs midazolam-treated patients | Patients admitted to the ICU ≥48 hours (including period prior to study enrolment) until the end of the 48-hour post study treatment monitoring or ICU discharge, whichever comes first. | 
| Evaluate the frequency of neurological symptoms or psychomotor dysfunction | Evaluate the frequency of neurological symptoms or psychomotor dysfunction during and up to 48 hours after discontinuation of isoflurane and midazolam treatment, and the association with duration of treatment, and total exposure (MAC hours and midazolam doses) over time. | During study treatment and up to 48 hours after discontinuation of isoflurane and midazolam | 
| Compare the 30 days/hospital mortality | Compare the 30 days/hospital mortality in isoflurane- vs midazolam-treated patients | From start of study treatment up to 30 days | 
| Compare ventilator-free days | Compare ventilator-free days up to 30 days in isoflurane- vs midazolam-treated patients. | From start of study treatment up to 30 days | 
| Compare the time in ICU/hospital | Compare the time in ICU/hospital up to 30 days in isoflurane- vs midazolam-treated patients. | From start of study treatment up to 30 days | 
| Compare ICU-free days | Compare ICU-free days up to 30 days in isoflurane- vs midazolam-treated patients. | From start of study treatment up to 30 days | 
| Compare the safety profile | Compare the safety profile in terms of experienced adverse events, safety laboratory values, blood gases, vital signs, body temperature and urinary output in isoflurane- vs midazolam-treated patients. | Baseline to end of study treatment, safety lab from baseline up to 48hrs post treatment, AEs from start study treatment up to day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sedation, isoflurane, mechanically ventilation, pediatric, midazolam