<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03799874</url>
  </required_header>
  <id_info>
    <org_study_id>2018P002051</org_study_id>
    <secondary_id>CDMRP-PR171025, W81XWH1810667</secondary_id>
    <nct_id>NCT03799874</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy Study of Inhaled Carbon Monoxide to Treat Acute Respiratory Distress Syndrome (ARDS)</brief_title>
  <official_title>A Phase II Trial of Inhaled Carbon Monoxide for the Treatment of Acute Respiratory Distress Syndrome (ARDS)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Brigham and Women's Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Weill Medical College of Cornell University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Duke University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Durham VA Medical Center</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
    <collaborator>
      <agency>New York Presbyterian Brooklyn Methodist Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Duke Regional Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>U.S. Army Medical Research Acquisition Activity</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
    <collaborator>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Brigham and Women's Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will be a multi-center, prospective, randomized, partially double-blind,&#xD;
      placebo-controlled Phase II clinical trial of inhaled CO (iCO) for the treatment of ARDS. The&#xD;
      trial will be conducted at 7 tertiary care medical centers including Weill Cornell&#xD;
      Medicine/NewYork-Presbyterian Hospital, Brigham and Women's Hospital (BWH), Massachusetts&#xD;
      General Hospital (MGH), Duke University Hospital, Durham Veterans Administration Medical&#xD;
      Center, New York-Presbyterian Brooklyn Methodist Hospital, and Duke Regional Hospital. The&#xD;
      purpose of this study is to evaluate the safety, tolerability, and efficacy of inhaled carbon&#xD;
      monoxide (iCO) for the treatment of ARDS and to examine the biologic readouts of low dose iCO&#xD;
      therapy in patients with ARDS&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Acute respiratory distress syndrome (ARDS) is a devastating disease affecting military,&#xD;
      veteran, and civilian populations. ARDS is a syndrome of severe acute lung inflammation and&#xD;
      hypoxemic respiratory failure with an incidence of 180,000 cases annually in the United&#xD;
      States. Despite recent advances in critical care management and lung protective ventilation&#xD;
      strategies, ARDS morbidity and mortality remain unacceptably high. The lack of specific&#xD;
      effective therapies for ARDS indicates a need for new treatments that target novel pathways.&#xD;
      Carbon monoxide (CO) represents a novel therapeutic modality in ARDS based on data obtained&#xD;
      in experimental models of ARDS over the past decade.&#xD;
&#xD;
      CO has been shown to be protective in experimental models of acute lung injury (ALI) and&#xD;
      sepsis. Furthermore, multiple human studies have demonstrated that experimental&#xD;
      administration of several different concentrations of CO is well tolerated and that low dose&#xD;
      inhaled CO can be safely administered to subjects in a controlled research environment. The&#xD;
      investigators have previously conducted a Phase I trial of low dose iCO in ARDS which&#xD;
      demonstrated that precise administration of low dose iCO (100 and 200 ppm) is feasible,&#xD;
      well-tolerated, and safe in patients with sepsis-induced ARDS.&#xD;
&#xD;
      The purpose of this study is to assess the safety and efficacy of low dose inhaled carbon&#xD;
      monoxide (iCO) therapy in mechanically ventilated patients with ARDS.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 1, 2019</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
    <masking_description>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.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Primary Safety Outcome: Number of pre-specified administration-related adverse events.</measure>
    <time_frame>7 days</time_frame>
    <description>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.&#xD;
Acute MI within 48 hours of study drug administration&#xD;
Acute cerebrovascular accident (CVA) within 48 hours of study drug administration&#xD;
New onset atrial or ventricular arrhythmia requiring DC cardioversion within 48 hours of study drug administration&#xD;
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&#xD;
Increase in COHb ≥ 10%&#xD;
Increase in lactate by ≥ 2 mmol/L within 6 hours of study drug administration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Primary Efficacy Outcome: Change in Mitochondrial DNA (mtDNA) level from day 1 to day 5</measure>
    <time_frame>5 days</time_frame>
