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

Phase 3

Completed

Conditions: Sedation

Interventions: Drug: Midazolam
Drug: Isoflurane

Registration Number: NCT04684238

Lead Sponsor: Sedana Medical

Brief Summary: This is a study to compare safety and efficacy of inhaled isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device (ACD)) versus intravenous midazolam for sedation in mechanically ventilated children admitted to an intensive care unit.

Detailed Description: 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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 94

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Drug: Midazolam	Midazolam	Midazolam for sedation in the ICU
Drug: Isoflurane	Isoflurane	Volatile for sedation in the ICU

Primary Outcome Measures

Name	Time	Method
Percentage of Time of Adequately Maintained Sedation Depth up to 48 Hours (± 6 Hours)	Minimum of 12 hours up to 48 hours (± 6 hours).	Percentage of time of adequately maintained sedation within the COMFORT-B interval (light, moderate or deep sedation) prescribed at randomisation, monitored every 2 h for a minimum of 12 h (up to 48 h ± 6 h)

Secondary Outcome Measures

Name	Time	Method
Compare the Use of Opioids	Last 4 hours of study treatment compared to first 4 hours of study treatment after first blinded COMFORT-B assessment (at +2 h from start of study drug initiation).	Dose of opioids during the last 4 h of study treatment, as compared to the first 4 h of study treatment after first blinded COMFORT-B assessment. This was a key secondary efficacy endpoint. Dose of opioids is expressed as fentanyl IV equivalents.
Compare Time From End of Study Drug Administration to Extubation	From end of study drug administration to extubation or end of extubation attempt	Time from end of study drug administration to extubation if study drug was terminated for extubation
Compare the Proportion of Time With Spontaneous Breathing	From initiation of study drug treatment to End of study treatment (up to 48h +/- 6h)	Proportion of observations with spontaneous breathing efforts during study treatment. This was a key secondary safety endpoint.
Evaluate Haemodynamic Effect as Indicated by Need for Additional Inotropic/Vasopressor Agent	From start of study treatment to end of study treatment (up to 48h +/- 6h)	Need for additional inotropic/vasopressor agent defined by change in Vasoactive-Inotropic Score (VIS) during study treatment period compared to baseline. The VIS quantifies the amount of cardiovascular support required by infants postoperatively according to the below calculation: VIS = dopamine (µg/kg/min) + dobutamine (µg/kg/min) + 100 × epinephrine (µg/kg/min) + 100 × norepinephrine (µg/kg/min) + 10 × milrinone (µg/kg/min) + 10,000 × vasopressin (U/kg/min). An increased VIS score correlates to an increase in inotropic/vasopressor agents.
Evaluate the Number of Patients With Withdrawal Symptom	From > 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 withdrawal symptoms in isoflurane- vs midazolam-treated patients according to SOS-PD.
Evaluate the Frequency of Delirium	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 delirium in isoflurane- vs midazolam-treated patients
Evaluate the Frequency of Neurological Symptoms or Psychomotor Dysfunction	During study treatment and up to 48 hours after discontinuation of isoflurane and midazolam	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.
Compare the 30 Days/Hospital Mortality	From start of study treatment up to 30 days	Compare the 30 days/hospital mortality in isoflurane- vs midazolam-treated patients
Compare the Time in ICU/Hospital	From start of study treatment up to 30 days	Compare the time in ICU at 30 days from start of study treatment period. This was a secondary safety endpoint. Patients that were withdrawn prior to day 30 were excluded from the analysis. Patients who died before day 30 were not considered withdrawals. For these patients, the days in ICU until day of death were considered ICU days.
Compare ICU-free Days	From start of study treatment up to 30 days	Compare ICU-free days up to 30 days in isoflurane- vs midazolam-treated patients.
Compare Ventilator-free Days	From start of study treatment up to 30 days	Ventilator-free days at 30 days from start of study treatment period.

Trial Locations

Locations (24): Hôpital Femme-Mère-Enfant Groupe Hospitalier Est
🇫🇷
Lyon, France
CHU de NANTES, Hôpital Mère-Enfant
🇫🇷
Nantes, France
Hôpital Robert-Debré AP-HP
🇫🇷
Paris, France
Hôpitaux Universitaires Paris Sud Site Bicetre
🇫🇷
Paris, France
Centre Hospitalier Universitaire de Reims
🇫🇷
Reims, France
Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre
🇫🇷
Strasbourg, France
Universitätsklinikum Köln
🇩🇪
Cologne, Germany
Universitätsklinik Freiburg
🇩🇪
Freiburg, Germany
Universitätsklinikum Hamburg-Eppendorf (UKE)
🇩🇪
Hamburg, Germany
Universitätsklinikum Jena
🇩🇪
Jena, Germany
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Hôpital Femme-Mère-Enfant Groupe Hospitalier Est
🇫🇷Lyon, France