Acute Respiratory Distress SyndromePhase 1NCT04870125
Safety Study of Inhaled Carbon Monoxide to Treat Pneumonia and Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)
A Phase 1 study testing Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%) and Inhaled Medical air in people with Acute Respiratory Distress Syndrome and Sepsis, run by Brigham and Women's Hospital at 6 sites in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Respiratory Distress Syndrome, Sepsis
- What is being tested?
- Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%) and Inhaled Medical air
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 5 participants
- Where
- 6 sitesUnited States
- Study dates
- 6 Dec 2023to 25 Oct 2024
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- All patients (age 18 and older) will be eligible for inclusion if they meet all of the following consensus criteria for sepsis and ARDS3,4 or if they meet the criteria for pneumonia as described below.
- 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)
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- 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.
Who cannot join
- 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)
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- 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
- Coronary artery bypass graft (CABG) surgery within 30 days
- Angina pectoris or use of nitrates with activities of daily living
- Severe cardiopulmonary disease classified as New York Heart Association (NYHA) class IV
- 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
- Burns > 40% total body surface area
- Severe airway inhalational injury
- Use of high frequency oscillatory ventilation
- Use of extracorporeal membrane oxygenation (ECMO)
- Use of inhaled pulmonary vasodilator therapy (eg. nitric oxide [NO] or prostaglandins)
- Diffuse alveolar hemorrhage from vasculitis
- Concurrent participation in other investigational drug study
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
United States6 sites
Massachusetts General Hospital
Boston, Massachusetts, 02114
Brigham and Women's Hospital
Boston, Massachusetts, 02115
New York-Presbyterian Brooklyn Methodist Hospital
Brooklyn, New York, 11215
Duke University Hospital
Durham, North Carolina, 27710
Weill Cornell Medical College
New York, New York, 10065
Washington University
St Louis, Missouri, 63110
About this study
Official title: A Phase Ib Trial of Inhaled Carbon Monoxide for the Treatment of Pneumonia and Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)
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.
Read the detailed description
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. Furthermore, no specific effective pharmacologic therapies currently exist. Sepsis, life-threatening organ dysfunction caused by a dysregulated host response to infection, represents a major risk for the development of ARDS and multi-organ dysfunction syndrome (MODS). In recent years, the number of patients with severe sepsis has risen to 750,000 per year in the U.S., which bears an alarming forecast for critically ill patients in the intensive care unit with significant risk for the development of ARDS. 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 sepsis-induced ARDS based on data obtained in experimental models of sepsis and 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 sepsis-induced 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 accuracy of a CFK equation-based iCO personalized dosing algorithm of inhaled carbon monoxide (iCO) to achieve a target COHb level of 6-8% in mechanically ventilated patients with sepsis-induced ARDS.
- Conditions
- Acute Respiratory Distress Syndrome, Sepsis
- Being tested
- Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%), Inhaled Medical air
- Medical subject headings
- Respiratory Distress Syndrome, Sepsis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%)Drug
Also called iCO
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.
Inhaled Medical airOther
Inhaled Medical Air for up to 90 minutes daily for 3 days.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Other: Inhaled Medical air |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
- Acute myocardial infarction within 48 hours of study drug administration
- Acute cerebrovascular accident (CVA) within 48 hours of study drug administration
- New onset atrial or ventricular arrhythmia requiring DC cardioversion within 48 hours of study drug administration
- 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
- Increase in COHb ≥ 10%
- Increase in lactate by ≥ 2 mmol/L within 6 hours of study drug administration
Measured: 7 days
Percentage Change Measured Relative to Target COHb Level
This was assessed by comparing the measured 90-minute COHb level and the target COHb level of 6-8% post exposure. We present average data from the two available subjects in the CO group and report as "Mean" with standard deviation.
Measured: Post exposure 90 min day 1
Variance of Measured Relative to Target COHb Level
This was assessed by comparing the measured 90-minute COHb level and the target COHb level of 6-8% post exposure. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the data from one available subject in the CO group and report as "Mean" without standard deviation, since measures of dispersion cannot be calculated.