    <description>Mitochondrial DNA (mtDNA) plasma levels will be measured by quantitative PCR of human NADH dehydrogenase 1.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Lung injury score (LIS) on days 1-5, and on day 7</measure>
    <time_frame>7 days</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PaO2/FiO2 ratio on days 1-5, and on day 7</measure>
    <time_frame>7 days</time_frame>
    <description>PaO2/FiO2 will be measured daily on days 1-5 and on day 7 in ventilated subjects.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oxygenation Index (OI) on days 1-5, and day 7</measure>
    <time_frame>7 days</time_frame>
    <description>The oxygenation index will be measured daily on days 1-5 and on day 7 in ventilated subjects. Oxygenation index is calculated as (FiO2 X mean airway pressure)/PaO2.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dead Space Fraction (Vd/Vt) on days 1-3, and day 7</measure>
    <time_frame>7 days</time_frame>
    <description>The dead space fraction will be measured daily on days 1-3 and on day 7 in ventilated subjects.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sequential Organ Failure Assessment (SOFA) score on days 1-5, 7, 14, 28</measure>
    <time_frame>28 days</time_frame>
    <description>Organ failure will be assessed using the SOFA score. SOFA scores will be assessed daily on days 1-5, and thereafter on days 7, 14, and 28, 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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in biomarkers of autophagy</measure>
    <time_frame>5 days</time_frame>
    <description>Autophagy markers (eg. LC3B) will be measured in plasma daily on days 1-3 and on day 5.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in biomarkers of inflammation and inflammasome activation</measure>
    <time_frame>5 days</time_frame>
    <description>Cytokine plasma levels (eg. IL-18) will be measured by ELISA daily on days 1-3 and on day 5.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in lipid mediators</measure>
    <time_frame>5 days</time_frame>
    <description>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 5.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in biomarkers of mitochondrial quality control</measure>
    <time_frame>5 days</time_frame>
    <description>Mitochondrial quality control biomarkers (eg. Pink1, Wipi1) will be measured in peripheral blood mononuclear cells (PBMCs) daily on days 1-3 and on day 5.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Ventilator-free days at day 28</measure>
    <time_frame>28 days</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>ICU-free days at day 28</measure>
    <time_frame>28 days</time_frame>
    <description>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).</description>
  </other_outcome>
  <other_outcome>
    <measure>Hospital-free days at day 60</measure>
    <time_frame>60 days</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Hospital mortality to day 28 and 60</measure>
    <time_frame>60 days</time_frame>
    <description>Mortality will be assessed on day 28 and day 60</description>
  </other_outcome>
  <other_outcome>
    <measure>Montreal Cognitive Assessment- MoCA-Blind</measure>
    <time_frame>6 months</time_frame>
    <description>The MoCA-Blind will be administered at 6 months via telephone interview to assess 4 items examining attention, verbal learning and memory, executive functions/language, and orientation. The test is scored out of 22 with 18 and above considered normal.</description>
  </other_outcome>
  <other_outcome>
    <measure>Hayling Sentence Completion Test</measure>
    <time_frame>6 months</time_frame>
    <description>The Hayling Sentence Completion Test will be administered at 6 months via telephone interview. The Hayling Sentence Completion Test is a neuropsychological test consisting of two types of sentence completion. The first section is scored based on time taken to complete the sentence. The second section is scored based on time taken to complete a sentence as well as the quality of answer. These scores are combined and scaled according to age.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">32</enrollment>
  <condition>Acute Respiratory Distress Syndrome</condition>
  <arm_group>
    <arm_group_label>Inhaled Carbon Monoxide</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Inhaled Carbon Monoxide at 200 ppm for up to 90 minutes daily for 3 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Medical air</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Inhaled Medical Air for up to 90 minutes daily for 3 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Inhaled Carbon Monoxide at 200 ppm</intervention_name>
    <description>Inhaled Carbon Monoxide at 200 ppm for 90 minutes daily for 3 days.</description>
    <arm_group_label>Inhaled Carbon Monoxide</arm_group_label>
    <other_name>iCO</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Inhaled Medical air</intervention_name>
