## Protocol Section
### Identification Module
**NCT ID:** NCT05849779

**Acronym:** IPA

**Brief Title:** Inhaled Sevoflurane for ARDS Prevention

**Official Title:** Randomized Clinical Trial of Inhaled Sedation With Sevoflurane in Critically Ill Patients at Risk of Developing the Acute Respiratory Distress Syndrome

#### Organization Study ID Info
**ID:** IPA trial (AOI 2019 JABAUDON)
#### Organization
**Class:** OTHER
**Full Name:** University Hospital, Clermont-Ferrand
### Status Module
#### Completion Date
**Date:** 2025-07-31

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-20

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-17

**Overall Status:** RECRUITING

#### Primary Completion Date
**Date:** 2025-05-31

**Type:** ESTIMATED

#### Start Date
**Date:** 2023-07-24

**Type:** ACTUAL

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2023-05-09
**Type:** ACTUAL
**Study First Submit Date:** 2023-04-27
**Study First Submit QC Date:** 2023-05-05
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** University Hospital, Clermont-Ferrand

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** This study focuses on patients who are at risk of developing a serious, life-threatening respiratory disease called Acute Respiratory Distress Syndrome (ARDS), which severely disrupts the function of their lungs.

Preclinical studies have shown that the use of a volatile anesthetic agent such as Sevoflurane could be beneficial in the treatment and prevention of this respiratory condition. By improving gas exchange and attenuating pulmonary inflammation in particular, this agent would make it possible to prevent deterioration or to restore pulmonary function more rapidly.

Half of the patients will receive inhaled sedation with sevoflurane and the other half will receive intravenous sedation already routinely used in participating ICUs (typically propofol, dexmedetomidine or a benzodiazepine, i.e. drugs approved for sedation).

The aim of this study is to assess whether the use of Sevoflurane could be beneficial in the prevention of ARDS.

**Detailed Description:** MAIN OBJECTIVE 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.

HYPOTHESIS The investigators hypothesized that a strategy of inhaled sedation with sevoflurane could be more effective than current intravenous sedation practice at improving pulmonary function during the early days of ICU admission, in patients at risk of ARDS.

### Conditions Module

**Conditions:**

- Acute Respiratory Distress Syndrome

**Keywords:**

- ARDS

- Sedation

- Inhaled sevoflurane

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

**Intervention Model Description:** Investigator-initiated, single-center, prospective, randomized, stratified, parallel-group clinical trial with blinded outcome assessment and concealed allocation of patients at risk of developing the ARDS to a strategy of inhaled sedation with sevoflurane or to a strategy of current intravenous sedation practice.

##### Masking Info

**Masking:** SINGLE

**Masking Description:** Patients will be followed up for primary and secondary endpoints by members of the research staff who will be unaware of the trial group allocation. Information on whether the primary and secondary outcomes occur will be collected and entered into the electronic web-based case report form (eCRF) by trial or clinical trained personal (clinical research associate), blinded to the allocation group, under the supervision of the local principal investigator (PI) or designee who will also be unaware of the trial group allocation.

Finally, the independent trial statistician and the members of the data monitoring and safety committee (DMSC) will also remain blinded for the allocation during analysis. However, the observation of differences in serious adverse events between the two groups will allow, for safety reasons may the DMSC deem necessary, to unblind allocation groups.

**Who Masked:**

- OUTCOMES_ASSESSOR

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 80

**Type:** ESTIMATED

**Phases:**

- PHASE3

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Sevoflurane as vaporized via the Anesthesia Conserving Device (Sedaconda-ACD-S, Sedana Medical, Danderyd, Sweden).

**Intervention Names:**

- Drug: Inhaled sedation with sevoflurane

**Label:** Inhaled sedation with sevoflurane

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** The investigators will not mandate the sedative type, but rather encourage the use of sedatives that are already routinely used in participating ICUs (typically a benzodiazepine, propofol, or dexmedetomidine, i.e. drugs approved for sedation).

