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

This study is currently recruiting participants.
Verified August 2017 by Mark A. Perrella, M.D., Brigham and Women's Hospital
Sponsor:
ClinicalTrials.gov Identifier:
NCT02425579
First Posted: April 24, 2015
Last Update Posted: August 30, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
Weill Medical College of Cornell University
Massachusetts General Hospital
Duke University
Information provided by (Responsible Party):
Mark A. Perrella, M.D., Brigham and Women's Hospital
March 17, 2015
April 24, 2015
August 30, 2017
April 2015
July 2018   (Final data collection date for primary outcome measure)
Number of administration associated adverse events. [ Time Frame: 60 Days ]
Same as current
Complete list of historical versions of study NCT02425579 on ClinicalTrials.gov Archive Site
  • Comparison between the calculated COHb level at 90 minutes using CFK equation and measured COHb level at 90 minutes [ Time Frame: 5 days ]
    The Coburn-Forster-Kane (CFK) equation will be used to calculate the estimated COHb level at 90 minutes for Cohorts 1 and 2. In Cohorts 3a and 3b, the CFK equation will be used to determine each subject's specified dose in order to achieve a COHb level of 6-8%
  • Mean daily Sequential Organ Failure Assessment (SOFA) score [ Time Frame: 14 days ]
  • PaO2/FiO2 ratio and Oxygenation Index [ Time Frame: 14 days ]
  • Acute lung injury (ALI) score [ Time Frame: 5 Days ]
  • Vasopressor-free days [ Time Frame: 14 days ]
  • ICU-free days [ Time Frame: 28 days ]
  • Hospital-free days [ Time Frame: 60 days ]
  • Plasma biomarkers of inflammation, lung epithelial injury,endothelial injury, markers of change in other end-organ function [ Time Frame: 5 days ]
  • Comparison between the calculated COHb level at 90 minutes using CFK equation and measured COHb level at 90 minutes [ Time Frame: 5 days ]
    The Coburn-Forster-Kane (CFK) equation will be used to calculate the estimated COHb level at 90 minutes for Cohorts 1 and 2. In Cohorts 3a and 3b, the CFK equation will be used to determine each subject's specified dose in order to achieve a COHb level of 6-8%
  • Mean daily Sequential Organ Failure Assessment (SOFA) score [ Time Frame: 14 days ]
  • PaO2/FiO2 ratio and Oxygenation Index [ Time Frame: 14 days ]
  • Acute lung injury (ALI) score [ Time Frame: 5 Days ]
  • Vasopressor-free days [ Time Frame: 14 days ]
  • ICU-free days [ Time Frame: 28 days ]
  • Hospital-free days [ Time Frame: 60 days ]
  • Plasma biomarkers of inflammation, lung epithelial injury,endothelial injury, markers of change in other end-organ function [ Time Frame: 5 days ]
  • Skeletal muscle biomarkers of mitochondrial biogenesis [ Time Frame: 7 days ]
Biomarkers [ Time Frame: 5 days ]
Specific Biomarkers: Plasma biomarkers of inflammation (IL-6, IL-8, IL-10, IL-1Ra, IL-18, IL1β, and circulating mitochondrial DNA), lung epithelial injury (RAGE), endothelial injury (vWF, Ang-2), markers of change in other end-organ function (e.g., creatinine, liver function tests, lactate)
Biomarkers [ Time Frame: 5 days ]
Specific Biomarkers: Plasma biomarkers of inflammation (IL-6, IL-8, IL-10, IL-1Ra, IL-18, ILβ, and circulating mitochondrial DNA), lung epithelial injury (RAGE), endothelial injury (vWF, Ang-2), markers of change in other end-organ function (e.g., creatinine, liver function tests, lactate)
 
Safety Study of Inhaled Carbon Monoxide to Treat Acute Respiratory Distress Syndrome (ARDS)
A Phase I Trial of Inhaled Carbon Monoxide for the Treatment of Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)
The purpose of this study is to assess the safety of inhaled carbon monoxide (iCO) in intubated patients with sepsis-induced ARDS.

The acute respiratory distress syndrome (ARDS) is a syndrome of severe acute lung inflammation and hypoxemic respiratory failure with an incidence of 180,000 cases annually in the U.S.Despite decades of research and recent advances in lung protective ventilator strategies, morbidity and mortality remain unacceptably high. Furthermore, no specific effective pharmacologic therapies currently exist. The lack of specific effective therapies for sepsis-related 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 and sepsis over the past decade.

CO has been shown to be protective in experimental models of Acute Lung Injury (ALI), including hyperoxia and endotoxin exposure, bleomycin, ischemia/reperfusion, and ventilator-induced lung injury (VILI). At low doses, CO has been shown to confer tissue protective effects in these ALI models. In addition, CO has been shown to decrease inflammation, enhance phagocytosis, and improve mortality in models of sepsis including endotoxemia, hemorrhagic shock, and cecal ligation and puncture (CLP). CO has also been shown to have beneficial therapeutic effects in pre-clinical models of disease including pulmonary hypertension, vascular injury, and transplantation. 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 purpose of this study is to assess the safety of inhaled CO therapy in mechanically ventilated patients with sepsis-induced ARDS.