    <description>Inhaled Medical Air for up to 90 minutes daily for 3 days.</description>
    <arm_group_label>Medical air</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        All intubated patients ≥ 18 years old with ARDS&#xD;
&#xD;
          1. ARDS is defined when all four of the following criteria are met:&#xD;
&#xD;
               1. A PaO2/FiO2 ratio ≤ 300 with at least 5 cm H2O positive end-expiratory airway&#xD;
                  pressure (PEEP)&#xD;
&#xD;
               2. Bilateral opacities on frontal chest radiograph (not fully explained by&#xD;
                  effusions, lobar/lung collapse, or nodules) within 1 week of a known clinical&#xD;
                  insult or new or worsening respiratory symptoms&#xD;
&#xD;
               3. A need for positive pressure ventilation by an endotracheal or tracheal tube&#xD;
&#xD;
               4. Respiratory failure not fully explained by cardiac failure or fluid overload;&#xD;
                  need objective assessment (e.g., echocardiography) to exclude hydrostatic edema&#xD;
                  if no risk factor present.&#xD;
&#xD;
          2. ARDS onset is defined as the time the last of criteria 1-4 are met. ARDS must persist&#xD;
             through the enrollment time window of 168 hours.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        An individual who meets any of the following criteria will be excluded from participation&#xD;
        in this study:&#xD;
&#xD;
          1. Age less than 18 years&#xD;
&#xD;
          2. Greater than 168 hours since ARDS onset&#xD;
&#xD;
          3. Pregnant or breastfeeding&#xD;
&#xD;
          4. Prisoner&#xD;
&#xD;
          5. Patient, surrogate, or physician not committed to full support (exception: a patient&#xD;
             will not be excluded if he/she would receive all supportive care except for attempts&#xD;
             at resuscitation from cardiac arrest)&#xD;
&#xD;
          6. No consent/inability to obtain consent or appropriate legal representative not&#xD;
             available&#xD;
&#xD;
          7. Physician refusal to allow enrollment in the trial&#xD;
&#xD;
          8. Moribund patient not expected to survive 24 hours&#xD;
&#xD;
          9. No arterial or central line/no intent to place an arterial or central line&#xD;
&#xD;
         10. No intent/unwillingness to follow lung protective ventilation strategy&#xD;
&#xD;
         11. Severe hypoxemia defined as SpO2 &lt; 95 or PaO2 &lt; 90 on FiO2 ≥ 0.9&#xD;
&#xD;
         12. Hemoglobin &lt; 7.0 g/dL&#xD;
&#xD;
         13. Subjects who are Jehovah's Witnesses or are otherwise unable or unwilling to receive&#xD;
             blood transfusions during hospitalization&#xD;
&#xD;
         14. Acute myocardial infarction (MI) or acute coronary syndrome (ACS) within the last 90&#xD;
             days&#xD;
&#xD;
         15. Coronary artery bypass graft (CABG) surgery within 30 days&#xD;
&#xD;
         16. Angina pectoris or use of nitrates with activities of daily living&#xD;
&#xD;
         17. Cardiopulmonary disease classified as NYHA class IV&#xD;
&#xD;
         18. Stroke (ischemic or hemorrhagic) within the prior 1 month, cardiac arrest requiring&#xD;
             CPR within the prior 72 hours, or inability to assess mental status following cardiac&#xD;
             arrest&#xD;
&#xD;
         19. Burns &gt; 40% total body surface area (TBSA)&#xD;
&#xD;
         20. Severe airway inhalational injury&#xD;
&#xD;
         21. Use of high frequency oscillatory ventilation&#xD;
&#xD;
         22. Use of extracorporeal membrane oxygenation (ECMO)&#xD;
&#xD;
         23. Concomitant use of inhaled pulmonary vasodilator therapy (eg. nitric oxide [NO] or&#xD;
             prostaglandins)&#xD;
&#xD;
         24. Diffuse alveolar hemorrhage from vasculitis&#xD;
&#xD;
         25. Concurrent participation in other investigational drug study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Rebecca Baron, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Brigham and Women's Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Brigham and Women's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63130</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>New York-Presbyterian Brooklyn Methodist Hospital</name>
      <address>
        <city>Brooklyn</city>
        <state>New York</state>
        <zip>11215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Weill Cornell Medical College</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke Regional Hospital</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27704</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke University Hospital</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>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.</citation>
