Precision Ventilation vs Standard Care for Acute Respiratory Distress Syndrome

Acute Respiratory Distress Syndrome Clinical Trial

— PREVENT VILI  

Official title:

PREcision VENTilation to Attenuate Ventilator-Induced Lung Injury: A Phase 3 Multicenter Randomized Clinical Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06066502
• Other study ID #: 2023P000682
• Secondary ID: 1U24HL1667841UG3
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: April 1, 2024
• Est. completion date: August 31, 2030

Study information

• Verified date: February 2024
• Source: Beth Israel Deaconess Medical Center
• Contact: Valerie Goodspeed, MPH
• Phone: 6176328055
• Email: vgoodspe[@]bidmc.harvad.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 1100
• Est. completion date: August 31, 2030
• Est. primary completion date: October 1, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

14. Limitation on life-sustaining care, other than do-not-resuscitate

15. Treating clinician refusal OR unwilling to use protocol-specified ventilator settings / modes

16. Prisoner

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Newborn
• Respiratory Failure
• Respiratory Insufficiency
• Syndrome

Intervention

Other:
• Precision ventilation
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.
• Guided usual care ventilation
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.

Locations

Country	Name	City	State
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Columbia University Medical Center	New York	New York

Sponsors (4)

Lead Sponsor	Collaborator
Beth Israel Deaconess Medical Center	Columbia University, Massachusetts General Hospital, National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (2)

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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Hemodynamic Instability Index through Hour 4 and daily through Day 7	A hemodynamic instability index will be computed per a six-level ordinal scale	From hour 4 through Day 7 from enrollment
Other	Shock-free days through Day 28	The number of days, regardless of consecutiveness, during which vasopressors have not been administered for at least 1 uninterrupted hour, through Day 28.	28 days from trial enrollment
Other	Duration of vasopressor support through Day 28	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.	28 days from trial enrollment
Other	Renal failure-free days through Day 28	The number of days between successful liberation from renal replacement therapy and Day 28.	28 days from trial enrollment
Other	Refractory hypoxemia through Day 28	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.	28 days from trial enrollment
Other	Refractory acidemia through Day 28	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.	28 days from trial enrollment
Other	Daily fluid balance through Day 7	The difference between total fluid intake and total fluid output, calculated daily through day 7.	7 days from trial enrollment
Other	Daily Sequential Organ Failure Assessment (SOFA) through Day 7	SOFA will be computed daily for live patients through Day 7, omitting Glasgow Coma Scale element.	7 days from trial enrollment
Other	Alveolar epithelial injury biomarkers	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.	3 days from trial enrollment
Other	Pro-fibrosis biomarkers	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.	3 days from trial enrollment
Other	Endothelial barrier function biomarkers	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.	3 days from trial enrollment
Other	Inflammatory cytokines	The change in plasma levels of Plasma interleukin-6 (IL6) and interleukin-8 (IL8) will be compared between baseline and Day 3.	3 days from trial enrollment
Primary	60-day mortality	All-cause, all-location mortality	60 days from trial enrollment
Secondary	28-day mortality	All-cause, all-location mortality	28 days from trial enrollment
Secondary	6-month mortality	All-cause, all-location mortality	6 months from trial enrollment
Secondary	A composite of alive and ventilator-free through 28 days	Alive and ventilator-free (AVF) is a composite outcome that incorporates survival and time to successful liberation from invasive mechanical ventilation among survivors in such a manner that death constitutes a more serious outcome. Every subject is compared to every other subject in the trial and assigned one number resulting from each comparison. Since mortality outcome is clinically more important, mortality takes precedence over days off the ventilator. The sum of scores for patients in the treatment group is compared to the sum of scores of subjects in the control group to form a test statistic by the Mann-Whitney technique.	28 days from trial enrollment
Secondary	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.	60 days from trial enrollment
Secondary	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.	28 days from trial enrollment
Secondary	Pneumothorax through Day 28	Any occurrence of pneumothorax through Day 28 or until successful liberation from IMV, whichever occurs first.	28 days from trial enrollment
Secondary	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.	60 days from trial enrollment
Secondary	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.	60 days from trial enrollment