Interventional
Phase 1
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Acute Respiratory Distress Syndrome (ARDS)
  • Drug: Inhaled Carbon Monoxide at 100ppm
    Inhaled Carbon Monoxide at 100ppm for up to 90 minutes daily for 5 days
    Other Name: iCO
  • Drug: Placebo for Inhaled Carbon Monoxide at 100ppm
    Inhaled Medical Air for up to 90 minutes daily for 5 days
    Other Name: Inhaled Medical Air
  • Drug: Inhaled Carbon Monoxide at 200ppm
    Inhaled Carbon Monoxide at 200ppm for 90 minutes daily for 5 days
    Other Name: iCO
  • Drug: Algorthim Specified dose of iCO to achieve COHb of 6-8%
    iCO not to exceed 500 ppm to achieve a COHb of 6-8% for up to 90 min for 5 days
    Other Name: iCO
  • Drug: Placebo for Inhaled Carbon Monoxide at 200ppm
    Inhaled Medical Air for up to 90 minutes daily for 5 days
    Other Name: Inhaled Medical Air
  • Drug: Placebo for Cohort 3
    Inhaled Medical Air for up to 90 minutes daily for 5 days
    Other Name: Inhaled Medical Air
  • Experimental: Cohort 1
    Inhaled Carbon Monoxide at 100 ppm for up to 90 minutes daily for 5 days
    Intervention: Drug: Inhaled Carbon Monoxide at 100ppm
  • Placebo Comparator: Cohort 1 (placebo)
    Inhaled Medical Air for up to 90 minutes daily for 5 days
    Intervention: Drug: Placebo for Inhaled Carbon Monoxide at 100ppm
  • Experimental: Cohort 2
    Inhaled Carbon Monoxide at 200 ppm for up to 90 minutes daily for 5 days
    Intervention: Drug: Inhaled Carbon Monoxide at 200ppm
  • Placebo Comparator: Cohort 2 (Placebo)
    Inhaled Medical Air for up to 90 minutes daily for 5 days
    Intervention: Drug: Placebo for Inhaled Carbon Monoxide at 200ppm
  • Experimental: Cohort 3
    Algorithm-specified dose of iCO (not to exceed 500 ppm) to achieve a COHb of 6-8% for up to 90 minutes daily for 5 days
    Intervention: Drug: Algorthim Specified dose of iCO to achieve COHb of 6-8%
  • Placebo Comparator: Cohort 3 (Placebo)
    Inhaled Medical Air for up to 90 minutes daily for 5 days
    Intervention: Drug: Placebo for Cohort 3
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
38
July 2018
July 2018   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  1. Patients with sepsis are defined as those with suspected or documented infection:

    Suspected or proven infection: Sites of infection include thorax, urinary tract, abdomen, skin, sinuses, central venous catheters, and central nervous system

    All eligible patients meet the new definition of sepsis (suspected or proven infection and a SOFA ≥ 2) as PaO2/FiO2 ratio < 300 = 2 SOFA points.

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

    • A PaO2/FiO2 ratio ≤ 300 with at least 5 cm H2O positive end-expiratory airway pressure (PEEP)
    • Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph
    • A need for positive pressure ventilation by an endotracheal or tracheal tube
    • No clinical evidence of left atrial hypertension for bilateral pulmonary infiltrates.
  3. ARDS onset is defined as the time the last of criteria 1-4 are met. ARDS must persist through the enrollment time window of 120 hours.
  4. Infiltrates considered "consistent with pulmonary edema" include any infiltrates not fully explained by mass, atelectasis, or effusion or opacities known to be chronic (greater than 1 week). Vascular redistribution, indistinct vessels, and indistinct heart borders alone are not considered "consistent with pulmonary edema" and thus would not count as qualifying opacities for this study.

Exclusion Criteria:

  1. Age less than 18 years
  2. Greater than 120 hours since ARDS onset
  3. Pregnant or breast-feeding
  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
  7. Physician refusal to allow enrollment in the trial
  8. Moribund patient not expected to survive 24 hours
  9. No arterial line/no intent to place an arterial line
  10. No intent/unwillingness to follow lung protective ventilation strategy
  11. Severe hypoxemia defined as SpO2 <95 or PaO2 <80 on FiO2 ≥0.8
  12. Hemoglobin < 7.5 g/dl or hemoglobin < 8 g/dl and actively bleeding
  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 3 months
  19. Diffuse alveolar hemorrhage from vasculitis
  20. Use of high frequency ventilation
  21. Participation in other interventional studies involving investigational agents
  22. Burns > 40% total body surface area
  23. Use of inhaled pulmonary vasodilator therapy (eg. NO or prostaglandins)
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact: Laura E Fredenburgh, MD 617-732-6625 lfredenburgh@rics.bwh.harvard.edu
Contact: Rebecca M Baron, MD 617-525-6642 rbaron@bwh.harvard.edu
United States
 
 
NCT02425579
1408015437
Yes
Not Provided
Plan to Share IPD: No
Mark A. Perrella, M.D., Brigham and Women's Hospital
Brigham and Women's Hospital
  • Weill Medical College of Cornell University
  • Massachusetts General Hospital
  • Duke University
Principal Investigator: Laura E Fredenburgh, MD Brigham and Women's Hospital
Brigham and Women's Hospital
August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP