E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients in ICU with risks of Acute Respiratory Distress Syndrome |
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E.1.1.1 | Medical condition in easily understood language |
Patients in ICU with risks of Acute Respiratory Distress Syndrome |
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E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy of inhaled sevoflurane, compared to current intravenous sedation practice, for improving PaO2/FiO2 in ICU patients at high risk for ARDS. |
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E.2.2 | Secondary objectives of the trial |
- Progression to ARDS, as defined by the Berlin criteria1 .
- Safety (clinical adverse events) of the two sedation strategies.
- Effects on the rate of pneumonia.
- Effects on respiratory mechanics.
- Effects on gas exchange and physiologic measures.
- Effects on ICU-acquired delirium.
- Effects on ICU-acquired weakness.
- Effects on hemodynamic measures and renal function (KDIGO criteria for acute kidney injury24).
- Effects on organ dysfunction.
- Effects on the duration of mechanical ventilation.
- Effects on 28-day mortality.
- Effects on the number of days off the ventilator at 28 days (ventilator-free days to day 28, VFD28), taking into account death as a competing event.
- Biological collection of plasma, alveolar edema fluid, and urine samples for future mechanistic and endotyping studies of the biological effects of sevoflurane.
- Presence of subphenotypes among patients at risk of developing ARDS;
- Hhealthcare-related costs during ICU stay and hospital stay.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥ 18 years
2. Admitted to participating ICUs with at least one known risk factor for ARDS and a LIPS equals to, or greater than, 4 (Appendix G)105
3. Patient under invasive mechanical ventilation
4. With expected duration of sedation superior or equal to 4 hours
5. Affiliation to the French Sécurité Sociale
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E.4 | Principal exclusion criteria |
- Patient under a tutelage measure
- Known pregnancy
- Presence of ARDS prior to randomization
- Endotracheal ventilation for greater than 24 hours prior to randomization
- Home mechanical ventilation (non-invasive ventilation or via tracheotomy) except for CPAP/BIPAP used solely for sleep-disordered breathing
- Tidal volume of 6 mL/kg predicted body weight (PBW) below 200 mL (i.e. height inferior to 134cm for a man and 139cm for a woman)
- Moribund patient, i.e. not expected to survive 24 hours despite intensive care
- Previous hypersensitivity or anaphylactic reaction to sevoflurane
- Medical history of malignant hyperthermia
- Long QT syndrome at risk of arrhythmic events
- Medical history of liver disease attributed to previous exposure to a halogenated agent (including sevoflurane)
- Suspected or proven intracranial hypertension
- Enrollment in another interventional trial with direct impact on oxygenation
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome is longitudinal evolution in the PaO2/FiO2 ratio |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day 5 after admission in ICU. |
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E.5.2 | Secondary end point(s) |
- Progression to ARDS will be assessed according to the Berlin criteria, including chest radiographs.
- Rate of pneumonia
- Ventilator-free days
- Organ failure-free days
- Mortality
- Length of ICU-stay
- Physiological measures
- ICU-acquired weakness
- ICU-acquired delirium
- Health economic analysis
- Biomarker measurements |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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A data monitoring and safety committee will be convened to discuss the continuation of this study in case of a between-group difference in severe adverse events (SAEs) or suspected unexpected severe adverse events (SUSAEs). |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 28 |
E.8.9.1 | In the Member State concerned days | 0 |