Safety and Efficacy Study of Inhaled Carbon Monoxide to Treat Acute Respiratory Distress Syndrome (ARDS)

NCT03799874 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 2018P002051CDMRP-PR171025, W81XWH1810667
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 7

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

Conditions

Acute Respiratory Distress Syndrome

Outcome Measures

Primary Outcomes (2)

• Primary Safety Outcome: Number of pre-specified administration-related adverse events.

  Safety of inhaled CO, defined by the incidence of pre-specified administration-related AEs (as defined below) and spontaneously reported AEs through study day 7. 1. Acute MI within 48 hours of study drug administration 2. Acute cerebrovascular accident (CVA) within 48 hours of study drug administration 3. New onset atrial or ventricular arrhythmia requiring DC cardioversion within 48 hours of study drug administration 4. Increased oxygenation requirements defined as: an increase in FiO2 of ≥ 0.2 AND increase in PEEP ≥ 5 cm H2O within 6 hours of study drug administration 5. Increase in COHb ≥ 10% 6. Increase in lactate by ≥ 2 mmol/L within 6 hours of study drug administration

  7 days

• Primary Efficacy Outcome: Change in Mitochondrial DNA (mtDNA) level from day 1 to day 5

  Mitochondrial DNA (mtDNA) plasma levels will be measured by quantitative PCR of human NADH dehydrogenase 1.

  5 days

Secondary Outcomes (9)

• Lung injury score (LIS) on days 1-5, and on day 7

  7 days

• PaO2/FiO2 ratio on days 1-5, and on day 7

  7 days

• Oxygenation Index (OI) on days 1-5, and day 7

  7 days

• Dead Space Fraction (Vd/Vt) on days 1-3, and day 7

  7 days

• Sequential Organ Failure Assessment (SOFA) score on days 1-5, 7, 14, 28

  28 days

Other Outcomes (6)

• Ventilator-free days at day 28

  28 days

• ICU-free days at day 28

  28 days

• Hospital-free days at day 60

  60 days

Study Arms (2)

Inhaled Carbon Monoxide

EXPERIMENTAL

Inhaled Carbon Monoxide at 200 ppm for up to 90 minutes daily for 3 days.

Drug: Inhaled Carbon Monoxide at 200 ppm

Medical air

PLACEBO COMPARATOR

Inhaled Medical Air for up to 90 minutes daily for 3 days.

Other: Inhaled Medical air

Interventions

Inhaled Carbon Monoxide at 200 ppm DRUG

Inhaled Carbon Monoxide at 200 ppm for 90 minutes daily for 3 days.

Also known as: iCO

Inhaled Carbon Monoxide

Inhaled Medical air OTHER

Inhaled Medical Air for up to 90 minutes daily for 3 days.

Medical air

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All intubated patients ≥ 18 years old with ARDS
• 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 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
• A need for positive pressure ventilation by an endotracheal or tracheal tube
• 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.
• 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.

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:
• Age less than 18 years
• Greater than 168 hours since ARDS onset
• Pregnant or breastfeeding
• Prisoner
• 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)
• No consent/inability to obtain consent or appropriate legal representative not available
• Physician refusal to allow enrollment in the trial
• Moribund patient not expected to survive 24 hours
• No arterial or central line/no intent to place an arterial or central line
• No intent/unwillingness to follow lung protective ventilation strategy
• Severe hypoxemia defined as SpO2 \< 95 or PaO2 \< 90 on FiO2 ≥ 0.9
• Hemoglobin \< 7.0 g/dL
• Subjects who are Jehovah's Witnesses or are otherwise unable or unwilling to receive blood transfusions during hospitalization
• Acute myocardial infarction (MI) or acute coronary syndrome (ACS) within the last 90 days

Sponsors & Collaborators

• Brigham and Women's Hospital: lead
• Massachusetts General Hospital: collaborator
• Weill Medical College of Cornell University: collaborator
• Duke University: collaborator
• Durham VA Medical Center: collaborator
• New York Presbyterian Brooklyn Methodist Hospital: collaborator
• Duke Regional Hospital: collaborator
• U.S. Army Medical Research Acquisition Activity: collaborator
• Washington University School of Medicine: collaborator

Study Sites (7)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Washington University

St Louis, Missouri, 63130, United States

Location

New York-Presbyterian Brooklyn Methodist Hospital

Brooklyn, New York, 11215, United States

Location

Weill Cornell Medical College

New York, New York, 10065, United States

Location

Duke Regional Hospital

Durham, North Carolina, 27704, United States

Location

Duke University Hospital

Durham, North Carolina, 27710, United States

Location

Related Publications (14)

• Nakahira K, Kyung SY, Rogers AJ, Gazourian L, Youn S, Massaro AF, Quintana C, Osorio JC, Wang Z, Zhao Y, Lawler LA, Christie JD, Meyer NJ, Mc Causland FR, Waikar SS, Waxman AB, Chung RT, Bueno R, Rosas IO, Fredenburgh LE, Baron RM, Christiani DC, Hunninghake GM, Choi AM. Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation. PLoS Med. 2013 Dec;10(12):e1001577; discussion e1001577. doi: 10.1371/journal.pmed.1001577. Epub 2013 Dec 31.