**Intervention Names:**

- Drug: Intravenous sedation (current practice)

**Label:** Intravenous sedation

**Type:** ACTIVE_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Inhaled sedation with sevoflurane

**Description:** In both arms, the management of sedation will be conducted in the broader picture of ICU patient care, as per current standard practice in participating ICUs, and following the current guidelines for Pain, Agitation, Delirium, Immobility, and Sleep Disruption (PADIS) published in 2018 by the Society of Critical Care Medicine.

Among many recommendations, this will include the monitoring and titration of both sedation and analgesia using validated scores such as the Richmond Agitation-Sedation Scale (RASS) for sedation. As a result of the current recommendations, the level, dose, and duration of sedation will vary among patients and will be decided by the treating clinicians. The choice of the analgesic drug(s) will be as per the treating clinicians.

Other aspects of critical care will adhere to standard care, including the use of the "Checklist for Lung Injury Prevention" (CLIP).

**Name:** Inhaled sedation with sevoflurane

**Other Names:**

- Experimental

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Intravenous sedation

**Description:** In both arms, the management of sedation will be conducted in the broader picture of ICU patient care, as per current standard practice in participating ICUs, and following the current guidelines for Pain, Agitation, Delirium, Immobility, and Sleep Disruption (PADIS) published in 2018 by the Society of Critical Care Medicine.

Among many recommendations, this will include the monitoring and titration of both sedation and analgesia using validated scores such as the Richmond Agitation-Sedation Scale (RASS) for sedation. As a result of the current recommendations, the level, dose, and duration of sedation will vary among patients and will be decided by the treating clinicians. The choice of the analgesic drug(s) will be as per the treating clinicians.

Other aspects of critical care will adhere to standard care, including the use of the "Checklist for Lung Injury Prevention" (CLIP).

**Name:** Intravenous sedation (current practice)

**Other Names:**

- Control

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** longitudinal evolution in the PaO2/FiO2 ratio

**Measure:** PaO2/FiO2 ratio

**Time Frame:** within 5 days from randomization

#### Secondary Outcomes

**Description:** Progression to ARDS will be assessed according to the Berlin criteria, including chest radiographs

**Measure:** Progression to ARDS

**Time Frame:** within 5 days from randomization

**Description:** Pneumonia will be defined according to the 3 following criteria:

* Two chest radiographs showing signs of pneumonia, or one in absence of cardiomyopathy or underlying pulmonary condition.
* One item among: body temperature ≥38.3°C without evident cause, leukocytes \<4000/mm3 or ≥12000/mm3
* Two items among: purulent secretions, cough or dyspnea, increased need for oxygen supplementation or ventilatory assistance.

**Measure:** Rate of pneumonia

**Time Frame:** Presence of pneumonia will be assessed daily until Day 5, and at Day 28 or ICU discharge, whichever comes first.

**Description:** Ventilator free days to day 28 are defined as the number of days from the time of initiating unassisted breathing to day 28 after randomization, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. If a patient returns to assisted breathing and subsequently achieves unassisted breathing to day 28, VFDs will be counted from the end of the last period of assisted breathing to day 28. A period of assisted breathing lasting less than 24 hours and for the purpose of a surgical procedure will not count against the VFD calculation. If a patient was receiving assisted breathing at day 27 or dies prior to day 28, VFDs will be zero.

**Measure:** Ventilator-free days to day 28

**Time Frame:** 28 days after randomization

**Description:** Organ failure is defined as present when the most abnormal vital signs or clinically available lab value meets the definition of clinically significant organ failure according to SOFA scores. Patients will be followed daily from randomization to day 5 for development of organ failures.

