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
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|
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|
|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.|
|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|
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 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.
- 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
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- Change in biomarkers of autophagy [ Time Frame: 5 days ]Autophagy markers (eg. LC3B) will be measured in plasma daily.
- Change in biomarkers of inflammation and inflammasome activation [ Time Frame: 5 days ]Cytokine plasma levels (eg. IL-18) will be measured daily by ELISA.
- 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.
- 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.
- 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.
- 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).
- 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.
- Hospital mortality to day 28 and 60 [ Time Frame: 60 days ]Mortality will be assessed on day 28 and day 60
- 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.
- 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.
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
|Contact: Laura E Fredenburgh, MDfirstname.lastname@example.org|
|Contact: Rebecca Baron, MDemail@example.com|
|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|
|Principal Investigator:||Laura E Fredenburgh, MD||Brigham and Women's Hospital|