Back to resultsA Multicenter Randomized Clinical Trial (RCT) of Ventilation for Acute Respiratory Distress Syndrome (ARDS) (PREVENT VILI)
Primary Purpose
Acute Respiratory Distress Syndrome, Respiratory Failure
Status
Not yet recruiting
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Precision ventilation
Guided usual care ventilation
Sponsored by
About this trial
This is an interventional treatment trial for Acute Respiratory Distress Syndrome focused on measuring critical care, critical illness, esophageal manometry, transpulmonary pressure, mechanical ventilation, lung stress
Eligibility Criteria
Inclusion Criteria: Age ≥ 18 years Moderate or severe ARDS, defined as meeting all of the following (a-e): Invasive ventilation with positive end-expiratory pressure (PEEP) ≥ 5 cm H2O 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 Bilateral lung opacities on chest imaging not fully explained by effusions, lobar collapse, or nodules Respiratory failure not fully explained by heart failure or fluid overload Onset within 1 week of clinical insult or new/worsening symptoms 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: Esophageal manometry used clinically 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). Gross barotrauma or chest tube inserted to treat barotrauma Esophageal varix or stricture; recent oropharyngeal or gastroesophageal surgery; or past esophagectomy Severe coagulopathy (platelet < 5000/µL or international normalized ratio [INR] > 4) Extracorporeal membrane oxygenation or carbon dioxide (CO2) removal Neuromuscular disease that impairs spontaneous breathing (including but not limited to amyotrophic lateral sclerosis, Guillain-Barré syndrome, spinal cord injury at C5 or above) Chronic supplemental oxygen, pulmonary fibrosis, or lung transplant Refractory shock: norepinephrine-equivalent dose ≥ 0.4 µg/kg/min or simultaneous receipt of ≥ 3 vasopressors Severe liver disease, defined as Child-Pugh Class C ICU admission for burn injury Current ICU stay > 2 weeks or hospital stay (including subacute hospitalization) > 4 weeks Estimated mortality > 50% over 6 months due to underlying chronic medical condition Limitation on life-sustaining care, other than do-not-resuscitate Treating clinician refusal OR unwilling to use protocol-specified ventilator settings / modes Prisoner
Sites / Locations
- Beth Israel Deaconess Medical Center
- Columbia University Medical Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Precision ventilation
Guided usual care
Arm Description
Ventilator support will be calibrated to maintain the range of lung stress typical of relaxed breathing in healthy adults. The ventilator management protocol takes into account pleural pressure, tidal volume and driving pressure, fraction of inspired oxygen (FiO2) and oxygen saturation (SpO2), and positive end-expiratory pressure (PEEP) titration.
Ventilator support will be managed by the clinical team per usual care with select protocol-based guard rails to avoid practice extremes beyond the current body of evidence. PEEP titration will be performed by the clinical team within the limits set in. The allowable combinations of PEEP and FiO2 in the control arm reflect pre-intervention usual care observed at baseline in the recent large federally-funded multicenter ARDS trials.
Outcomes
Primary Outcome Measures
60-day mortality
All-cause, all-location mortality
Secondary Outcome Measures
28-day mortality
All-cause, all-location mortality
6-month mortality
All-cause, all-location mortality
Alive and ventilator-free through 28 days
Alive and ventilator-free (AVF) is a composite outcomes that incorporates survival and time to successful liberation from invasive mechanical ventilation among survivors.
Time to successful liberation from invasive mechanical ventilation (IMV) through 60 days
Number of days from initiation of IMV until the patient is breathing for a period of at least 48 consecutive hours without invasive mechanical ventilation.
Barotrauma through Day 28
Any occurrence of pneumothorax, pneumomediastinum, subcutaneous emphysema, or chest tube insertion for barotrauma through Day 28 or until successful liberation from IMV, whichever occurs first.
Pneumothorax through Day 28
Any occurrence of pneumothorax through Day 28 or until successful liberation from IMV, whichever occurs first.