**Measure:** Organ failure to day 5

**Time Frame:** 5 days after randomization

**Description:** The occurrence of death in the ICU will be recorded until day 28.

**Measure:** Mortality at day 28

**Time Frame:** 28 days after randomization

**Description:** The total number of days from admission to ICU discharge will be recorded until day 28

**Measure:** Length of ICU-stay up to 28 days

**Time Frame:** 28 days after randomization

**Description:** - Oxygenation Index on study days 1-5

**Measure:** Physiological measures: Oxygenation

**Time Frame:** 28 days after randomization

**Description:** - PaCO2 on study days 1-5

**Measure:** Physiological measures: PaCO2

**Time Frame:** 28 days after randomization

**Description:** - Arterial pH on study days 1-5

**Measure:** Physiological measures: pH

**Time Frame:** 28 days after randomization

**Description:** - Level of PEEP (and static auto-PEEP in patients under controlled ventilation) on study days 1-5

**Measure:** Physiological measures: PEEP

**Time Frame:** 28 days after randomization

**Description:** - Plateau pressure, static compliance of the respiratory system on study day 1-5

**Measure:** Physiological measures: Plateau pressure

**Time Frame:** 28 days after randomization

**Description:** - Development of pneumothorax through day 28

**Measure:** Physiological measures: Pneumothorax

**Time Frame:** 28 days after randomization

**Description:** - Time to switching from controlled to pressure-support ventilation through day 5

**Measure:** Physiological measures: Switch from controlled to pressure-support ventilation

**Time Frame:** 28 days after randomization

**Description:** - Airway occlusion pressure at 0.1 s (P0.1), an index of respiratory drive, on the day the patient is switched to pressure-support ventilation if within 5 days since randomization

**Measure:** Physiological measures: Airway occlusion pressure

**Time Frame:** 28 days after randomization

**Description:** - Hemodynamic measures (mean arterial pressure, dose of infused norepinephrine or other vasopressor, serum lactate level) on study days 1-5

**Measure:** Hemodynamic measures

**Time Frame:** 28 days after randomization

**Description:** - KDIGO criteria for acute kidney injury 24 through day 5

**Measure:** Physiological measures: Acute kidney injury

**Time Frame:** 28 days after randomization

**Description:** - Supraventricular tachycardia (SVT) or new onset atrial fibrillation through day 5

**Measure:** Physiological measures: Supraventricular tachycardia

**Time Frame:** 28 days after randomization

**Description:** The Confusion Assessment Method for the ICU (CAM-ICU, Appendix C )97 will be assessed daily from study entry to study day 28, death or ICU discharge, whichever comes first.

**Measure:** ICU-acquired delirium

**Time Frame:** 28 days after randomization

**Description:** Plasma samples will be collected from indwelling catheters (when available) at study entry and on days 1, 2, 3, 4, 5 in order to assemble a biological collection aimed at further investigating the effects of inhaled sedation with sevoflurane in patients with ARDS.

The investigators will also collect whole blood samples at study entry and on day 2 for future studies of macrophage activation profiles and RNA and DNA studies.

**Measure:** Biomarker measurements

**Time Frame:** from inclusion to 5 days

### Eligibility Module

**Eligibility Criteria:** 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 D)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

Exclusion Criteria:

* Patient under judicial protection, guardianship or supervision, as defined by art L1121-8 of the Public Health Code
* Patient under psychiatric care as defined by art. L1121-6 of the Public Health Code
* Patient deprived of their freedom by judiciary or administrative order
* 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 or to the intravenous sedation agent routinely used in the participating ICU (such as midazolam, propofol, or dexmedetomidine)
* Absolute contra-indications to the intravenous sedation agent routinely used in the participating ICU (such as midazolam, propofol, or dexmedetomidine)
* 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

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** llaclautre_perrier@chu-clermontferrand.fr

**Name:** Lise Laclautre

**Phone:** +33473754963

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Clermont-ferrand

**Contacts:**

***Contact 1:***

- **Email:** dmorand@chu-clermontferrand.fr

- **Name:** Dominique Morand

- **Phone:** +33684894678

- **Role:** CONTACT

**Country:** France

**Facility:** CHU Clermont-Ferrand

**State:** Not Required For This Country

**Status:** RECRUITING

**Zip:** 63000

#### Overall Officials

**Official 1:**

**Affiliation:** University Hospital, Clermont-Ferrand

**Name:** Matthieu JABAUDON

**Role:** PRINCIPAL_INVESTIGATOR

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000004194

- Term: Disease

- ID: D000010335

- Term: Pathologic Processes

- ID: D000008171

- Term: Lung Diseases

- ID: D000012140

- Term: Respiratory Tract Diseases

- ID: D000012120

- Term: Respiration Disorders

- ID: D000007235

- Term: Infant, Premature, Diseases

- ID: D000007232

- Term: Infant, Newborn, Diseases

- ID: D000055370

- Term: Lung Injury

### Condition Browse Module - Browse Branches

- Abbrev: BC08

- Name: Respiratory Tract (Lung and Bronchial) Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC16

