Clinical trial NCT02425579: Safety Study of Inhaled Carbon Monoxide to Treat Acute Respiratory Distress Syndrome (ARDS)
Official title: A Phase I Trial of Inhaled Carbon Monoxide for the Treatment of Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Respiratory Distress Syndrome (ARDS)
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: Weill Medical College of Cornell University
name: Massachusetts General Hospital
name: Duke University
First posted: 2015-04-24
Enrollment: 12
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: The purpose of this study is to assess the safety of inhaled carbon monoxide (iCO) in intubated patients with sepsis-induced ARDS.

Detailed description: The acute respiratory distress syndrome (ARDS) is a syndrome of severe acute lung inflammation and hypoxemic respiratory failure with an incidence of 180,000 cases annually in the U.S.Despite decades of research and recent advances in lung protective ventilator strategies, morbidity and mortality remain unacceptably high. Furthermore, no specific effective pharmacologic therapies currently exist. The lack of specific effective therapies for sepsis-related 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 and sepsis over the past decade.

CO has been shown to be protective in experimental models of Acute Lung Injury (ALI), including hyperoxia and endotoxin exposure, bleomycin, ischemia/reperfusion, and ventilator-induced lung injury (VILI). At low doses, CO has been shown to confer tissue protective effects in these ALI models. In addition, CO has been shown to decrease inflammation, enhance phagocytosis, and improve mortality in models of sepsis including endotoxemia, hemorrhagic shock, and cecal ligation and puncture (CLP). CO has also been shown to have beneficial therapeutic effects in pre-clinical models of disease including pulmonary hypertension, vascular injury, and transplantation. 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 purpose of this study is to assess the safety of inhaled CO therapy in mechanically ventilated patients with sepsis-induced ARDS.

Eligibility criteria: Inclusion Criteria:

1. Patients with sepsis are defined as those with suspected or documented infection:

   Suspected or proven infection: Sites of infection include thorax, urinary tract, abdomen, skin, sinuses, central venous catheters, and central nervous system

   All eligible patients meet the new definition of sepsis (suspected or proven infection and a SOFA ≥ 2) as PaO2/FiO2 ratio \< 300 = 2 SOFA points.
2. ARDS is defined when all four of the following criteria are met:

   * A PaO2/FiO2 ratio ≤ 300 with at least 5 cm H2O positive end-expiratory airway pressure (PEEP)
   * Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph
   * A need for positive pressure ventilation by an endotracheal or tracheal tube
   * No clinical evidence of left atrial hypertension for bilateral pulmonary infiltrates.
3. ARDS onset is defined as the time the last of criteria 1-4 are met. ARDS must persist through the enrollment time window of 120 hours.
4. Infiltrates considered "consistent with pulmonary edema" include any infiltrates not fully explained by mass, atelectasis, or effusion or opacities known to be chronic (greater than 1 week). Vascular redistribution, indistinct vessels, and indistinct heart borders alone are not considered "consistent with pulmonary edema" and thus would not count as qualifying opacities for this study.

Exclusion Criteria:

1. Age less than 18 years
2. Greater than 120 hours since ARDS onset
3. Pregnant or breast-feeding
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
7. Physician refusal to allow enrollment in the trial
8. Moribund patient not expected to survive 24 hours
9. No arterial line/no intent to place an arterial line
10. No intent/unwillingness to follow lung protective ventilation strategy
11. Severe hypoxemia defined as oxygenation saturation (SpO2) \<95 or PaO2 \<80 on FiO2 ≥0.8
12. Hemoglobin \< 7.5 g/dl or hemoglobin \< 8 g/dl and actively bleeding
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 New York Heart Association (NYHA) class IV
18. Stroke (ischemic or hemorrhagic) within the prior 3 months
19. Diffuse alveolar hemorrhage from vasculitis
20. Use of high frequency ventilation
21. Participation in other interventional studies involving investigational agents
22. Burns \> 40% total body surface area
23. Use of inhaled pulmonary vasodilator therapy (eg. NO or prostaglandins)

Primary outcomes:
measure: Number of administration associated adverse events.
timeFrame: 60 Days if remains in the ICU
measure: Incidence of serious adverse events (SAEs).
timeFrame: 60 Days if remains in the ICU
Secondary outcomes:
measure: Comparison between the calculated carboxyhemoglobin (COHb) level at 90 minutes using the Coburn-Forster-Kane (CFK) equation and measured COHb level at 90 minutes
timeFrame: 5 days
measure: Mean daily Sequential Organ Failure Assessment (SOFA) score
timeFrame: 7 days
measure: Partial pressure of arterial oxygen (PaO2)/FiO2 ratio
timeFrame: 5 days
measure: Oxygenation index (OI)
timeFrame: 5 days
measure: Lung injury score (LIS)
timeFrame: 7 Days
measure: Vasopressor-free days
timeFrame: 28 days
measure: Ventilator-free days (VFDs)
timeFrame: 28 days
measure: ICU-free days
timeFrame: 28 days
measure: Hospital-free days
timeFrame: 60 days
Other outcomes:
measure: Plasma biomarkers of inflammation, lung epithelial injury,endothelial injury, markers of change in other end-organ function
timeFrame: 5 days
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: New York
country: United States
facility: Weill Cornell Medical College/NewYork-Presbyterian
state: New York
city: Durham
country: United States
facility: Duke Univesity Hospital
state: North Carolina
Study officials:
affiliation: Brigham and Women's Hospital
name: Laura E Fredenburgh, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fredenburgh LE, Perrella MA, Barragan-Bradford D, Hess DR, Peters E, Welty-Wolf KE, Kraft BD, Harris RS, Maurer R, Nakahira K, Oromendia C, Davies JD, Higuera A, Schiffer KT, Englert JA, Dieffenbach PB, Berlin DA, Lagambina S, Bouthot M, Sullivan AI, Nuccio PF, Kone MT, Malik MJ, Porras MAP, Finkelsztein E, Winkler T, Hurwitz S, Serhan CN, Piantadosi CA, Baron RM, Thompson BT, Choi AM. A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS. JCI Insight. 2018 Dec 6;3(23):e124039. doi: 10.1172/jci.insight.124039.