Intensive care unit (ICU) length of stay through Day 60
Number of days in the ICU from enrollment until the last transfer out of ICU, hospital discharge, death, or Day 60, whichever occurs first.
Hospital length of stay through Day 60
Number of days in the hospital from enrollment until hospital discharge, death, or Day 60, whichever occurs first.
Full Information
NCT ID
NCT06066502
First Posted
September 27, 2023
Last Updated
September 27, 2023
Sponsor
Beth Israel Deaconess Medical Center
Collaborators
Columbia University, Massachusetts General Hospital, National Heart, Lung, and Blood Institute (NHLBI)
1. Study Identification
Unique Protocol Identification Number
NCT06066502
Brief Title
A Multicenter Randomized Clinical Trial (RCT) of Ventilation for Acute Respiratory Distress Syndrome (ARDS)
Acronym
PREVENT VILI
Official Title
PREcision VENTilation to Attenuate Ventilator-Induced Lung Injury: A Phase 3 Multicenter Randomized Clinical Trial
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
January 1, 2024 (Anticipated)
Primary Completion Date
October 1, 2029 (Anticipated)
Study Completion Date
August 31, 2030 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Beth Israel Deaconess Medical Center
Collaborators
Columbia University, Massachusetts General Hospital, National Heart, Lung, and Blood Institute (NHLBI)
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Respiratory Distress Syndrome, Respiratory Failure
Keywords
critical care, critical illness, esophageal manometry, transpulmonary pressure, mechanical ventilation, lung stress
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
Participant
Masking Description
Study team and leadership will be blinded to all analyses throughout the study. Unblinded statistician will perform analyses for the Data and Safety Monitoring Board (DSMB) and be sequestered from the remainder of the team.
Allocation
Randomized
Enrollment
1100 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Precision ventilation
Arm Type
Experimental
Arm Description
Ventilator support will be calibrated to maintain the range of lung stress typical of relaxed breathing in healthy adults. The ventilator management protocol takes into account pleural pressure, tidal volume and driving pressure, fraction of inspired oxygen (FiO2) and oxygen saturation (SpO2), and positive end-expiratory pressure (PEEP) titration.
Arm Title
Guided usual care
Arm Type
Active Comparator
Arm Description
Ventilator support will be managed by the clinical team per usual care with select protocol-based guard rails to avoid practice extremes beyond the current body of evidence. PEEP titration will be performed by the clinical team within the limits set in. The allowable combinations of PEEP and FiO2 in the control arm reflect pre-intervention usual care observed at baseline in the recent large federally-funded multicenter ARDS trials.
Intervention Type
Other
Intervention Name(s)
Precision ventilation
Intervention Description
The intervention arm prioritizes mitigation of ventilator-induced-lung-injury by individualizing support to patient-specific mechanics in an integrated approach to limit overdistension and atelectrauma. This is accomplished in this arm by titration of tidal volume to limitation of driving pressure at 12 centimeters of water (cmH2O) or less and using esophageal manometry to titrate PEEP to a transpulmonary pressure of 0 cmH2O with adjustments in respiratory rate to allow for permissive hypercapnia and FiO2 adjustments to assure adequate oxygenation.
Intervention Type
Other
Intervention Name(s)
Guided usual care ventilation
Intervention Description
The comparison arm allows clinician discretion when titrating PEEP and tidal volume, while setting general targets for allowable PEEP/FiO2 combinations, target range for SpO2, and target range for tidal volume. This arm applies routine best-practice guidelines. This includes maintenance of tidal volumes of 6-8 cc/kg of ideal body weight, limiting plateau pressures to 30 cmH2O or less and application of PEEP-FiO2 combinations which include a wide range of typical usual care with esophageal manometry only for data collection and not clinical adjustment.