- Name: Diseases and Abnormalities at or Before Birth

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: BC26

- Name: Wounds and Injuries

- Abbrev: BXS

- Name: Urinary Tract, Sexual Organs, and Pregnancy Conditions

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M14965

- Name: Respiratory Distress Syndrome

- Relevance: HIGH

- As Found: Respiratory Distress Syndrome

- ID: M14964

- Name: Respiratory Distress Syndrome, Newborn

- Relevance: HIGH

- As Found: Respiratory Distress Syndrome

- ID: M16355

- Name: Syndrome

- Relevance: HIGH

- As Found: Syndrome

- ID: M19010

- Name: Critical Illness

- Relevance: LOW

- As Found: Unknown

- ID: M27137

- Name: Respiratory Aspiration

- Relevance: LOW

- As Found: Unknown

- ID: M28144

- Name: Acute Lung Injury

- Relevance: HIGH

- As Found: Acute Respiratory Distress Syndrome

- ID: M28143

- Name: Lung Injury

- Relevance: LOW

- As Found: Unknown

- ID: M11168

- Name: Lung Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M14977

- Name: Respiratory Tract Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M14957

- Name: Respiration Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M25869

- Name: Premature Birth

- Relevance: LOW

- As Found: Unknown

- ID: M10279

- Name: Infant, Premature, Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M10276

- Name: Infant, Newborn, Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T4927

- Name: Respiratory Distress Syndrome, Infant

- Relevance: HIGH

- As Found: Respiratory Distress Syndrome

- ID: T192

- Name: Acute Respiratory Distress Syndrome

- Relevance: HIGH

- As Found: Acute Respiratory Distress Syndrome

- ID: T170

- Name: Acute Graft Versus Host Disease

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000012128

- Term: Respiratory Distress Syndrome

- ID: D000012127

- Term: Respiratory Distress Syndrome, Newborn

- ID: D000055371

- Term: Acute Lung Injury

- ID: D000013577

- Term: Syndrome

### Intervention Browse Module - Ancestors

- ID: D000010975

- Term: Platelet Aggregation Inhibitors

- ID: D000018685

- Term: Anesthetics, Inhalation

- ID: D000018681

- Term: Anesthetics, General

- ID: D000000777

- Term: Anesthetics

- ID: D000002492

- Term: Central Nervous System Depressants

- ID: D000045505

- Term: Physiological Effects of Drugs

### Intervention Browse Module - Browse Branches

- Abbrev: Analg

- Name: Analgesics

- Abbrev: CNSDep

- Name: Central Nervous System Depressants

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: PlAggInh

- Name: Platelet Aggregation Inhibitors

### Intervention Browse Module - Browse Leaves

- ID: M22662

- Name: Dexmedetomidine

- Relevance: LOW

- As Found: Unknown

- ID: M18307

- Name: Propofol

- Relevance: LOW

- As Found: Unknown

- ID: M4107

- Name: Anesthetics

- Relevance: LOW

- As Found: Unknown

- ID: M1673

- Name: Sevoflurane

- Relevance: HIGH

- As Found: Metabolic

- ID: M4032

- Name: Analgesics

- Relevance: LOW

- As Found: Unknown

- ID: M10043

- Name: Hypnotics and Sedatives

- Relevance: LOW

- As Found: Unknown

- ID: M13865

- Name: Platelet Aggregation Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M20765

- Name: Anesthetics, Inhalation

- Relevance: LOW

- As Found: Unknown

- ID: M20761

- Name: Anesthetics, General

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000077149

- Term: Sevoflurane

### Misc Info Module

- Version Holder: 2024-05-24