    <PMID>24391478</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>12133657</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>25770182</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>19465554</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>26320156</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>9149675</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>15557136</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>1194155</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>5430001</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>11704374</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>11247913</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>26186946</PMID>
  </reference>
  <reference>
    <citation>Fredenburgh LE, Perrella MA, Barragan-Bradford D, Hess DR, Peters E, Welty-Wolf KE, Kraft BD, Harris RS, Maurer R, Nakahira K, Oromendia C, Davies JD, Higuera A, Schiffer KT, Englert JA, Dieffenbach PB, Berlin DA, Lagambina S, Bouthot M, Sullivan AI, Nuccio PF, Kone MT, Malik MJ, Porras MAP, Finkelsztein E, Winkler T, Hurwitz S, Serhan CN, Piantadosi CA, Baron RM, Thompson BT, Choi AM. A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS. JCI Insight. 2018 Dec 6;3(23):e124039. doi: 10.1172/jci.insight.124039.</citation>
    <PMID>30518685</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>29100885</PMID>
  </reference>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>December 6, 2018</study_first_submitted>
  <study_first_submitted_qc>January 9, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 10, 2019</study_first_posted>
  <last_update_submitted>August 22, 2022</last_update_submitted>
  <last_update_submitted_qc>August 22, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 23, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Brigham and Women's Hospital</investigator_affiliation>
    <investigator_full_name>Rebecca Baron</investigator_full_name>
    <investigator_title>Associate Professor of Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Respiratory Distress Syndrome</mesh_term>
    <mesh_term>Respiratory Distress Syndrome, Newborn</mesh_term>
    <mesh_term>Acute Lung Injury</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carbon Monoxide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03799874
org study id: 2018P002051
secondary id: CDMRP-PR171025, W81XWH1810667
nct id: NCT03799874
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Care Provider)
masking description: 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.
measure: Primary Safety Outcome: Number of pre-specified administration-related adverse events.
time frame: 7 days
description: 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 MI 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
measure: Primary Efficacy Outcome: Change in Mitochondrial DNA (mtDNA) level from day 1 to day 5
time frame: 5 days
description: Mitochondrial DNA (mtDNA) plasma levels will be measured by quantitative PCR of human NADH dehydrogenase 1.
measure: Lung injury score (LIS) on days 1-5, and on day 7
time frame: 7 days
description: 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).
measure: PaO2/FiO2 ratio on days 1-5, and on day 7
time frame: 7 days
description: PaO2/FiO2 will be measured daily on days 1-5 and on day 7 in ventilated subjects.
measure: Oxygenation Index (OI) on days 1-5, and day 7
time frame: 7 days
description: The oxygenation index will be measured daily on days 1-5 and on day 7 in ventilated subjects. Oxygenation index is calculated as (FiO2 X mean airway pressure)/PaO2.
measure: Dead Space Fraction (Vd/Vt) on days 1-3, and day 7
time frame: 7 days
description: The dead space fraction will be measured daily on days 1-3 and on day 7 in ventilated subjects.
measure: Sequential Organ Failure Assessment (SOFA) score on days 1-5, 7, 14, 28
time frame: 28 days
description: Organ failure will be assessed using the SOFA score. SOFA scores will be assessed daily on days 1-5, and thereafter on days 7, 14, and 28, 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.
measure: Change in biomarkers of autophagy
time frame: 5 days
description: Autophagy markers (eg. LC3B) will be measured in plasma daily on days 1-3 and on day 5.
measure: Change in biomarkers of inflammation and inflammasome activation
time frame: 5 days
description: Cytokine plasma levels (eg. IL-18) will be measured by ELISA daily on days 1-3 and on day 5.
measure: Change in lipid mediators
time frame: 5 days
description: 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 5.
measure: Change in biomarkers of mitochondrial quality control
time frame: 5 days
description: Mitochondrial quality control biomarkers (eg. Pink1, Wipi1) will be measured in peripheral blood mononuclear cells (PBMCs) daily on days 1-3 and on day 5.
measure: Ventilator-free days at day 28
time frame: 28 days
description: 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.
measure: ICU-free days at day 28
time frame: 28 days
description: 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).
measure: Hospital-free days at day 60
time frame: 60 days
description: 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.
