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| ID | Type | Description | Link |
|---|---|---|---|
| CDMRP-PR171025, W81XWH1810667 | Other Grant/Funding Number | United States Army Medical Research Acquisition Activity |
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| Name | Class |
|---|---|
| Massachusetts General Hospital | OTHER |
| Weill Medical College of Cornell University | OTHER |
| Duke University | OTHER |
| Durham VA Medical Center |
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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
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Inhaled Carbon Monoxide | Experimental | Inhaled Carbon Monoxide at 200 ppm for up to 90 minutes daily for 3 days. |
|
| Medical air | Placebo Comparator | Inhaled Medical Air for up to 90 minutes daily for 3 days. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Inhaled Carbon Monoxide at 200 ppm | Drug | Inhaled Carbon Monoxide at 200 ppm for 90 minutes daily for 3 days. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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.
| 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. The number presented is the percentage average difference from beginning to end of treatment. Limited number of measurements prevents variance 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. | 5 days |
| Measure | Description | Time Frame |
|---|---|---|
| Lung Injury Score (LIS) on Days 1-5, and on Days 1-7 | 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. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the average of data from the available subjects in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the average of data from the available subjects in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. |
Inclusion Criteria:
All intubated patients ≥ 18 years old with ARDS
ARDS is defined when all four of the following criteria are met:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Rebecca Baron, MD | Brigham and Women's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Massachusetts General Hospital | Boston | Massachusetts | 02114 | United States | ||
| Brigham and Women's Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24391478 | Background | 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. | |
| 12133657 |
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After consent. Subjects were randomized to either placebo or inhaled CO. Study procedures started the following day after randomization. The study recruited a total of 4 subjects and was closed due to low enrollment.
First recruited subject date was 9/30/2019 and last recruited subject was 4/5/2021. The study treatment was 3 days and follow up during 60 days during hospitalization and up to 6 months follow up. Screening was conducted in Intensive Care Units and qualifying subjects were consented by study physicians at Brigham and Women's Hospital, Duke University Hospital and New York Presbyterian Brooklyn Methodist Hospital.
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| ID | Title | Description |
|---|---|---|
| FG000 | Inhaled Carbon Monoxide | Inhaled Carbon Monoxide at 200 ppm for up to 90 minutes daily for 3 days. |
| FG001 | Medical Air | Inhaled Medical Air for up to 90 minutes daily for 3 days. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 27, 2022 |
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| FED |
| New York Presbyterian Brooklyn Methodist Hospital | OTHER |
| Duke Regional Hospital | OTHER |
| U.S. Army Medical Research Acquisition Activity | FED |
| Washington University School of Medicine | OTHER |
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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.
| Inhaled Medical air | Other | Inhaled Medical Air for up to 90 minutes daily for 3 days. |
|
| 7 days |
| Percent Change in PaO2/FiO2 Ratio on Days 1-5, and on Days 1-7 | PaO2/FiO2 will be measured daily on days 1-5 and days 1-7 in ventilated subjects. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the average of data from the available subjects in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. | 7 days |
| Percent Change in Oxygenation Index (OI) on Days 1-5, and Days 1-7 | The oxygenation index will be measured on days 1-5 and on days 1-7 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. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the average of data from the available subjects in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. | 7 days |
| Percent Change in Dead Space Fraction (Vd/Vt) on Days 1-3, and Days 1-7 | The dead space fraction will be measured days 1-3 and days 1-7 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). The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the average of data from the available subjects in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. | 7 days |
| Percent Change in Sequential Organ Failure Assessment (SOFA) Score on Days 1-5, and Days 1-7. | Organ failure will be assessed using the SOFA score. SOFA scores will be assessed daily on days 1-5 and day 7, 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 5 and 7 for the enrolled subjects). The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the average of data from the available subjects in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. | 1-5 and 1-7 days |
| Absolute Value of Biomarkers of Inflammation and Inflammasome Activation | Cytokine plasma levels (eg. IL-1B) will be measured by ELISA daily on days 1-3 and on day 4. We report the absolute Mean Fluorescent Intensity (MFI) of each sample at pretreatment time point of day 4. 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 "Number" without standard deviation, since measures of dispersion cannot be calculated. | 4 days |
| Percent Change in Lipid Mediators | Lipid mediators (LM) and specialized pro-resolving mediators (SPMs) will be measured in plasma using liquid chromatography-tandem mass spectrometry (LC-MS-MS) based methods daily on days 1-3 and on day 4. The percentage change from baseline at day 1 to post treatment at day 4 is reported. A representative LM is shown (14-HDHA (14-hydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid) is an oxidized metabolite of omega-3 docosahexaenoic acid (DHA)). 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 "Number" without standard deviation, since measures of dispersion cannot be calculated. | 4 days |
| 28 days |
| ICU-free Days at Day 28 | ICU-free days are the number of days that the patient is alive and free from ICU care within 28 days. Is calculated by subtracting the total number of days that the patient is free from the ICU from 28. Patients who die within 28 days are automatically assigned "0" ICU free days. We present data of ICU free days for enrolled subjects. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the average of data from the available subjects in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. | 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. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the average of data from the available subjects in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. | 60 days |
