Clinical trial NCT03799874: Safety and Efficacy Study of Inhaled Carbon Monoxide to Treat Acute Respiratory Distress Syndrome (ARDS)
Official title: A Phase II Trial of Inhaled Carbon Monoxide for the Treatment of Acute Respiratory Distress Syndrome (ARDS)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Acute Respiratory Distress Syndrome
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: Massachusetts General Hospital
name: Weill Medical College of Cornell University
name: Duke University
name: Durham VA Medical Center
name: New York Presbyterian Brooklyn Methodist Hospital
name: Duke Regional Hospital
name: U.S. Army Medical Research Acquisition Activity
name: Washington University School of Medicine
First posted: 2019-01-10
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will be a multi-center, prospective, randomized, partially double-blind, placebo-controlled Phase II clinical trial of inhaled CO (iCO) for the treatment of ARDS. The trial will be conducted at 7 tertiary care medical centers including Weill Cornell Medicine/NewYork-Presbyterian Hospital, Brigham and Women's Hospital (BWH), Massachusetts General Hospital (MGH), Duke University Hospital, Durham Veterans Administration Medical Center, New York-Presbyterian Brooklyn Methodist Hospital, and Duke Regional Hospital. The purpose of this study is to evaluate the safety, tolerability, and efficacy of inhaled carbon monoxide (iCO) for the treatment of ARDS and to examine the biologic readouts of low dose iCO therapy in patients with ARDS

Detailed description: Acute respiratory distress syndrome (ARDS) is a devastating disease affecting military, veteran, and civilian populations. ARDS is a syndrome of severe acute lung inflammation and hypoxemic respiratory failure with an incidence of 180,000 cases annually in the United States. Despite recent advances in critical care management and lung protective ventilation strategies, ARDS morbidity and mortality remain unacceptably high. The lack of specific effective therapies for ARDS indicates a need for new treatments that target novel pathways. Carbon monoxide (CO) represents a novel therapeutic modality in ARDS based on data obtained in experimental models of ARDS over the past decade.

CO has been shown to be protective in experimental models of acute lung injury (ALI) and sepsis. Furthermore, multiple human studies have demonstrated that experimental administration of several different concentrations of CO is well tolerated and that low dose inhaled CO can be safely administered to subjects in a controlled research environment. The investigators have previously conducted a Phase I trial of low dose iCO in ARDS which demonstrated that precise administration of low dose iCO (100 and 200 ppm) is feasible, well-tolerated, and safe in patients with sepsis-induced ARDS.

The purpose of this study is to assess the safety and efficacy of low dose inhaled carbon monoxide (iCO) therapy in mechanically ventilated patients with ARDS.

Eligibility criteria: Inclusion Criteria:

All intubated patients ≥ 18 years old with ARDS

1. ARDS is defined when all four of the following criteria are met:

   1. A PaO2/FiO2 ratio ≤ 300 with at least 5 cm H2O positive end-expiratory airway pressure (PEEP)
   2. Bilateral opacities on frontal chest radiograph (not fully explained by effusions, lobar/lung collapse, or nodules) within 1 week of a known clinical insult or new or worsening respiratory symptoms
   3. A need for positive pressure ventilation by an endotracheal or tracheal tube
   4. Respiratory failure not fully explained by cardiac failure or fluid overload; need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor present.
2. ARDS onset is defined as the time the last of criteria 1-4 are met. ARDS must persist through the enrollment time window of 168 hours.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Age less than 18 years
2. Greater than 168 hours since ARDS onset
3. Pregnant or breastfeeding
4. Prisoner
5. Patient, surrogate, or physician not committed to full support (exception: a patient will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest)
6. No consent/inability to obtain consent or appropriate legal representative not available
7. Physician refusal to allow enrollment in the trial
8. Moribund patient not expected to survive 24 hours
9. No arterial or central line/no intent to place an arterial or central line
10. No intent/unwillingness to follow lung protective ventilation strategy
11. Severe hypoxemia defined as SpO2 \< 95 or PaO2 \< 90 on FiO2 ≥ 0.9
12. Hemoglobin \< 7.0 g/dL
13. Subjects who are Jehovah's Witnesses or are otherwise unable or unwilling to receive blood transfusions during hospitalization
14. Acute myocardial infarction (MI) or acute coronary syndrome (ACS) within the last 90 days
15. Coronary artery bypass graft (CABG) surgery within 30 days
16. Angina pectoris or use of nitrates with activities of daily living
17. Cardiopulmonary disease classified as NYHA class IV
18. Stroke (ischemic or hemorrhagic) within the prior 1 month, cardiac arrest requiring CPR within the prior 72 hours, or inability to assess mental status following cardiac arrest
19. Burns \> 40% total body surface area (TBSA)
20. Severe airway inhalational injury
21. Use of high frequency oscillatory ventilation
22. Use of extracorporeal membrane oxygenation (ECMO)
23. Concomitant use of inhaled pulmonary vasodilator therapy (eg. nitric oxide \[NO\] or prostaglandins)
24. Diffuse alveolar hemorrhage from vasculitis
25. Concurrent participation in other investigational drug study

Primary outcomes:
measure: Primary Safety Outcome: Number of pre-specified administration-related adverse events.
timeFrame: 7 days
measure: Primary Efficacy Outcome: Change in Mitochondrial DNA (mtDNA) level from day 1 to day 5
timeFrame: 5 days
Secondary outcomes:
measure: Lung injury score (LIS) on days 1-5, and on day 7
timeFrame: 7 days
measure: PaO2/FiO2 ratio on days 1-5, and on day 7
timeFrame: 7 days
measure: Oxygenation Index (OI) on days 1-5, and day 7
timeFrame: 7 days
measure: Dead Space Fraction (Vd/Vt) on days 1-3, and day 7
timeFrame: 7 days
measure: Sequential Organ Failure Assessment (SOFA) score on days 1-5, 7, 14, 28
timeFrame: 28 days
measure: Change in biomarkers of autophagy
timeFrame: 5 days
measure: Change in biomarkers of inflammation and inflammasome activation
timeFrame: 5 days
measure: Change in lipid mediators
timeFrame: 5 days
measure: Change in biomarkers of mitochondrial quality control
timeFrame: 5 days
Other outcomes:
measure: Ventilator-free days at day 28
timeFrame: 28 days
measure: ICU-free days at day 28
timeFrame: 28 days
measure: Hospital-free days at day 60
timeFrame: 60 days
measure: Hospital mortality to day 28 and 60
timeFrame: 60 days
measure: Montreal Cognitive Assessment- MoCA-Blind
timeFrame: 6 months
measure: Hayling Sentence Completion Test
timeFrame: 6 months
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Brooklyn
country: United States
facility: New York-Presbyterian Brooklyn Methodist Hospital
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Durham
country: United States
facility: Duke Regional Hospital
state: North Carolina
city: Durham
country: United States
facility: Duke University Hospital
state: North Carolina
Study officials:
affiliation: Brigham and Women's Hospital
name: Rebecca Baron, MD
role: PRINCIPAL_INVESTIGATOR
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