measure: Hospital mortality to day 28 and 60
time frame: 60 days
description: Mortality will be assessed on day 28 and day 60
measure: Montreal Cognitive Assessment- MoCA-Blind
time frame: 6 months
description: The MoCA-Blind will be administered at 6 months via telephone interview to assess 4 items examining attention, verbal learning and memory, executive functions/language, and orientation. The test is scored out of 22 with 18 and above considered normal.
measure: Hayling Sentence Completion Test
time frame: 6 months
description: The Hayling Sentence Completion Test will be administered at 6 months via telephone interview. The Hayling Sentence Completion Test is a neuropsychological test consisting of two types of sentence completion. The first section is scored based on time taken to complete the sentence. The second section is scored based on time taken to complete a sentence as well as the quality of answer. These scores are combined and scaled according to age.
arm group label: Inhaled Carbon Monoxide
arm group type: Experimental
description: Inhaled Carbon Monoxide at 200 ppm for up to 90 minutes daily for 3 days.
arm group label: Medical air
arm group type: Placebo Comparator
description: Inhaled Medical Air for up to 90 minutes daily for 3 days.
intervention type: Drug
intervention name: Inhaled Carbon Monoxide at 200 ppm
description: Inhaled Carbon Monoxide at 200 ppm for 90 minutes daily for 3 days.
arm group label: Inhaled Carbon Monoxide
other name: iCO
intervention type: Other
intervention name: Inhaled Medical air
description: Inhaled Medical Air for up to 90 minutes daily for 3 days.
arm group label: Medical air
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Rebecca Baron, MD
role: Principal Investigator
affiliation: Brigham and Women's Hospital
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
citation: Nakahira K, Kyung SY, Rogers AJ, Gazourian L, Youn S, Massaro AF, Quintana C, Osorio JC, Wang Z, Zhao Y, Lawler LA, Christie JD, Meyer NJ, Mc Causland FR, Waikar SS, Waxman AB, Chung RT, Bueno R, Rosas IO, Fredenburgh LE, Baron RM, Christiani DC, Hunninghake GM, Choi AM. Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation. PLoS Med. 2013 Dec;10(12):e1001577; discussion e1001577. doi: 10.1371/journal.pmed.1001577. Epub 2013 Dec 31.
PMID: 24391478
citation: Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet. 2002 Jul 20;360(9328):219-23. doi: 10.1016/S0140-6736(02)09459-X.
PMID: 12133657
citation: Jung SS, Moon JS, Xu JF, Ifedigbo E, Ryter SW, Choi AM, Nakahira K. Carbon monoxide negatively regulates NLRP3 inflammasome activation in macrophages. Am J Physiol Lung Cell Mol Physiol. 2015 May 15;308(10):L1058-67. doi: 10.1152/ajplung.00400.2014. Epub 2015 Mar 13.
PMID: 25770182
citation: 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
citation: 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
citation: 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
citation: 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
citation: 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
citation: 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
citation: 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
citation: 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
citation: 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
citation: Fredenburgh LE, Perrella MA, Barragan-Bradford D, Hess DR, Peters E, Welty-Wolf KE, Kraft BD, Harris RS, Maurer R, Nakahira K, Oromendia C, Davies JD, Higuera A, Schiffer KT, Englert JA, Dieffenbach PB, Berlin DA, Lagambina S, Bouthot M, Sullivan AI, Nuccio PF, Kone MT, Malik MJ, Porras MAP, Finkelsztein E, Winkler T, Hurwitz S, Serhan CN, Piantadosi CA, Baron RM, Thompson BT, Choi AM. A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS. JCI Insight. 2018 Dec 6;3(23):e124039. doi: 10.1172/jci.insight.124039.
PMID: 30518685
citation: 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
responsible party type: Principal Investigator
investigator affiliation: Brigham and Women's Hospital
investigator full name: Rebecca Baron
investigator title: Associate Professor of Medicine
mesh term: Respiratory Distress Syndrome
mesh term: Respiratory Distress Syndrome, Newborn
mesh term: Acute Lung Injury
mesh term: Syndrome
mesh term: Carbon Monoxide
sharing ipd: No