| Hospital Mortality to Day 28 and 60 | Mortality will be assessed on day 28 and day 60 | 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. 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 "Number", since given measures of dispersion cannot be calculated. | 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: 1: Impaired 2: Abnormal 3: Poor 4: Low Average 5: Moderate Average 6: Average 7: High Average 8: Good 9: Superior 10: Very Superior Higher scores= Better executive functioning Lower scores= Greater impairment. 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 "Number", since given measures of dispersion cannot be calculated. | 6 months |
| Boston |
| Massachusetts |
| 02115 |
| United States |
| Washington University | St Louis | Missouri | 63130 | United States |
| New York-Presbyterian Brooklyn Methodist Hospital | Brooklyn | New York | 11215 | United States |
| Weill Cornell Medical College | New York | New York | 10065 | United States |
| Duke Regional Hospital | Durham | North Carolina | 27704 | United States |
| Duke University Hospital | Durham | North Carolina | 27710 | United States |
| 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. |
| 25770182 | 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. |
| 19465554 | 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. |
| 26320156 | 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. |
| 9149675 | 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. |
| 15557136 | 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. |
| 1194155 | 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. |
| 5430001 | 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. |
| 11704374 | 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. |
| 11247913 | 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. |
| 26186946 | 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. |
| 30518685 | 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. |
| 29100885 | 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. |
| COMPLETED |
|
| NOT COMPLETED |
|
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Inhaled Carbon Monoxide | Inhaled Carbon Monoxide at 200 ppm for up to 90 minutes daily for 3 days. |
| BG001 | Medical Air | Inhaled Medical Air for up to 90 minutes daily for 3 days. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Baseline Critical Illness: Acute Respiratory Distress Syndrome (ARDS) | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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.
| All subjects were analyzed for safety measures. | Posted | Count of Participants | Participants | 7 days |
|
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| Primary | 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. The number presented is the percentage average difference from beginning to end of treatment. Limited number of measurements prevents variance 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. | Percentage reduction pre-day 1 Vs. post-day 5 exposure for those subjects with 5 exposures. | Posted | Mean | Standard Deviation | Percent change in Mitochondrial DNA | 5 days |
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| Secondary | Lung Injury Score (LIS) on Days 1-5, and on Days 1-7 | 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. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the average of data from the available subjects in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. | Lung injury score (LIS) on days 1-5, and on days 1-7 | Posted | Mean | Standard Deviation | Percent change in Lung Injury Score | 7 days |
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| Secondary | Percent Change in PaO2/FiO2 Ratio on Days 1-5, and on Days 1-7 | PaO2/FiO2 will be measured daily on days 1-5 and days 1-7 in ventilated subjects. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the average of data from the available subjects in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. | Percent change in PaO2/FiO2 ratio on days 1-5, and on days 1-7. | Posted | Mean | Standard Deviation | Percent change in PaO2/FiO2 ratio | 7 days |
|
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| Secondary | Percent Change in Oxygenation Index (OI) on Days 1-5, and Days 1-7 | The oxygenation index will be measured on days 1-5 and on days 1-7 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. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the average of data from the available subjects in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. | Oxygenation Index (OI) on days 1-5, and days 1-7 | Posted | Mean | Standard Deviation | Percent change in O2 index from baseline | 7 days |
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| Secondary | Percent Change in Dead Space Fraction (Vd/Vt) on Days 1-3, and Days 1-7 | The dead space fraction will be measured days 1-3 and days 1-7 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). The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the average of data from the available subjects in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. | Percent change in Dead Space Fraction (Vd/Vt) on days 1-3, and days 1-7 | Posted | Mean | Standard Deviation | Percent change in Dead Space | 7 days |
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| Secondary | Percent Change in Sequential Organ Failure Assessment (SOFA) Score on Days 1-5, and Days 1-7. | Organ failure will be assessed using the SOFA score. SOFA scores will be assessed daily on days 1-5 and day 7, 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 5 and 7 for the enrolled subjects). The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the average of data from the available subjects in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. | We present changes in SOFA score over the time of hospitalization, over the time of ICU admission (up to days 5 and 7 for the enrolled subjects). Limited number of measurements prevents variance and measures of dispersion analyses when the number of subjects is not sufficient. | Posted | Mean | Standard Deviation | Percent change in SOFA score | 1-5 and 1-7 days |
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| Secondary | Absolute Value of Biomarkers of Inflammation and Inflammasome Activation | Cytokine plasma levels (eg. IL-1B) will be measured by ELISA daily on days 1-3 and on day 4. We report the absolute Mean Fluorescent Intensity (MFI) of each sample at pretreatment time point of day 4. 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 "Number" without standard deviation, since measures of dispersion cannot be calculated. | Due to limited number of samples only one time point was measured in available samples (one placebo subject and one CO subject) at Day 4. | Posted | Number | Raw MFI units for IL-1B | 4 days |