  PMID: 24391478 BACKGROUND

• Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet. 2002 Jul 20;360(9328):219-23. doi: 10.1016/S0140-6736(02)09459-X.

  PMID: 12133657 BACKGROUND

• Jung SS, Moon JS, Xu JF, Ifedigbo E, Ryter SW, Choi AM, Nakahira K. Carbon monoxide negatively regulates NLRP3 inflammasome activation in macrophages. Am J Physiol Lung Cell Mol Physiol. 2015 May 15;308(10):L1058-67. doi: 10.1152/ajplung.00400.2014. Epub 2015 Mar 13.

  PMID: 25770182 BACKGROUND

• Rhodes MA, Carraway MS, Piantadosi CA, Reynolds CM, Cherry AD, Wester TE, Natoli MJ, Massey EW, Moon RE, Suliman HB. Carbon monoxide, skeletal muscle oxidative stress, and mitochondrial biogenesis in humans. Am J Physiol Heart Circ Physiol. 2009 Jul;297(1):H392-9. doi: 10.1152/ajpheart.00164.2009. Epub 2009 May 22.

  PMID: 19465554 BACKGROUND

• Fredenburgh LE, Kraft BD, Hess DR, Harris RS, Wolf MA, Suliman HB, Roggli VL, Davies JD, Winkler T, Stenzler A, Baron RM, Thompson BT, Choi AM, Welty-Wolf KE, Piantadosi CA. Effects of inhaled CO administration on acute lung injury in baboons with pneumococcal pneumonia. Am J Physiol Lung Cell Mol Physiol. 2015 Oct 15;309(8):L834-46. doi: 10.1152/ajplung.00240.2015. Epub 2015 Aug 28.

  PMID: 26320156 BACKGROUND

• Hausberg M, Somers VK. Neural circulatory responses to carbon monoxide in healthy humans. Hypertension. 1997 May;29(5):1114-8. doi: 10.1161/01.hyp.29.5.1114.

  PMID: 9149675 BACKGROUND

• Mayr FB, Spiel A, Leitner J, Marsik C, Germann P, Ullrich R, Wagner O, Jilma B. Effects of carbon monoxide inhalation during experimental endotoxemia in humans. Am J Respir Crit Care Med. 2005 Feb 15;171(4):354-60. doi: 10.1164/rccm.200404-446OC. Epub 2004 Nov 19.

  PMID: 15557136 BACKGROUND

• Peterson JE, Stewart RD. Predicting the carboxyhemoglobin levels resulting from carbon monoxide exposures. J Appl Physiol. 1975 Oct;39(4):633-8. doi: 10.1152/jappl.1975.39.4.633.

  PMID: 1194155 BACKGROUND

• Stewart RD, Peterson JE, Baretta ED, Bachand RT, Hosko MJ, Herrmann AA. Experimental human exposure to carbon monoxide. Arch Environ Health. 1970 Aug;21(2):154-64. doi: 10.1080/00039896.1970.10667214. No abstract available.

  PMID: 5430001 BACKGROUND

• Zevin S, Saunders S, Gourlay SG, Jacob P, Benowitz NL. Cardiovascular effects of carbon monoxide and cigarette smoking. J Am Coll Cardiol. 2001 Nov 15;38(6):1633-8. doi: 10.1016/s0735-1097(01)01616-3.

  PMID: 11704374 BACKGROUND

• Ren X, Dorrington KL, Robbins PA. Respiratory control in humans after 8 h of lowered arterial PO2, hemodilution, or carboxyhemoglobinemia. J Appl Physiol (1985). 2001 Apr;90(4):1189-95. doi: 10.1152/jappl.2001.90.4.1189.

  PMID: 11247913 BACKGROUND

• Pecorella SR, Potter JV, Cherry AD, Peacher DF, Welty-Wolf KE, Moon RE, Piantadosi CA, Suliman HB. The HO-1/CO system regulates mitochondrial-capillary density relationships in human skeletal muscle. Am J Physiol Lung Cell Mol Physiol. 2015 Oct 15;309(8):L857-71. doi: 10.1152/ajplung.00104.2015. Epub 2015 Jul 17.

  PMID: 26186946 BACKGROUND

• 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.

  PMID: 30518685 BACKGROUND

• Rosas IO, Goldberg HJ, Collard HR, El-Chemaly S, Flaherty K, Hunninghake GM, Lasky JA, Lederer DJ, Machado R, Martinez FJ, Maurer R, Teller D, Noth I, Peters E, Raghu G, Garcia JGN, Choi AMK. A Phase II Clinical Trial of Low-Dose Inhaled Carbon Monoxide in Idiopathic Pulmonary Fibrosis. Chest. 2018 Jan;153(1):94-104. doi: 10.1016/j.chest.2017.09.052. Epub 2017 Oct 31.

  PMID: 29100885 BACKGROUND

MeSH Terms

Conditions

Respiratory Distress Syndrome

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders

Study Officials

• Rebecca Baron, MD

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Masking Details: The study drug will be blinded to the study staff using identical tanks containing either CO or placebo air. The administering respiratory therapist (RT) and a physician study staff member will be unblinded to the treatment assignments.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: December 6, 2018
• First Posted: January 10, 2019
• Study Start: July 1, 2019
• Primary Completion: January 1, 2026
• Study Completion: January 1, 2026
• Last Updated: August 24, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)