Measured: Post exposure 90 min day 2
Variance of Measured Relative to Target COHb Level
This was assessed by comparing the measured 90-minute COHb level and the target COHb level of 6-8% post exposure. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the data from one available subject in the CO group and report as "Mean" without standard deviation, since measures of dispersion cannot be calculated.
Measured: Post exposure 90 min day 3
Secondary outcomes (13)
Lung Injury Score (LIS) on Days 1-5 Days
The Lung Injury Score (LIS) is a composite 4-point scoring system including the PaO2/FiO2, PEEP, quasi-static respiratory compliance, and the extent of infiltrates on the chest X-ray. Each of the four components is categorized from 0 to 4, where a higher number is worse. The total Lung Injury Score is obtained by dividing the aggregate sum by the number of components used. Previous randomized clinical trials in ARDS have shown that a decreased LIS correlates with improvement in lung physiology as well as important clinical outcomes including mortality and ventilator-free days (VFDs). The number presented is the average difference from beginning to end of treatment. We present the average of data from the 2 available subjects in each group and report as "Mean" with standard deviation.
Measured: 5 days
Percent Change in PaO2/FiO2 Ratio Between Baseline and Day 5
PaO2/FiO2 was to be measured on days 1-5 in ventilated subjects. We are providing percent change in PaO2/FiO2 ratio from baseline to day 5. We present the average of data from the 2 available subjects in each group and report as "Mean" with standard deviation.
Measured: Baseline to day 5
Oxygenation Index (OI) on Days 1-5 Days
The oxygenation index will be measured on days 1-5 in ventilated subjects. Oxygenation index is calculated as (FiO2 X mean airway pressure)/PaO2. We provide change in Oi from baseline. Oi is only measured when subjects are ventilated, therefore not all timepoints are available. Limited number of measurements prevents variance and measures of dispersion analyses; therefore we present the data from the subjects available in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated.
Measured: 5 days
Dead Space Fraction (Vd/Vt) on Days 1-3
The dead space fraction will be measured days 1-3 in ventilated subjects. We present change in dead space fraction between initial and final measurements that were available (measurements only taken while the subjects were intubated). We present the data from the subjects available in each group and report as "Mean" with standard deviation.
Measured: Day 3
Sequential Organ Failure Assessment (SOFA) Score on Days 1-5.
Organ failure will be assessed using the SOFA score. SOFA scores will be assessed daily on days 1-5, as the SOFA score has been shown to be a reliable prognostic indicator of outcomes in critically ill patients. To calculate the Sequential Organ Failure Assessment (SOFA) score, each of the six components (Respiratory, Coagulation, Liver, Cardiovascular, Central Nervous System, Renal) is categorized from 0-4, where a higher number is worse. The SOFA score (0-24) will be calculated by summing all six components. We present changes in SOFA score over the time of hospitalization, over the time of ICU admission (up to days 3 and 5 for the enrolled subjects). We present the data from the subjects available in each group and report as "Mean" with standard deviation.
Measured: 1-5 days
Ventilator-free Days at Day 28
Ventilator-free days to day 28 are defined as the number of days from the time of initiating unassisted breathing to day 28 after randomization, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. If a subject returns to assisted breathing and subsequently achieves unassisted breathing to day 28, VFDs will be counted from the end of the last period of assisted breathing to day 28. Participants who do not survive to day 28 are assigned zero ventilator-free days. We present data of ventilator free days for enrolled subjects. Note that one subject in the medical air group died at day 9. We present the data from the subjects available in each group and report as "Mean" with standard deviation.
Measured: 28 days
ICU-free Days at Day 28
ICU-free days will be assessed on day 28. ICU-free days is defined as the number of days between randomization and day 28 in which the patient is in the ICU (for any part of a day). We present average number of ICU free days. Please note that one subject in the medical air group died at day 9. We present the data from the subjects available in each group and report as "Mean" with standard deviation.