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| Secondary | Percent Change in Lipid Mediators | Lipid mediators (LM) and specialized pro-resolving mediators (SPMs) will be measured in plasma using liquid chromatography-tandem mass spectrometry (LC-MS-MS) based methods daily on days 1-3 and on day 4. The percentage change from baseline at day 1 to post treatment at day 4 is reported. A representative LM is shown (14-HDHA (14-hydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid) is an oxidized metabolite of omega-3 docosahexaenoic acid (DHA)). 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 "Number" without standard deviation, since measures of dispersion cannot be calculated. | Due to limited number of samples only one time point was measured in available samples (one placebo subject and one CO subject) at Day 4. | Posted | Number | Percent change 14-HDHA | 4 days |
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| Other Pre-specified | 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. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the average of data from the available subjects in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. | Posted | Mean | Standard Deviation | Days | 28 days |
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| Other Pre-specified | ICU-free Days at Day 28 | ICU-free days are the number of days that the patient is alive and free from ICU care within 28 days. Is calculated by subtracting the total number of days that the patient is free from the ICU from 28. Patients who die within 28 days are automatically assigned "0" ICU free days. We present data of ICU free days for enrolled subjects. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the average of data from the available subjects in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. | Posted | Mean | Standard Deviation | Days | 28 days |
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| Other Pre-specified | 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. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the average of data from the available subjects in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. | Posted | Mean | Standard Deviation | Number of Hospital free Days at day 60 | 60 days |
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| Other Pre-specified | Hospital Mortality to Day 28 and 60 | Mortality will be assessed on day 28 and day 60 | Posted | Count of Participants | Participants | 60 days |
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| Other Pre-specified | 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. 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 "Number", since given measures of dispersion cannot be calculated. | Of the 4 subjects, only one subject completed the test at 6 months. Of the remaining 3 subjects, two died and one did not complete the test. | Posted | Number | scores on a scale | 6 months |
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| Other Pre-specified | 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: 1: Impaired 2: Abnormal 3: Poor 4: Low Average 5: Moderate Average 6: Average 7: High Average 8: Good 9: Superior 10: Very Superior Higher scores= Better executive functioning Lower scores= Greater impairment. 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 "Number", since given measures of dispersion cannot be calculated. | Of the 4 subjects, only one subject completed the test at 6 months. Of the remaining 3 subjects, two died and one did not complete the test. | Posted | Number | scores on a scale | 6 months |
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Adverse events were monitored from enrollment to day 7. All-Cause Mortality was assessed up to 60 days.
Daily follow-up of pre-specified clinical monitoring.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Inhaled Carbon Monoxide | Inhaled Carbon Monoxide at 200 ppm for up to 90 minutes daily for 3 days. | 2 | 3 | 3 | 3 | 0 | 3 |
| EG001 | Medical Air | Inhaled Medical Air for up to 90 minutes daily for 3 days. | 0 | 1 | 1 | 1 | 1 | 1 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Intracranial hemorrhage | Nervous system disorders | MedDRA 20 | Systematic Assessment | Acute cerebrovascular accident (CVA) within 48 hours of study drug administration |
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| Upper gastrointestinal hemorrhage | Gastrointestinal disorders | MedDRA 20 | Systematic Assessment | Acute upper gastrointestinal bleed secondary to gastric and duodenal ulcers |
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| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA 20 | Systematic Assessment | Extracorporeal Membrane Oxygenation (ECMO) was initiated by the clinical team on Study Day 5 for management of worsening hypoxemic and hypercarbic respiratory failure secondary to ARDS. |
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| Laryngeal edema | Respiratory, thoracic and mediastinal disorders | MedDRA 20 | Systematic Assessment | Laryngeal edema: respiratory failure, respiratory muscle weakness, volume overload, tracheomalacia, and upper airway edema. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Wound infection | Infections and infestations | MedDRA 20 | Systematic Assessment | The subject developed lesion on the thigh that became necrotic. |
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| Seizure | Nervous system disorders | MedDRA 20 | Systematic Assessment | The subject had an isolated seazure during a bronchoscopy |
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Due to low enrollment, a limited number of measurements prevents us from estimating measures of variance and dispersion.
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Rebecca Baron MD, Co-PI | Brigham and Women's Hospital | 6177326660 | rbaron@bwh.harvard.edu |
| Mar 24, 2026 |
| Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Apr 6, 2026 | May 19, 2026 | ICF_001.pdf |
Not provided
| ID | Term |
|---|---|
| D012128 | Respiratory Distress Syndrome |
| ID | Term |
|---|---|
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D012120 | Respiration Disorders |
Not provided
Not provided
| >=65 years |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| New arrhythmia requiring DC cardioversion within 48 hours of study drug administration |
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| Increased oxygenation: increased FiO2 ≥ 0.2 AND PEEP ≥ 5 cm H2O within 6 hrs of drug administration |
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| Increase in COHb ≥ 10% |
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| Increase in lactate by ≥ 2 mmol/L within 6 hours of study drug administration |
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Inhaled Medical Air for up to 90 minutes daily for 3 days. |
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