Primary Outcome Measure Information:
Title
60-day mortality
Description
All-cause, all-location mortality
Time Frame
60 days from trial enrollment
Secondary Outcome Measure Information:
Title
28-day mortality
Description
All-cause, all-location mortality
Time Frame
28 days from trial enrollment
Title
6-month mortality
Description
All-cause, all-location mortality
Time Frame
6 months from trial enrollment
Title
Alive and ventilator-free through 28 days
Description
Alive and ventilator-free (AVF) is a composite outcomes that incorporates survival and time to successful liberation from invasive mechanical ventilation among survivors.
Time Frame
28 days from trial enrollment
Title
Time to successful liberation from invasive mechanical ventilation (IMV) through 60 days
Description
Number of days from initiation of IMV until the patient is breathing for a period of at least 48 consecutive hours without invasive mechanical ventilation.
Time Frame
60 days from trial enrollment
Title
Barotrauma through Day 28
Description
Any occurrence of pneumothorax, pneumomediastinum, subcutaneous emphysema, or chest tube insertion for barotrauma through Day 28 or until successful liberation from IMV, whichever occurs first.
Time Frame
28 days from trial enrollment
Title
Pneumothorax through Day 28
Description
Any occurrence of pneumothorax through Day 28 or until successful liberation from IMV, whichever occurs first.
Time Frame
28 days from trial enrollment
Title
Intensive care unit (ICU) length of stay through Day 60
Description
Number of days in the ICU from enrollment until the last transfer out of ICU, hospital discharge, death, or Day 60, whichever occurs first.
Time Frame
60 days from trial enrollment
Title
Hospital length of stay through Day 60
Description
Number of days in the hospital from enrollment until hospital discharge, death, or Day 60, whichever occurs first.
Time Frame
60 days from trial enrollment
Other Pre-specified Outcome Measures:
Title
Hemodynamic Instability Index through Hour 4 and daily through Day 7
Description
A hemodynamic instability index will be computed per a six-level ordinal scale
Time Frame
From hour 4 through Day 7 from enrollment
Title
Shock-free days through Day 28
Description
The number of days, regardless of consecutiveness, during which vasopressors have not been administered for at least 1 uninterrupted hour, through Day 28.
Time Frame
28 days from trial enrollment
Title
Duration of vasopressor support through Day 28
Description
A component of the shock-free days composite outcome, calculated as number of days, regardless of consecutiveness, during which the patient required vasopressor support for at least 1 uninterrupted hour of the day.
Time Frame
28 days from trial enrollment
Title
Renal failure-free days through Day 28
Description
The number of days between successful liberation from renal replacement therapy and Day 28.
Time Frame
28 days from trial enrollment
Title
Refractory hypoxemia through Day 28
Description
Any occurrence of SpO2 < 88% continuously for at least 30 minutes' duration despite valid pulse-oximetry waveform and protocol-directed ventilatory support, through Day 28 or until successful liberation from IMV, whichever occurs first.
Time Frame
28 days from trial enrollment
Title
Refractory acidemia through Day 28
Description
Any occurrence of arterial pH < 7.15 on two consecutive measures at least 30 minutes apart despite protocol-directed ventilatory support, through Day 28 or until successful liberation from IMV, whichever occurs first.
Time Frame
28 days from trial enrollment
Title
Daily fluid balance through Day 7
Description
The difference between total fluid intake and total fluid output, calculated daily through day 7.
Time Frame
7 days from trial enrollment
Title
Daily Sequential Organ Failure Assessment (SOFA) through Day 7
Description
SOFA will be computed daily for live patients through Day 7, omitting Glasgow Coma Scale element.
Time Frame
7 days from trial enrollment
Title
Alveolar epithelial injury biomarkers
Description
The change in plasma levels of Plasma Soluble Receptor for Advanced glycation end-products (sRAGE) and surfactant protein D (SP-D) will be compared between baseline and Day 3.
Time Frame
3 days from trial enrollment
Title
Pro-fibrosis biomarkers
Description
The change in plasma levels of Plasma procollagen-III N-terminal peptide (P3NP) and matrix metalloproteinase-7 (MMP7) will be compared between baseline and Day 3.
