Safety Study of Inhaled Carbon Monoxide to Treat Pneumonia and Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)

NCT04870125 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 2021P0007451R61HL153011-01
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 6

Brief Summary

This study is a multi-center, randomized, partially double-blind, and placebo-controlled Phase Ib clinical trial of inhaled CO (iCO) for the treatment of sepsis-induced acute respiratory distress syndrome (ARDS). The purpose of this study is to evaluate the safety and accuracy of a Coburn-Forster-Kane (CFK) equation-based personalized iCO dosing algorithm to achieve a target carboxyhemoglobin (COHb) level of 6-8% in patients with sepsis-induced ARDS. We will also examine the biologic readouts of low dose iCO therapy in patients with sepsis-induced ARDS.

Conditions

Sepsis; Acute Respiratory Distress Syndrome

Outcome Measures

Primary Outcomes (2)

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

  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 myocardial infarction 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

• Accuracy of the Coburn-Forster-Kane (CFK) equation-based personalized iCO dosing algorithm to achieve a COHb level of 6-8%

  This will be assessed by comparing the measured 90-minute COHb level and the target COHb level of 6-8% daily on days 1-3.

  day 1, day 2, and day 3

Secondary Outcomes (11)

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

  7 days

• PaO2/FiO2 ratio on days 1-5 and 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 (4)

• Change in biomarkers of mitochondrial dysfunction

  5 days

• Change in biomarkers of inflammasome activation

  5 days

• Change in biomarkers of necroptosis

  5 days

Study Arms (2)

Inhaled Carbon Monoxide

EXPERIMENTAL

Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%) for up to 90 minutes daily for 3 days.

Drug: Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%)

Medical air

PLACEBO COMPARATOR

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

Other: Inhaled Medical air

Interventions

Inhaled Medical air OTHER

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

Medical air

Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%) DRUG

Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%) for up to 90 minutes daily for 3 days.

Also known as: iCO

Inhaled Carbon Monoxide

Eligibility Criteria

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

You may qualify if:

• Patients with sepsis are defined as those with life-threatening organ dysfunction caused by a dysregulated host response to infection:
• Suspected or proven infection: Sites of infection include thorax, urinary tract, abdomen, skin, sinuses, central venous catheters, and central nervous system
• Increase in Sequential Organ Failure Assessment (SOFA) Score ≥ 2 over baseline
• 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 is present
• Pneumonia (without ARDS or sepsis) will be defined as a unilateral or bilateral lung infiltrate on chest X-ray or chest CT (not fully explained by effusions, lobar/lung collapse or nodules) in the setting of receiving mechanical ventilation, a new suspected respiratory infection, an increase in SOFA score less than 2 at the time of randomization (baseline).
• Pneumonia (with sepsis, without ARDS) will be defined as a unilateral or bilateral lung infiltrate on chest X-ray or chest CT (not fully explained by effusions, lobar/lung collapse or nodules) in the setting of receiving mechanical ventilation and a new suspected respiratory infection with an increase in SOFA score of ≥ 2 over baseline at the time of randomization. Pneumonia with bilateral opacities, PaO2/FiO2 ratio ≤ 300, or an increase in SOFA score greater than or equal to 2 over baseline will continue to be considered ARDS and sepsis.

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 line 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
• Duke University: collaborator
• Weill Medical College of Cornell University: collaborator
• Massachusetts General Hospital: collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Washington University School of Medicine: collaborator

Study Sites (6)

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, 63110, 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 University Hospital

Durham, North Carolina, 27710, United States

Location

Related Publications (12)

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• Bathoorn E, Slebos DJ, Postma DS, Koeter GH, van Oosterhout AJ, van der Toorn M, Boezen HM, Kerstjens HA. Anti-inflammatory effects of inhaled carbon monoxide in patients with COPD: a pilot study. Eur Respir J. 2007 Dec;30(6):1131-7. doi: 10.1183/09031936.00163206. Epub 2007 Aug 22.

  PMID: 17715164 BACKGROUND

MeSH Terms

Conditions

Respiratory Distress Syndrome; Sepsis

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Rebecca M Baron, MD

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Masking Details: The study drug assignment will be blinded to the subject, clinical team, study coordinators, and other study staff with the exception of the administering study staff (respiratory therapist and physician or physician alone), who will be unblinded to the treatment assignment to ensure subject safety.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: 2:1 randomization to iCO versus placebo medical air

Study Record Dates

• First Submitted: April 26, 2021
• First Posted: May 3, 2021
• Study Start: December 6, 2023
• Primary Completion: October 25, 2024
• Study Completion: March 31, 2026
• Last Updated: January 12, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: According to NHLBI guidelines
• Access Criteria: According to NHLBI guidelines

Locations

US (6)