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

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)

Time frame: Minimum of 12 hours up to 48 hours (± 6 hours).

Population: Full Analysis set (FAS): The FAS included all randomised patients who received IMP and had at least a 6-hour sedation period and at least 3 blinded COMFORT-B-assessments. The FAS followed the intention-to-treat principle, i.e., patients were analysed according to the treatment group they were assigned to at randomisation. The main statistical analysis was performed on this population.

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)

Time frame: Minimum of 12 hours up to 48 hours (± 6 hours).

Population: The PP analysis set included all patients in the FAS without any major protocol deviation affecting the primary analysis. To be included in the PP analysis patients had to have been sedated for at least 12h (which was interpreted as 12 h of study sedative treatment from start of IMP), with at least 50% of the planned COMFORT-B assessments performed.

Compare ICU-free days up to 30 days in isoflurane- vs midazolam-treated patients.

Time frame: From start of study treatment up to 30 days

Population: Safety analysis set (only patients not withdrawn prior to day 30). This was a secondary safety endpoint. 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 the 30 days/hospital mortality in isoflurane- vs midazolam-treated patients

Time frame: From start of study treatment up to 30 days

Proportion of observations with spontaneous breathing efforts during study treatment. This was a key secondary safety endpoint.

Time frame: From initiation of study drug treatment to End of study treatment (up to 48h +/- 6h)

Population: Full Analysis Set

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 Patients that were withdrawn prior to day 30 were excluded from the analysis.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.

Time frame: From start of study treatment up to 30 days

Population: Safety analysis set (only patients not withdrawn prior to day 30)

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.

Time frame: 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).

Population: FAS: Patients with 8 hours or more of study treatment from first blinded COMFORT-B assessment.

Dose of opioids from first blinded COMFORT-B assessment (at +2 h from start of study drug) to end of study treatment period. This was a key secondary efficacy endpoint. Dose of opioids was expressed as fentanyl IV equivalents.

Time frame: From first blinded COMFORT-B assessment (at +2 h from start of study drug initiation) to end of the study treatment period

Population: The FAS included all randomised patients who received IMP and had at least a 6-hour sedation period and at least 3 blinded COMFORT-B-assessments. The FAS followed the intention-to-treat (ITT) principle, i.e., patients were analysed according to the treatment group they were assigned to at randomisation.

Time from end of study drug administration to extubation if study drug was terminated for extubation

Time frame: From end of study drug administration to extubation or end of extubation attempt

Population: Subgroup of patients with endotracheal tube where wake-up was initiated at end of study treatment

Ventilator-free days at 30 days from start of study treatment period.

Time frame: From start of study treatment up to 30 days

Population: Safety analysis set (only patients not withdrawn prior to day 30)

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.

Time frame: From start of study treatment to end of study treatment (up to 48h +/- 6h)

Population: Safety analysis set

Evaluate the frequency of delirium in isoflurane- vs midazolam-treated patients

Time frame: 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 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.

Time frame: During study treatment and up to 48 hours after discontinuation of isoflurane and midazolam

Evaluate the frequency of withdrawal symptoms in isoflurane- vs midazolam-treated patients according to SOS-PD.

Time frame: 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.