Time Frame
3 days from trial enrollment
Title
Endothelial barrier function biomarkers
Description
The change in plasma levels of Plasma angiopoietin-2 and vascular endothelial growth factor receptor 1 (VEGFR1, also known as FLT1) will be compared between baseline and Day 3.
Time Frame
3 days from trial enrollment
Title
Inflammatory cytokines
Description
The change in plasma levels of Plasma interleukin-6 (IL6) and interleukin-8 (IL8) will be compared between baseline and Day 3.
Time Frame
3 days from trial enrollment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age ≥ 18 years
Moderate or severe ARDS, defined as meeting all of the following (a-e):
Invasive ventilation with positive end-expiratory pressure (PEEP) ≥ 5 cm H2O
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
Bilateral lung opacities on chest imaging not fully explained by effusions, lobar collapse, or nodules
Respiratory failure not fully explained by heart failure or fluid overload
Onset within 1 week of clinical insult or new/worsening symptoms
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:
Esophageal manometry used clinically
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).
Gross barotrauma or chest tube inserted to treat barotrauma
Esophageal varix or stricture; recent oropharyngeal or gastroesophageal surgery; or past esophagectomy
Severe coagulopathy (platelet < 5000/µL or international normalized ratio [INR] > 4)
Extracorporeal membrane oxygenation or carbon dioxide (CO2) removal
Neuromuscular disease that impairs spontaneous breathing (including but not limited to amyotrophic lateral sclerosis, Guillain-Barré syndrome, spinal cord injury at C5 or above)
Chronic supplemental oxygen, pulmonary fibrosis, or lung transplant
Refractory shock: norepinephrine-equivalent dose ≥ 0.4 µg/kg/min or simultaneous receipt of ≥ 3 vasopressors
Severe liver disease, defined as Child-Pugh Class C
ICU admission for burn injury
Current ICU stay > 2 weeks or hospital stay (including subacute hospitalization) > 4 weeks
Estimated mortality > 50% over 6 months due to underlying chronic medical condition
Limitation on life-sustaining care, other than do-not-resuscitate
Treating clinician refusal OR unwilling to use protocol-specified ventilator settings / modes
Prisoner
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Valerie Goodspeed, MPH
Phone
6176328055
Email
vgoodspe@bidmc.harvad.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Nancy Ringwood, RN
Phone
617-724-9836
Email
nringwood@mgh.harvard.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Daniel Talmor, MD MPH
Organizational Affiliation
Beth Israel Deaconess Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jeremy Beitler, MD MPH
Email
jrb2266@cumc.columbia.edu
First Name & Middle Initial & Last Name & Degree
Alexis Serra
Email
als2336@cumc.columbia.edu
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Data will be made publicly available via the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) repository. As per BioLINCC policy, data will be submitted within one year of completion of the final follow up assessment, or within one year of primary manuscript publication, whichever comes first.
IPD Sharing Time Frame
Data will become available within one year of completion of the final follow up assessment, or within one year of primary manuscript publication, whichever comes first. Data will be available for 10 years.
IPD Sharing Access Criteria
Outside investigators who wish to use data will submit a formal request, including rationale, analysis plan, and local Institutional Review Board (IRB) determination. The PREVENT VILI Executive Committee will review and respond to all requests. All data sharing will be codified by the appropriate contract / data use agreement. Recipient researchers must promise in writing to never attempt to access identifiable health/medical information or to attempt to identify the subject(s) who provided the specimen/data. Any intent to use materials or data for commercial purposes must be clearly disclosed as part of the request.
Citations:
PubMed Identifier
30776290
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.
Results Reference
background
PubMed Identifier
31112383
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.
Results Reference
background
Learn more about this trial
A Multicenter Randomized Clinical Trial (RCT) of Ventilation for Acute Respiratory Distress Syndrome (ARDS)
We'll reach out to this number within 24 hrs