"Continuous Positive Airway Pressure on Venovenous extracorporeaL Membrane Oxygenation for Acute respIratory Distress syndrOme" (CALMDOWN)

"Continuous Positive Airway Pressure on Venovenous extracorporeaL Membrane Oxygenation for Acute respIratory Distress syndrOme" - CALMDOWN

The CALMDOWN trial is a prospective, open-label, multicenter, comparative, controlled trial randomizing patients who received near apneic ventilation vs usual care on ECMO (ultra-protective lung ventilation).

The study goal is to investigate the benefit of early apneic ventilation in the most severe forms of acute respiratory distress syndrome (ARDS) rescued by ECMO.

Indeed, our hypothesis is that that early (near) apneic ventilation on venovenous ECMO for severe ARDS can enhance ventilator injury prevention and therefore reduce ECMO duration and mortality at Day 60.

Study Overview

• Status: Recruiting
• Conditions: Acute Respiratory Distress Syndrome; Extracorporeal Membrane Oxygenation Complication
• Intervention / Treatment: Device: ECMO + ultra-protective lung ventilation; Device: ECMO + near apneic ventilation

• Study Type: Interventional
• Enrollment (Estimated): 280
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Matthieu SCHMIDT, MD; Phone Number: 01 42 16 29 37; Email: matthieu.schmidt@aphp.fr

Study Locations

• France
  • Bobigny, France
    • Recruiting
    • Avicenne Hospital
    • Contact: Johanna OZIEL; Phone Number: 01 48 95 52 41; Email: johanna.oziel@aphp.fr
  • Bordeaux, France
    • Recruiting
    • Haut Levèque Hospital - CHU Bordeaux
    • Contact: Benjamin REPUSSEAU; Email: Benjamin.Repusseau@chu-bordeaux.fr
  • Créteil, France
    • Recruiting
    • Henri Mondor Hospital
    • Contact: Armand MEKONTSO-DESSAP; Phone Number: 01 45 17 85 11; Email: armand.dessap@aphp.fr
  • Lyon, France
    • Recruiting
    • Croix-Rousse Hospital - HCL
    • Contact: Jean-Christophe RICHARD; Phone Number: +33 4 72 04 17 62; Email: j-christophe.richard@chu-lyon.fr
  • Marseille, France
    • Recruiting
    • North Hospital - APHM
    • Contact: Christophe GUERVILLY; Phone Number: +33 4 91 96 58 42; Email: christophe.guervilly@ap-hm.fr
  • Metz, France
    • Recruiting
    • Mercy Hospital - CHR Metz
    • Contact: Benjamin PEQUIGNOT; Email: benjamin.pequignot@chr-metz-thionville.fr
  • Nancy, France
    • Recruiting
    • Brabois Hospital - CHRU Nancy
    • Contact: Matthieu KOSZUSTKI; Phone Number: +33 3 83 15 30 17; Email: m.koszutski@chru-nancy.fr
  • Orléans, France
    • Recruiting
    • Chu Orleans
    • Contact: François BARBIER; Phone Number: +33 2 38 22 99 39; Email: francois.barbier@chu-orleans.fr
  • Paris, France
    • Recruiting
    • Pitié-Salpêtrière Hospital
    • Contact: Matthieu SCHMIDT; Phone Number: 01 42 16 29 37; Email: matthieu.schmidt@aphp.fr
  • Rennes, France
    • Recruiting
    • Pontchaillou Hospital - CHU Rennes
    • Contact: Arnaud GACOUIN; Phone Number: +33 2 99 28 97 31; Email: arnaud.gacouin@chu-rennes.fr
  • Tours, France
    • Recruiting
    • CHU Tours
    • Contact: Emmanuelle MERCIER; Phone Number: +33 2 47 47 38 55; Email: emmanuelle.mercier@univ-tours.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Severe acute respiratory distress syndrome refractory to conventional therapy placed on VV-ECMO support in the 48 hours (maximum tolerance : +2h) preceding inclusion.
2. Obtain informed consent from a close relative or surrogate. According to the specifications of emergency inclusion, randomization without the close relative/surrogate consent could be performed if the patient is unable to give his/her consent and when the close relative/surrogate/family member are absent. Close relative/surrogate/family member consent will be asked as soon as possible after randomization. The patient will be asked as soon as possible to give his/her consent for the continuation of the trial when his/her condition will allow.
3. French Social security registration (except AME)

Exclusion Criteria:

1. Age < 18
2. Pregnancy or breastfeeding
3. Initiation of VV-ECMO > 48 h (maximum tolerance : +2h)
4. Cardiac arrest with cumulated no flow time >10 minutes before ECMO (within 48 hours prior to inclusion)
5. Irreversible neurological pathology
6. End-stage chronic lung disease
7. Contraindications for high PEEP level: untreated pneumothorax, barotrauma
8. Irreversible ARDS with no hope for lung function recovery
9. Patient moribund on the day of randomization, SAPS II >90
10. Liver cirrhosis (Child B or C)
11. Lung transplantation
12. Burns on more than 20 % of the body surface
13. Participation in another interventional study with a similar primary endpoint (mortality, lung transplantation, or duration of ECMO) or being in the exclusion period at the end of a previous study
14. Individuals under guardianship, or permanently legally incompetent adults