Measured: 28 days
Hospital-free Days at Day 60
Hospital-free days will be assessed on day 60. Hospital-free days are days alive post hospital discharge through day 60. Patients who die on or prior to day 60 are assigned zero hospital-free days. We present hospital free days at day 60. Please note that one subject in the air group died at day 9. We present the data from the subjects available in each group and report as "Mean" with standard deviation.
Measured: 60 days
Hospital Mortality to Day 28 and 60
Mortality will be assessed on day 28 and day 60.
Measured: 60 days
Montreal Cognitive Assessment- MoCA-Blind
Montreal Cognitive Assessment - Blind Version (MoCA-Blind) The MoCA-Blind is a remote adaptation of the Montreal Cognitive Assessment (MoCA) used as a screening assessment for detecting cognitive impairment. It is administered via telephone interview.
The MoCA-Blind assesses the following cognitive domains (points):
- Attention (0-6)
- Language: (0-3 (Repetition (0-2) and fluency (0-1))
- Abstraction (0-2)
- Memory: Delayed recall (0-5)
- Orientation (0-6)
The minimum score is 0 and maximum score is 22 points. Calculated as the sum of all domains. Interpretation: Higher scores indicate better cognitive functioning. Lower scores indicate worse cognitive functioning (greater cognitive impairment). A score of 18 or above is within the normal range. A limited number of measurements prevents variance and dispersion analyses; therefore, we report available group data as "means" without standard deviation where dispersion cannot be calculated.
Measured: 3 months
Montreal Cognitive Assessment- MoCA-Blind
Montreal Cognitive Assessment - Blind Version (MoCA-Blind) The MoCA-Blind is a remote adaptation of the Montreal Cognitive Assessment (MoCA) used as a screening assessment for detecting cognitive impairment. It is administered via telephone interview.
The MoCA-Blind assesses the following cognitive domains (points):
- Attention (0-6)
- Language: (0-3 (Repetition (0-2) and fluency (0-1))
- Abstraction (0-2)
- Memory: Delayed recall (0-5)
- Orientation (0-6)
The minimum score is 0 and maximum score is 22 points. Calculated as the sum of all domains. Interpretation: Higher scores indicate better cognitive functioning. Lower scores indicate worse cognitive functioning (greater cognitive impairment). A score of 18 or above is within the normal range. A limited number of measurements prevents variance and dispersion analyses; therefore, we report available group data as "means" without standard deviation, since dispersion cannot be calculated.
Measured: 6 months
Hayling Sentence Completion Test
The Hayling Sentence Completion Test assesses executive functioning (response initiation and inhibition), administered via telephone. With 30 sentence-completion items split into 2 sections (15 each).
Sections:
- 1: Response initiation (time to provide a contextually appropriate word).
- 2: Response inhibition (time and error score for providing an unrelated word).
Scores (response time and errors) from both sections are combined and converted to an age-adjusted standardized total score.
Total combined standardized score ranges from 1-10:
- Impaired
- Abnormal
- Poor
- Low Average
- Moderate Average
- Average
- High Average
- Good
- Superior
- Very Superior
Higher scores= Better executive functioning Lower scores= Greater impairment. A limited number of measurements prevents variance and dispersion analyses; therefore, we report available group data as "means" without standard deviation where dispersion cannot be calculated.
Measured: 3 months
Hayling Sentence Completion Test
The Hayling Sentence Completion Test assesses executive functioning (response initiation and inhibition), administered via telephone. With 30 sentence-completion items split into 2 sections (15 each).
Sections:
- 1: Response initiation (time to provide a contextually appropriate word).
- 2: Response inhibition (time and error score for providing an unrelated word).
Scores (response time and errors) from both sections are combined and converted to an age-adjusted standardized total score.
