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

Study Overview
=================
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

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.

Official Title
-----------------
A Phase II Trial of Inhaled Carbon Monoxide for the Treatment of Acute Respiratory Distress Syndrome (ARDS)

Conditions
-----------------
Acute Respiratory Distress Syndrome

Intervention / Treatment
-----------------
* Drug: Inhaled Carbon Monoxide at 200 ppm
* Other: Inhaled Medical air


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: All intubated patients ≥ 18 years old with ARDS 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 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 A need for positive pressure ventilation by an endotracheal or tracheal tube 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. 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: Age less than 18 years Greater than 168 hours since ARDS onset Pregnant or breastfeeding Prisoner 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) No consent/inability to obtain consent or appropriate legal representative not available Physician refusal to allow enrollment in the trial Moribund patient not expected to survive 24 hours No arterial or central line/no intent to place an arterial or central line No intent/unwillingness to follow lung protective ventilation strategy Severe hypoxemia defined as SpO2 < 95 or PaO2 < 90 on FiO2 ≥ 0.9 Hemoglobin < 7.0 g/dL Subjects who are Jehovah's Witnesses or are otherwise unable or unwilling to receive blood transfusions during hospitalization Acute myocardial infarction (MI) or acute coronary syndrome (ACS) within the last 90 days Coronary artery bypass graft (CABG) surgery within 30 days Angina pectoris or use of nitrates with activities of daily living Cardiopulmonary disease classified as NYHA class IV 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 Burns > 40% total body surface area (TBSA) Severe airway inhalational injury Use of high frequency oscillatory ventilation Use of extracorporeal membrane oxygenation (ECMO) Concomitant use of inhaled pulmonary vasodilator therapy (eg. nitric oxide [NO] or prostaglandins) Diffuse alveolar hemorrhage from vasculitis Concurrent participation in other investigational drug study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inhaled Carbon Monoxide<br>Inhaled Carbon Monoxide at 200 ppm for up to 90 minutes daily for 3 days. | Drug: Inhaled Carbon Monoxide at 200 ppm<br>* Inhaled Carbon Monoxide at 200 ppm for 90 minutes daily for 3 days.<br>* Other names: iCO;|
| Placebo Comparator: Medical air<br>Inhaled Medical Air for up to 90 minutes daily for 3 days. | Other: Inhaled Medical air<br>* Inhaled Medical Air for up to 90 minutes daily for 3 days.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Safety Outcome: Number of pre-specified administration-related adverse events. | 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 | 7 days | 
| Primary Efficacy Outcome: Change in Mitochondrial DNA (mtDNA) level from day 1 to day 5 | Mitochondrial DNA (mtDNA) plasma levels will be measured by quantitative PCR of human NADH dehydrogenase 1. | 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lung injury score (LIS) on days 1-5, and on day 7 | 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). | 7 days | 
| PaO2/FiO2 ratio on days 1-5, and on day 7 | PaO2/FiO2 will be measured daily on days 1-5 and on day 7 in ventilated subjects. | 7 days | 
| Oxygenation Index (OI) on days 1-5, and day 7 | 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. | 7 days | 
| Dead Space Fraction (Vd/Vt) on days 1-3, and day 7 | The dead space fraction will be measured daily on days 1-3 and on day 7 in ventilated subjects. | 7 days | 
| Sequential Organ Failure Assessment (SOFA) score on days 1-5, 7, 14, 28 | 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. | 28 days | 
| Change in biomarkers of autophagy | Autophagy markers (eg. LC3B) will be measured in plasma daily on days 1-3 and on day 5. | 5 days | 
| Change in biomarkers of inflammation and inflammasome activation | Cytokine plasma levels (eg. IL-18) will be measured by ELISA daily on days 1-3 and on day 5. | 5 days | 
| Change in lipid mediators | 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. | 5 days | 
| Change in biomarkers of mitochondrial quality control | 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. | 5 days |