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of care : ultra-protective lung ventilation; Patients will receive ultra-protective lung ventilation as it uses on usual care on ECMO.	Device: ECMO + ultra-protective lung ventilation; Ultra-protective lung ventilation will be used up to the ECMO weaning. This group will receive ultra-protective lung ventilation with BIPAP/APRV or VCV mode setting a PEEP >10 cmH2O, ΔP 14-15 cmH2O, RR 15-20/min, Vt 3-4ml/kg and lowest FiO2 to maintain SpO2>92%. The use of prone positioning during ECMO will be left at the physician's discretion.
Experimental: Intervention group : near apneic ventilation; Patients will received near apneic ventilation during the first 3 days of ECMO.	Device: ECMO + near apneic ventilation; Near apneic ventilation will be use during the first 3 days of ECMO. Patients will be ventilated in BIPAP/APRV or pressure-controlled ventilation. PEEP will be set to maintain the same mean airway pressure obtained during the standardized ventilation period pre-randomization to prevent lung derecruitment (PEEP ≥15cmH2O). If BIPAP/APRV is used, an RR of 2-4/min will be set with high pressure set at 30cmH20 for 3 sec. If pressure-controlled ventilation is selected, a respiratory rate of two sigh breaths/min with 30 cmH2O plateau pressure will be applied. Each sigh breath will be of three seconds duration. Neuromuscular blockade and sedation could be used at the discretion of the attending physician. After 3 days on ECMO, apneic ventilation could be pursued (at the physician's discretion). If not, ultra-protective lung ventilation will be applied (i.e standard of care). Prone positioning on ECMO will be left to the physicians' discretion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of the application of early apneic ventilation on four components : mortality status at D60, need for lung transplantation at D60, persisting ECMO at D60, number of days alive between randomization and day 60 without ECMO	These components will be summarized in a composite, hierarchical outcome. Each patient will be compared with every other patient in the study and assigned a score (tie: 0, win: +1, loss: -1) for each pairwise comparison based on whom fared better. If one patient survived without lung transplantation or ECMO still ongoing at day 60 and the other did not, scores of +1 and -1 will be assigned, respectively. If both patients in the pairwise comparison survived without lung transplant or ECMO still ongoing at day 60, the assigned score will depend on which patient had more days free from ECMO: the patient with more days off ECMO will receive a score of +1, while the patient with fewer days will receive a score of -1. If both patients survived and had the same number of days off ECMO, or if both patients died or had a lung transplant, they will be both assigned a score of 0 for that pairwise comparison.	Day 0 to Day 60