Total combined standardized score ranges from 1-10:
- Impaired
- Abnormal
- Poor
- Low Average
- Moderate Average
- Average
- High Average
- Good
- Superior
- Very Superior
Higher scores= Better executive functioning Lower scores= Greater impairment. A limited number of measurements prevents variance and dispersion analyses; therefore, we report available group data as "means" without standard deviation, since dispersion cannot be calculated.
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 May 2021
- Study start6 Dec 2023
- Primary completion25 Oct 2024
- Study completion25 Oct 2024
Why it stopped: Due to low enrollment, the study was halted early.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Acute Respiratory Distress SyndromeStudies of the same condition, open and under way.
- More trials run by Brigham and Women's HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- 2:1 randomization to iCO versus placebo medical air
- Masking
- Double blind
- Who is masked
- Participant, Care provider
- Enrolment
- 5 participants (actual)
Sponsor and investigators
- Lead sponsor
- Brigham and Women's Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Weill Medical College of Cornell University, Massachusetts General Hospital, Duke University, National Heart, Lung, and Blood Institute (NHLBI), Washington University School of Medicine
- Responsible party
- Principal investigator, Rebecca Baron, Brigham and Women's Hospital
- Investigators
- Rebecca M Baron, MD, Principal investigator, Brigham and Women's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04870125
- Sponsor's protocol ID
- 2021P000745
- Other IDs
- 1R61HL153011-01
- Status last verified
- May 2026
- First submitted
- 26 Apr 2021
- Last updated
- 26 May 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: We will submit de-identified datasets and associated documentation from the clinical trial to the NHLBI data repository Biological Specimen and Data Repository Information Coordinating Center (BioLINCC).
Publications
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.
PubMed 30518685Fredenburgh 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.
PubMed 26320156Rosas 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.
PubMed 29100885Stewart 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.
PubMed 5430001Peterson 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.
PubMed 1194155Hausberg 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.
PubMed 9149675Zevin 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.
PubMed 11704374Ren 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.
PubMed 11247913Mayr 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.
PubMed 15557136Rhodes 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.
PubMed 19465554Pecorella 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.
PubMed 26186946Bathoorn 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.
PubMed 17715164
Study at a glance
From the registry record, last updated by the sponsor on 26 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase Ib Trial of Inhaled Carbon Monoxide for the Treatment of Pneumonia and Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)
- ClinicalTrials.gov ID
- NCT04870125
- Acronym / sponsor ID
- 2021P000745
- Conditions
- Acute Respiratory Distress Syndrome, Sepsis
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Due to low enrollment, the study was halted early.
- Enrolment
- 5 participants (actual)
- Lead sponsor
- Brigham and Women's HospitalUniversity, hospital or other
- Collaborators
- Weill Medical College of Cornell University, Massachusetts General Hospital, Duke University, National Heart, Lung, and Blood Institute (NHLBI), Washington University School of Medicine
- Study start
- 6 Dec 2023 (actual)
- Primary completion
- 25 Oct 2024 (actual)
- Study completion
- 25 Oct 2024 (actual)
- First posted
- 3 May 2021 (actual)
- Results
- Posted 26 May 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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. Furthermore, no specific effective pharmacologic therapies currently exist. Sepsis, life-threatening organ dysfunction caused by a dysregulated host response to infection, represents a major risk for the development of ARDS and multi-organ dysfunction syndrome (MODS). In recent years, the number of patients with severe sepsis has risen to 750,000 per year in the U.S., which bears an alarming forecast for critically ill patients in the intensive care unit with significant risk for the development of ARDS. 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 sepsis-induced ARDS based on data obtained in experimental models of sepsis and 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 sepsis-induced 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 accuracy of a CFK equation-based iCO personalized dosing algorithm of inhaled carbon monoxide (iCO) to achieve a target COHb level of 6-8% in mechanically ventilated patients with sepsis-induced ARDS.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, care provider)
- Number of arms
- 2
- Model description
- 2:1 randomization to iCO versus placebo medical air
| Arm | Type | Receives |
|---|---|---|
| Inhaled Carbon Monoxide | Experimental | Drug: Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%)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. |
| Medical air | Placebo comparator | Other: Inhaled Medical airInhaled Medical Air for up to 90 minutes daily for 3 days. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- All patients (age 18 and older) will be eligible for inclusion if they meet all of the following consensus criteria for sepsis and ARDS3,4 or if they meet the criteria for pneumonia as described below.
