Clinical trial NCT06066502: Precision Ventilation vs Standard Care for Acute Respiratory Distress Syndrome
Official title: PREcision VENTilation to Attenuate Ventilator-Induced Lung Injury: A Phase 3 Multicenter Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Acute Respiratory Distress Syndrome
Respiratory Failure
Keywords: critical care
critical illness
esophageal manometry
transpulmonary pressure
mechanical ventilation
lung stress
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: NYU Langone Health
name: Massachusetts General Hospital
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2023-10-04
Enrollment: 1100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomized to the intervention arm or control arm.

Participants in the intervention group (precision ventilation), will have mechanical ventilation using settings directed by the amount of air pressure in the chest and lungs, using esophageal manometry. The treating clinical team is not masked to esophageal and transpulmonary pressure values and can view these data throughout the period of protocol-directed ventilation.

Participants in the control group (guided usual care), will have ventilator support (low tidal volume mechanical ventilation) managed by the clinical team per usual care. The treating clinical team is masked to esophageal and transpulmonary pressure values and cannot view or be informed of these data at any time during the period of protocol-directed ventilation. An esophageal catheter will be inserted strictly for monitoring of respiratory mechanics by study staff, but values will not be used to titrate the ventilator.
Primary purpose: TREATMENT

Brief summary: The goal of this interventional study is to compare standard mechanical ventilation to a lung-stress oriented ventilation strategy in patients with Acute Respiratory Distress Syndrome (ARDS). Participants will be ventilated according to one of two different strategies. The main question the study hopes to answer is whether the personalized ventilation strategy helps improve survival.

Detailed description: ARDS is a devastating condition that places a heavy burden on public health resources. Recent changes in the practice of mechanical ventilation have improved survival in ARDS, but mortality remains unacceptably high.

This application is for support of a phase III multi-centered, randomized controlled trial of mechanical ventilation, directed by driving pressure and esophageal manometry, in patients with moderate or severe ARDS. The primary hypothesis is that precise ventilator titration to maintain lung stress within 0-12 centimeters of water (cm H2O), the normal physiological range experienced during relaxed breathing, will improve 60-day mortality, compared to guided usual care.

Specific Aim 1: To determine the effect on mortality of the precision ventilation strategy, compared to guided usual care, in patients with moderate or severe ARDS.

• Hypothesis 1: The precision ventilation strategy will decrease 60-day mortality (primary trial endpoint).

Specific Aim 2: To evaluate the effects on lung injury of the precision ventilation strategy, compared to guided usual care, in patients with moderate or severe ARDS.

* Hypothesis 2a: The precision ventilation strategy will improve clinical pulmonary recovery, defined using the composite endpoint alive and ventilator-free (AVF).
* Hypothesis 2b: The precision ventilation strategy will attenuate alveolar epithelial injury.

Specific Aim 3: To evaluate the hemodynamic safety profile of the precision ventilation strategy, compared to guided usual care, in patients with moderate or severe ARDS.

• Hypothesis 3: The precision ventilation strategy will decrease hemodynamic instability, measured as shock-free days through Day 28.

Eligibility criteria: Inclusion Criteria:

1. Age ≥ 18 years
2. Moderate or severe ARDS, defined as meeting all of the following (a-e):

   1. Invasive ventilation with positive end-expiratory pressure (PEEP) ≥ 5 cm H2O
   2. Hypoxemia as characterized by: If arterial blood gas (ABG) available: the partial pressure of oxygen in the arterial blood (PaO2)/FiO2 ≤ 200 mm Hg, or, if ABG not available OR overt clinical deterioration in oxygenation since last ABG: SpO2/FiO2 ≤ 235 with SpO2 ≤ 97% (both conditions) on two representative assessments between 1 to 6 hours apart
   3. Bilateral lung opacities on chest imaging not fully explained by effusions, lobar collapse, or nodules
   4. Respiratory failure not fully explained by heart failure or fluid overload
   5. Onset within 1 week of clinical insult or new/worsening symptoms
3. Early in ARDS course

   * Within 48 hours since meeting last moderate-severe ARDS criterion (#2 above)
   * Current invasive ventilation episode not more than 4 days duration
   * Current severe hypoxemic episode (receipt of invasive ventilation, noninvasive ventilation, or high-flow nasal cannula) not more than 10 days duration

Exclusion Criteria:

1. Esophageal manometry used clinically
2. Severe brain injury: including suspected elevated intracranial pressure, cerebral edema, or Glasgow coma score (GCS) ≤ 8 directly caused by severe brain injury (e.g., ischemia/hemorrhage).
3. Gross barotrauma or chest tube inserted to treat barotrauma
4. Esophageal varix or stricture; recent oropharyngeal or gastroesophageal surgery; or past esophagectomy
5. Severe coagulopathy (platelet \< 5000/µL or international normalized ratio \[INR\] \> 4)
6. Extracorporeal membrane oxygenation or carbon dioxide (CO2) removal
7. Neuromuscular disease that impairs spontaneous breathing (including but not limited to amyotrophic lateral sclerosis, Guillain-Barré syndrome, spinal cord injury at C5 or above)
8. Chronic supplemental oxygen, pulmonary fibrosis, or lung transplant
9. Refractory shock: norepinephrine-equivalent dose ≥ 0.4 µg/kg/min or simultaneous receipt of ≥ 3 vasopressors
10. Severe liver disease, defined as Child-Pugh Class C
11. ICU admission for burn injury
12. Current ICU stay \> 2 weeks or hospital stay (including subacute hospitalization) \> 4 weeks
13. Estimated mortality \> 50% over 6 months due to underlying chronic medical condition as assessed by the study physician
14. Moribund patient not expected to survive 24 hours as assessed by the study physician; if cardiopulmonary resuscitation (CPR) was provided, assessment for moribund status must occur at least 6 hours after CPR was completed
15. Limitation on life-sustaining care, other than do-not-resuscitate, or expectation by treating clinical team that a limitation on life-sustained care will be adopted within next 24 hours.
16. Treating clinician refusal
17. Prisoner

Primary outcomes:
measure: 60-day mortality
timeFrame: 60 days from trial enrollment
Secondary outcomes:
measure: 28-day mortality
timeFrame: 28 days from trial enrollment
measure: Alive and ventilator-free through 28 days
timeFrame: 28 days from trial enrollment
measure: Alive and Respiratory Support-Free
timeFrame: 28 days from trial enrollment
measure: Barotrauma through Day 14
timeFrame: 14 days from trial enrollment
Other outcomes:
measure: Hemodynamic Instability Index through Hour 4 and daily through Day 7
timeFrame: From hour 4 through Day 7 from enrollment
measure: Shock-free days through Day 28
timeFrame: 28 days from trial enrollment
measure: Duration of vasopressor support through Day 28
timeFrame: 28 days from trial enrollment
measure: Renal failure-free days through Day 28
timeFrame: 28 days from trial enrollment
measure: Refractory hypoxemia through Day 14
timeFrame: 14 days from trial enrollment
measure: Refractory acidemia through Day 14
timeFrame: 14 days from trial enrollment
measure: Daily Sequential Organ Failure Assessment (SOFA) through Day 7
timeFrame: 7 days from trial enrollment
measure: ICU length of stay
timeFrame: 60 days
measure: Hospital length of stay
timeFrame: 60 days
measure: Alveolar epithelial injury biomarkers
timeFrame: 2 days from trial enrollment
measure: Pro-fibrosis biomarkers
timeFrame: 2 days from trial enrollment
measure: Endothelial barrier function biomarkers
timeFrame: 2 days from trial enrollment
measure: Inflammatory biomarkers
timeFrame: 2 days from trial enrollment
Locations:
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: La Jolla
country: United States
facility: University of California, San Diego
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles Medical Center
state: California
city: Los Angeles
country: United States
facility: Cedar-Sinai Medical Center
state: California
city: San Franciso
country: United States
facility: University of California, San Francisco
state: California
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Bronx
country: United States
facility: Albert Einstein College of Medicine/Montefiore Medical Center
state: New York
city: New York City
country: United States
facility: NYU Lagone Health
state: New York
city: Winston-Salem
country: United States
facility: Atrium Health Wake Forest Baptist
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Wexner Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Murray
country: United States
facility: Intermountain Health
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: University of Washingont/Harborview Medical Center
state: Washington
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Daniel Talmor, MD MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Beitler JR, Sarge T, Banner-Goodspeed VM, Gong MN, Cook D, Novack V, Loring SH, Talmor D; EPVent-2 Study Group. Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2019 Mar 5;321(9):846-857. doi: 10.1001/jama.2019.0555.
citation: National Heart, Lung, and Blood Institute PETAL Clinical Trials Network; Moss M, Huang DT, Brower RG, Ferguson ND, Ginde AA, Gong MN, Grissom CK, Gundel S, Hayden D, Hite RD, Hou PC, Hough CL, Iwashyna TJ, Khan A, Liu KD, Talmor D, Thompson BT, Ulysse CA, Yealy DM, Angus DC. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019 May 23;380(21):1997-2008. doi: 10.1056/NEJMoa1901686. Epub 2019 May 19.