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Efficacy of early apneic ventilation during VV-ECMO on mortality is defined as overall survival between inclusion and D60	From Day 1 to Day 60
Mortality	Efficacy of early apneic ventilation during VV-ECMO on mortality is defined as overall survival between inclusion and D90	From Day 1 to Day 90
Need for lung transplant	Efficacy of early apneic ventilation during VV-ECMO on the need for lung transplant is defined as lung transplant between inclusion and D60	From Day 1 to Day 60
Need for lung transplant	Efficacy of early apneic ventilation during VV-ECMO on the need for a lung transplant is defined as lung transplant between inclusion and D90	From Day 1 to Day 90
Duration of ECMO support	Defined as total duration with ECMO support between inclusion and D60	From Day 1 to Day 60
Duration of ECMO support	Defined as total duration with ECMO support between inclusion and D90	From Day 1 to Day 90
Duration of invasive mechanical ventilation	Defined as total duration of invasive mechanical ventilation between inclusion and D60	From Day 1 to Day 60
Duration of invasive mechanical ventilation	Defined as total duration of invasive mechanical ventilation between inclusion and D90	From Day 1 to Day 90
Duration of Intensive Care Unit	Defined as total duration spent in intensive care unit between inclusion and D60	From Day 1 to Day 60
Duration of Intensive Care Unit	Defined as total duration spent in intensive care unit between inclusion and D90	From Day 1 to Day 90
Hospital length of stay	Defined as total duration spent at the hospital between inclusion and D60	From Day 1 to Day 60
Hospital length of stay	Defined as total duration spent at the hospital between inclusion and D90	From Day 1 to Day 90
ECMO free days	Efficacy of early apneic ventilation during VV-ECMO on ECMO-free days is defined as the number of ECMO free-days between inclusion and D60	From Day 1 to Day 60
ECMO free days	Efficacy of early apneic ventilation during VV-ECMO on ECMO-free days is defined as number of ECMO free-days between inclusion and D90	From Day 1 to Day 90
Invasive mechanical ventilation free days	Efficacy of early apneic ventilation during VV-ECMO on invasive mecanical ventilation-free days between inclusion and D60	From Day 1 to Day 60
Invasive mechanical ventilation free days	Efficacy of early apneic ventilation during VV-ECMO on invasive mecanical ventilation-free days between inclusion and D90	From Day 1 to Day 90
Renal replacement therapy-free days	Efficacy of early apneic ventilation during VV-ECMO on renal function is defined as number of renal replacement therapy-free days between inclusion and D60	From Day 1 to Day 60
Renal replacement therapy-free days	Efficacy of early apneic ventilation during VV-ECMO on renal function is defined as renal replacement therapy-free days between inclusion and D90	From Day 1 to Day 90
Continuous neuromuscular blockade-free days	Efficacy of early apneic ventilation during VV-ECMO on continuous neuromuscular blockade is defined as number of continuous neuromuscular blockade-free days between inclusion and D60	From Day 1 to Day 60
Continuous neuromuscular blockade-free days	Efficacy of early apneic ventilation during VV-ECMO on continuous neuromuscular blockade is defined as number of continuous neuromuscular blockade-free days between inclusion and D90	From Day 1 to Day 90
Intervention side effects (ventilation-associated pneumonia)	Defined as the incidence of ventilation-associated pneumonia between inclusion and D14	From Day 1 to Day D14
Intervention side effets (need for inotropes or vasopressors)	Defined as the incidence of need for inotropes or vasopressors within 14 days on ECMO	From Day 1 to Day 14
Intervention side effets (intravenous sedation consumption)	Defined as the incidence of intravenous sedation consumption during the first 14 days on ECMO	From Day 1 to Day 14
Acute cor pulmonale	Defined as the incidence of acute cor pulmonale between inclusion and D60	From Day 1 to Day 60
Acute cor pulmonale	Defined as the incidence of acute cor pulmonale between inclusion and D90	From Day 1 to Day 90
Pneumothorax	Defined as the incidence of pneumothorax between inclusion and D60	From Day 1 to Day 60
Pneumothorax	Defined as the incidence of pneumothorax between inclusion and D90	From Day 1 to Day 90
Severe refractory hypoxemia on ECMO	Defined as the incidence of refractory severe hypoxemia between inclusion and D60	From Day 1 to Day 60
Severe refractory hypoxemia on ECMO	Defined as the incidence of refractory severe hypoxemia between inclusion and D90	From Day 1 to Day 90
Compliance of the respiratory system at D7	Effect of near apneic ventilation on the improvement of the compliance of the respiratory system (ml/cmH2O) at D7	From Day 1 to Day 7
Compliance of the respiratory system at D10	Effect of near apneic ventilation on the improvement of the compliance of the respiratory system (ml/cmH2O) at D10	From Day 1 to Day 10
Compliance of the respiratory system at D14	Effect of near apneic ventilation on the improvement of the compliance of the respiratory system (ml/cmH2O) at D14	From Day 1 to Day 14
Compliance of the respiratory system at D28	Effect of near apneic ventilation on the improvement of the compliance of the respiratory system (ml/cmH2O) at D28	From Day 1 to Day 28
Compliance of the respiratory system at D60	Effect of near apneic ventilation on the improvement of the compliance of the respiratory system (ml/cmH2O) at D60	From Day 1 to Day 60
Right ventricular function at D3	Effect of near apneic ventilation on right ventricular function evaluated by echocardiograohy (RV/LV diameter ratio) at D3 on ECMO following randomization	From Day 1 to Day 3
Right ventricular function at D7	Effect of near apneic ventilation on right ventricular function evaluated by echocardiograohy (RV/LV diameter ratio) at D7 on ECMO following randomization	From Day 1 to Day 7
Right ventricular function at D14	Effect of near apneic ventilation on right ventricular function evaluated by echocardiograohy (RV/LV diameter ratio) at D14 on ECMO following randomization	From Day 1 to Day 14
Right ventricular function at D28	Effect of near apneic ventilation on right ventricular function evaluated by echocardiograohy (RV/LV diameter ratio) at D28 on ECMO following randomization	From Day 1 to Day 28
Right ventricular function at D60	Effect of near apneic ventilation on right ventricular function evaluated by echocardiograohy (RV/LV diameter ratio) at D60 on ECMO following randomization	From Day 1 to Day 60

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): May 6, 2025
• Primary Completion (Estimated): May 6, 2029
• Study Completion (Estimated): May 6, 2030

Study Registration Dates

• First Submitted: January 22, 2025
• First Submitted That Met QC Criteria: February 3, 2025
• First Posted (Actual): February 7, 2025

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 8, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: ARDS; ECMO; CPAP
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Respiration Disorders; Respiratory Distress Syndrome; Therapeutics; Surgical Procedures, Operative; Respiratory Therapy; Extracorporeal Circulation; Extracorporeal Membrane Oxygenation
• Other Study ID Numbers: APHP230850

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients.

Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.

• IPD Sharing Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor.
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No