- Patients with sepsis are defined as those with life-threatening organ dysfunction caused by a dysregulated host response to infection:
- ARDS is defined when all four of the following criteria are met:
- 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.
Key exclusion criteria (26 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%)Also: iCOInhaled 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 |
| Inhaled Medical airInhaled Medical Air for up to 90 minutes daily for 3 days. | Other | Medical air |
Primary outcome
Primary Safety Outcome: Number of Pre-specified Administration-related Adverse Events (AEs).
Time frame: 7 days
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
Percentage Change Measured Relative to Target COHb Level
Time frame: Post exposure 90 min day 1
This was assessed by comparing the measured 90-minute COHb level and the target COHb level of 6-8% post exposure. We present average data from the two available subjects in the CO group and report as "Mean" with standard deviation.
Variance of Measured Relative to Target COHb Level
Time frame: Post exposure 90 min day 2
This was assessed by comparing the measured 90-minute COHb level and the target COHb level of 6-8% post exposure. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the data from one available subject in the CO group and report as "Mean" without standard deviation, since measures of dispersion cannot be calculated.
Variance of Measured Relative to Target COHb Level
Time frame: Post exposure 90 min day 3
This was assessed by comparing the measured 90-minute COHb level and the target COHb level of 6-8% post exposure. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the data from one available subject in the CO group and report as "Mean" without standard deviation, since measures of dispersion cannot be calculated.
13 secondary outcomes
Lung Injury Score (LIS) on Days 1-5 Days
Time frame: 5 days
Percent Change in PaO2/FiO2 Ratio Between Baseline and Day 5
Time frame: Baseline to day 5
Oxygenation Index (OI) on Days 1-5 Days
Time frame: 5 days
Dead Space Fraction (Vd/Vt) on Days 1-3
Time frame: Day 3
Sequential Organ Failure Assessment (SOFA) Score on Days 1-5.
Time frame: 1-5 days
Ventilator-free Days at Day 28
Time frame: 28 days
ICU-free Days at Day 28
Time frame: 28 days
Hospital-free Days at Day 60
Time frame: 60 days
Hospital Mortality to Day 28 and 60
Time frame: 60 days
Montreal Cognitive Assessment- MoCA-Blind
Time frame: 3 months
Montreal Cognitive Assessment- MoCA-Blind
Time frame: 6 months
Hayling Sentence Completion Test
Time frame: 3 months
Hayling Sentence Completion Test
Time frame: 6 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 May 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 30518685Fredenburgh 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.
- Background: PubMed 26320156Fredenburgh 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.
- Background: PubMed 29100885Rosas 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.
- Background: PubMed 5430001Stewart 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.
- Background: PubMed 1194155Peterson 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.
- Background: PubMed 9149675Hausberg 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.
- Background: PubMed 11704374Zevin 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.
- Background: PubMed 11247913Ren 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.
- Background: PubMed 15557136Mayr 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.
- Background: PubMed 19465554Rhodes 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.
- Background: PubMed 26186946Pecorella 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.
- Background: PubMed 17715164Bathoorn 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.
- Individual participant dataSharing planned: Yes. We will submit de-identified datasets and associated documentation from the clinical trial to the NHLBI data repository Biological Specimen and Data Repository Information Coordinating Center (BioLINCC).
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rebecca M Baron, MD principal investigator
Brigham and Women's Hospital
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%) and Inhaled Medical air in people with Acute Respiratory Distress Syndrome and Sepsis, run by Brigham and Women's Hospital at 6 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 26 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 May 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Primary Safety Outcome: Number of Pre-specified Administration-related Adverse Events (AEs). (time frame: 7 days). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04870125, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 May 2026.