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

Sponsor
Brigham and Women's Hospital (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT03799874
Collaborator
Massachusetts General Hospital (Other), Weill Medical College of Cornell University (Other), Duke University (Other), Durham VA Medical Center (U.S. Fed), New York Presbyterian Brooklyn Methodist Hospital (Other), Duke Regional Hospital (Other), U.S. Army Medical Research Acquisition Activity (U.S. Fed), Washington University School of Medicine (Other)
32
Enrollment
7
Locations
2
Arms
53
Anticipated Duration (Months)
4.6
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will be a multi-center, prospective, randomized, partially double-blind, placebo-controlled Phase II clinical trial of inhaled CO (iCO) for the treatment of ARDS. The trial will be conducted at 7 tertiary care medical centers including Weill Cornell Medicine/NewYork-Presbyterian Hospital, Brigham and Women's Hospital (BWH), Massachusetts General Hospital (MGH), Duke University Hospital, Durham Veterans Administration Medical Center, New York-Presbyterian Brooklyn Methodist Hospital, and Duke Regional Hospital. The purpose of this study is to evaluate the safety, tolerability, and efficacy of inhaled carbon monoxide (iCO) for the treatment of ARDS and to examine the biologic readouts of low dose iCO therapy in patients with ARDS

Condition or Disease Intervention/Treatment Phase
  • Drug: Inhaled Carbon Monoxide at 200 ppm
  • Other: Inhaled Medical air
 Phase 2

Detailed Description

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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
32 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
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.
Primary Purpose:
Treatment
Official Title:
A Phase II Trial of Inhaled Carbon Monoxide for the Treatment of Acute Respiratory Distress Syndrome (ARDS)
Actual Study Start Date :
Jul 1, 2019
Anticipated Primary Completion Date :
Dec 1, 2023
Anticipated Study Completion Date :
Dec 1, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Inhaled Carbon Monoxide

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

Drug: Inhaled Carbon Monoxide at 200 ppm
Inhaled Carbon Monoxide at 200 ppm for 90 minutes daily for 3 days.
Other Names:
  • iCO

    		•
    Placebo Comparator: Medical air

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

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

    Outcome Measures

    Primary Outcome Measures

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

    2. Primary Efficacy Outcome: Change in Mitochondrial DNA (mtDNA) level from day 1 to day 5 [5 days]

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

    Secondary Outcome Measures

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

    2. PaO2/FiO2 ratio on days 1-5, and on day 7 [7 days]

      PaO2/FiO2 will be measured daily on days 1-5 and on day 7 in ventilated subjects.

    3. Oxygenation Index (OI) on days 1-5, and day 7 [7 days]

      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.

    4. Dead Space Fraction (Vd/Vt) on days 1-3, and day 7 [7 days]

      The dead space fraction will be measured daily on days 1-3 and on day 7 in ventilated subjects.

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

      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.

    6. Change in biomarkers of autophagy [5 days]

      Autophagy markers (eg. LC3B) will be measured in plasma daily on days 1-3 and on day 5.

    7. Change in biomarkers of inflammation and inflammasome activation [5 days]

      Cytokine plasma levels (eg. IL-18) will be measured by ELISA daily on days 1-3 and on day 5.

    8. Change in lipid mediators [5 days]

      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.

    9. Change in biomarkers of mitochondrial quality control [5 days]

      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.

    Other Outcome Measures

    1. Ventilator-free days at day 28 [28 days]

      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.

    2. ICU-free days at day 28 [28 days]

      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).

    3. Hospital-free days at day 60 [60 days]

      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.

    4. Hospital mortality to day 28 and 60 [60 days]

      Mortality will be assessed on day 28 and day 60

    5. Montreal Cognitive Assessment- MoCA-Blind [6 months]

      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.

    6. Hayling Sentence Completion Test [6 months]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    All intubated patients ≥ 18 years old with ARDS

    1. ARDS is defined when all four of the following criteria are met:

    2. A PaO2/FiO2 ratio ≤ 300 with at least 5 cm H2O positive end-expiratory airway pressure (PEEP)

    3. 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

    4. A need for positive pressure ventilation by an endotracheal or tracheal tube

    5. Respiratory failure not fully explained by cardiac failure or fluid overload; need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor present.

    6. 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:

    1. Age less than 18 years

    2. Greater than 168 hours since ARDS onset

    3. Pregnant or breastfeeding

    4. Prisoner

    5. 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)

    6. No consent/inability to obtain consent or appropriate legal representative not available

    7. Physician refusal to allow enrollment in the trial

    8. Moribund patient not expected to survive 24 hours

    9. No arterial or central line/no intent to place an arterial or central line

    10. No intent/unwillingness to follow lung protective ventilation strategy

    11. Severe hypoxemia defined as SpO2 < 95 or PaO2 < 90 on FiO2 ≥ 0.9

    12. Hemoglobin < 7.0 g/dL

    13. Subjects who are Jehovah's Witnesses or are otherwise unable or unwilling to receive blood transfusions during hospitalization

    14. Acute myocardial infarction (MI) or acute coronary syndrome (ACS) within the last 90 days

    15. Coronary artery bypass graft (CABG) surgery within 30 days

    16. Angina pectoris or use of nitrates with activities of daily living

    17. Cardiopulmonary disease classified as NYHA class IV

    18. 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

    19. Burns > 40% total body surface area (TBSA)

    20. Severe airway inhalational injury

    21. Use of high frequency oscillatory ventilation

    22. Use of extracorporeal membrane oxygenation (ECMO)

    23. Concomitant use of inhaled pulmonary vasodilator therapy (eg. nitric oxide [NO] or prostaglandins)

    24. Diffuse alveolar hemorrhage from vasculitis

    25. Concurrent participation in other investigational drug study

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Massachusetts General Hospital Boston Massachusetts United States 02114
    2 Brigham and Women's Hospital Boston Massachusetts United States 02115
    3 Washington University Saint Louis Missouri United States 63130
    4 New York-Presbyterian Brooklyn Methodist Hospital Brooklyn New York United States 11215
    5 Weill Cornell Medical College New York New York United States 10065
    6 Duke Regional Hospital Durham North Carolina United States 27704
    7 Duke University Hospital Durham North Carolina United States 27710

    Sponsors and Collaborators

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

    Investigators

    • Principal Investigator: Rebecca Baron, MD, Brigham and Women's Hospital

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Rebecca Baron, Associate Professor of Medicine, Brigham and Women's Hospital
    ClinicalTrials.gov Identifier:
    NCT03799874
    Other Study ID Numbers:
    • 2018P002051
    • CDMRP-PR171025, W81XWH1810667
    First Posted:
    Jan 10, 2019
    Last Update Posted:
    Aug 23, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Respiratory Distress Syndrome
    Respiratory Distress Syndrome, Newborn
    Acute Lung Injury
    Syndrome
    Carbon Monoxide

    Study Results

    No Results Posted as of Aug 23, 2022