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

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety of inhaled carbon monoxide (iCO) in intubated patients with sepsis-induced ARDS.

Detailed Description
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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.

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

Conditions
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Acute Respiratory Distress Syndrome (ARDS)

Intervention / Treatment
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* Drug: Inhaled Carbon Monoxide at 100ppm (4 participants)
* Drug: Placebo for Inhaled Carbon Monoxide at 100ppm (2 participants)
* Drug: Inhaled Carbon Monoxide at 200ppm (4 participants)
* Drug: Placebo for Inhaled Carbon Monoxide at 200ppm (2 participants)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. 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. 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: Age less than 18 years Greater than 120 hours since ARDS onset Pregnant or breast-feeding 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 Physician refusal to allow enrollment in the trial Moribund patient not expected to survive 24 hours No arterial line/no intent to place an arterial line No intent/unwillingness to follow lung protective ventilation strategy Severe hypoxemia defined as oxygenation saturation (SpO2) <95 or PaO2 <80 on FiO2 ≥0.8 Hemoglobin < 7.5 g/dl or hemoglobin < 8 g/dl and actively bleeding 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 New York Heart Association (NYHA) class IV Stroke (ischemic or hemorrhagic) within the prior 3 months Diffuse alveolar hemorrhage from vasculitis Use of high frequency ventilation Participation in other interventional studies involving investigational agents Burns > 40% total body surface area Use of inhaled pulmonary vasodilator therapy (eg. NO or prostaglandins)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Inhaled Carbon Monoxide at 100 ppm for up to 90 minutes daily for 5 days | Drug: Inhaled Carbon Monoxide at 100ppm (4 participants)<br>* Inhaled Carbon Monoxide at 100ppm for up to 90 minutes daily for 5 days<br>* Other names: iCO;|
| Placebo Comparator: Cohort 1 (placebo)<br>Inhaled Medical Air for up to 90 minutes daily for 5 days | Drug: Placebo for Inhaled Carbon Monoxide at 100ppm (2 participants)<br>* Inhaled Medical Air for up to 90 minutes daily for 5 days<br>* Other names: Inhaled Medical Air;|
| Experimental: Cohort 2<br>Inhaled Carbon Monoxide at 200 ppm for up to 90 minutes daily for 5 days | Drug: Inhaled Carbon Monoxide at 200ppm (4 participants)<br>* Inhaled Carbon Monoxide at 200ppm for 90 minutes daily for 5 days<br>* Other names: iCO;|
| Placebo Comparator: Cohort 2 (Placebo)<br>Inhaled Medical Air for up to 90 minutes daily for 5 days | Drug: Placebo for Inhaled Carbon Monoxide at 200ppm (2 participants)<br>* Inhaled Medical Air for up to 90 minutes daily for 5 days<br>* Other names: Inhaled Medical Air;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of administration associated adverse events. | Acute myocardial infarction (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 direct current (DC) cardioversion within 48 hours of study drug administration Increased oxygenation requirements defined as: an increase in fraction of inspired oxygen (FiO2) of greater than or equal to 0.2 AND increase in PEEP greater than or equal to 5 cm of water (H2O) within 6 hours of study drug administration Increase in any protocol-specified measurement of carboxyhemoglobin (COHb) greater than or equal to 10% Increase in lactate by greater than or equal to 2 mmol/L within 6 hours of study drug administration | 60 Days if remains in the ICU | 
| Incidence of serious adverse events (SAEs). | An SAE is any event that is fatal or immediately life threatening, is permanently disabling, or severely incapacitating, or requires or prolongs inpatient hospitalization. Important medical events that may not result in death, be life threatening, or require hospitalization may be considered SAEs when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed above. | 60 Days if remains in the ICU | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison between the calculated carboxyhemoglobin (COHb) level at 90 minutes using the Coburn-Forster-Kane (CFK) equation and measured COHb level at 90 minutes | The Coburn-Forster-Kane (CFK) equation will be used to calculate the estimated COHb level at 90 minutes for Cohorts 1 and 2. | 5 days | 
| Mean daily Sequential Organ Failure Assessment (SOFA) score | Organ failure will be assessed using the SOFA score. SOFA scores will be assessed daily on days 1-5, and day 7, as the SOFA score has been shown to be a reliable prognostic indicator of outcomes in critically ill patients. | 7 days | 
| Partial pressure of arterial oxygen (PaO2)/FiO2 ratio | PaO2/FiO2 will be measured daily on days 1-5 if a subject remains mechanically ventilated. | 5 days | 
| Oxygenation index (OI) | The OI will be measured daily on days 1-5 if a subject remains mechanically ventilated. | 5 days | 
| Lung injury score (LIS) | The 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. 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 | 
| Vasopressor-free days | Ventilator-free days will be assessed on day 28. | 28 days | 
| Ventilator-free days (VFDs) | 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. | 28 days | 
| ICU-free days | ICU-free days will be assessed on day 28. | 28 days | 
| Hospital-free days | Hospital-free days will be assessed on day 60. | 60 days |