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

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ClinicalTrials.gov Identifier: NCT03799874
Recruitment Status : Not yet recruiting
First Posted : January 10, 2019
Last Update Posted : January 10, 2019
Sponsor:
Collaborators:
Massachusetts General Hospital
Weill Medical College of Cornell University
Duke University
Durham VA Medical Center
Information provided by (Responsible Party):
Laura E Fredenburgh, Brigham and Women's Hospital

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 5 tertiary care medical centers including Weill Cornell Medicine/NewYork-Presbyterian Hospital, Brigham and Women's Hospital (BWH), Massachusetts General Hospital (MGH), Duke University Hospital, and the Durham Veterans Administration Medical Center.

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
Acute Respiratory Distress Syndrome Drug: Inhaled Carbon Monoxide at 200ppm 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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 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)
Estimated Study Start Date : January 2019
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022


Arm Intervention/treatment
Experimental: Inhaled Carbon Monoxide
Inhaled Carbon Monoxide at 200 ppm for up to 90 minutes daily for 5 days.
Drug: Inhaled Carbon Monoxide at 200ppm
Inhaled Carbon Monoxide at 200ppm for 90 minutes daily for 5 days.
Other Name: iCO

Placebo Comparator: Medical air
Inhaled Medical Air for up to 90 minutes daily for 5 days.
Other: Inhaled Medical air
Inhaled Medical Air for up to 90 minutes daily for 5 days.




Primary Outcome Measures :
  1. Primary Safety Outcome: Number of pre-specified administration-related adverse events. [ Time Frame: 7 days ]

    Safety of inhaled CO, defined by the incidence of pre-specified administration-related AEs (as defined below) and spontaneously reported AEs through study day 7.

    1. Acute MI within 48 hours of study drug administration
    2. Acute cerebrovascular accident (CVA) within 48 hours of study drug administration
    3. New onset atrial or ventricular arrhythmia requiring DC cardioversion within 48 hours of study drug administration
    4. Increased oxygenation requirements defined as: an increase in FiO2 of ≥ 0.2 AND increase in PEEP ≥ 5 cm H2O within 6 hours of study drug administration
    5. Increase in COHb ≥ 10%
    6. Increase in lactate by ≥ 2 mmol/L within 6 hours of study drug administration

  2. Primary Efficacy Outcome: Lung injury score (LIS) on days 1 through 5 and day 7 [ Time Frame: 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).

  3. PaO2/FiO2 ratio on days 1-5, and day 7 [ Time Frame: 7 days ]
    PaO2/FiO2 will be measured daily for 7 days in ventilated subjects.

  4. Oxygenation Index (OI) on days 1-5, and day 7 [ Time Frame: 7 days ]
    The oxygenation index will be measured daily for 7 days in ventilated subjects. Oxygenation index is calculated as (FiO2 X mean airway pressure)/PaO2.

  5. Dead Space Fraction (Vd/Vt) on days 1-5, and day 7 [ Time Frame: 7 days ]
    The dead space fraction will be measured daily for 7 days in ventilated subjects.

  6. Sequential Organ Failure Assessment (SOFA) score on days 1-5, 7, 14, 28 [ Time Frame: 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.


Secondary Outcome Measures :
  1. Change in biomarkers of mitochondrial dysfunction [ Time Frame: 5 days ]
    Mitochondrial DNA (mtDNA) plasma levels will be measured daily by quantitative PCR of human NADH dehydrogenase 1.

  2. Change in biomarkers of autophagy [ Time Frame: 5 days ]
    Autophagy markers (eg. LC3B) will be measured in plasma daily.

  3. Change in biomarkers of inflammation and inflammasome activation [ Time Frame: 5 days ]
    Cytokine plasma levels (eg. IL-18) will be measured daily by ELISA.

  4. Change in lipid mediators [ Time Frame: 5 days ]
    Lipid mediators (LM) and specialized pro-resolving mediators (SPMs) will be measured in plasma daily using liquid chromatography-tandem mass spectrometry (LC-MS-MS) based methods.

  5. Change in biomarkers of mitochondrial quality control [ Time Frame: 5 days ]
    Mitochondrial quality control biomarkers (eg. Pink1, Wipi1) will be measured in peripheral blood mononuclear cells (PBMCs) daily.


Other Outcome Measures:
  1. Ventilator-free days at day 28 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 60 days ]
    Mortality will be assessed on day 28 and day 60

  5. Montreal Cognitive Assessment- MoCA-Blind [ Time Frame: 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 [ Time Frame: 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. Theses scores are combined and scaled according to age.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

All intubated patients ≥ 18 years old with ARDS

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

    1. A PaO2/FiO2 ratio ≤ 300 with at least 5 cm H2O positive end-expiratory airway pressure (PEEP)
    2. 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
    3. A need for positive pressure ventilation by an endotracheal or tracheal tube
    4. 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.
  2. 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.

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 120 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 < 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) or anoxic/hypoxic brain injury or traumatic brain injury (TBI) within the prior 3 months
  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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03799874


Contacts
Contact: Laura E Fredenburgh, MD 617-525-9563 lfredenburgh@bwh.harvard.edu
Contact: Rebecca Baron, MD 617-525-6642 rbaron@bwh.harvard.edu

Locations
United States, Massachusetts
Massachusetts General Hospital Not yet recruiting
Boston, Massachusetts, United States, 02114
Contact: Marcos Vidal Melo, MD         
Brigham and Women's Hospital Not yet recruiting
Boston, Massachusetts, United States, 02115
Contact: Laura E Fredenburgh, MD         
United States, New York
Weill Cornell Medical College Not yet recruiting
New York, New York, United States, 10065
Contact: Maria Plataki, MD         
United States, North Carolina
Duke University Hospital Not yet recruiting
Durham, North Carolina, United States, 27710
Contact: Claude Piantadosi, MD         
Durham VA Medical Center Not yet recruiting
Durham, North Carolina, United States, 27710
Contact: Karen Welty-Wolf, MD         
Sponsors and Collaborators
Brigham and Women's Hospital
Massachusetts General Hospital
Weill Medical College of Cornell University
Duke University
Durham VA Medical Center
Investigators
Principal Investigator: Laura E Fredenburgh, MD Brigham and Women's Hospital

Publications:

Responsible Party: Laura E Fredenburgh, Assistant Professor, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT03799874     History of Changes
Other Study ID Numbers: COARDS2
First Posted: January 10, 2019    Key Record Dates
Last Update Posted: January 10, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
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:
Syndrome
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Acute Lung Injury
Disease
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Lung Injury
Carbon Monoxide
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Gasotransmitters
Neurotransmitter Agents
Physiological Effects of Drugs