Safety Study of Inhaled Carbon Monoxide to Treat Pneumonia and Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)

Study Overview
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Brief Summary
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This study is a multi-center, randomized, partially double-blind, and placebo-controlled Phase Ib clinical trial of inhaled CO (iCO) for the treatment of sepsis-induced acute respiratory distress syndrome (ARDS). The purpose of this study is to evaluate the safety and accuracy of a Coburn-Forster-Kane (CFK) equation-based personalized iCO dosing algorithm to achieve a target carboxyhemoglobin (COHb) level of 6-8% in patients with sepsis-induced ARDS. We will also examine the biologic readouts of low dose iCO therapy in patients with sepsis-induced ARDS.

Detailed Description
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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. Furthermore, no specific effective pharmacologic therapies currently exist. Sepsis, life-threatening organ dysfunction caused by a dysregulated host response to infection, represents a major risk for the development of ARDS and multi-organ dysfunction syndrome (MODS). In recent years, the number of patients with severe sepsis has risen to 750,000 per year in the U.S., which bears an alarming forecast for critically ill patients in the intensive care unit with significant risk for the development of ARDS. 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 sepsis-induced ARDS based on data obtained in experimental models of sepsis and 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 sepsis-induced 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 accuracy of a CFK equation-based iCO personalized dosing algorithm of inhaled carbon monoxide (iCO) to achieve a target COHb level of 6-8% in mechanically ventilated patients with sepsis-induced ARDS.

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

Conditions
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Sepsis, Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Drug: Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%)
* Other: Inhaled Medical air


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients (age 18 and older) will be eligible for inclusion if they meet all of the following consensus criteria for sepsis and ARDS3,4 or if they meet the criteria for pneumonia as described below. Patients with sepsis are defined as those with life-threatening organ dysfunction caused by a dysregulated host response to infection: Suspected or proven infection: Sites of infection include thorax, urinary tract, abdomen, skin, sinuses, central venous catheters, and central nervous system Increase in Sequential Organ Failure Assessment (SOFA) Score ≥ 2 over baseline 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 is present Pneumonia (without ARDS or sepsis) will be defined as a unilateral or bilateral lung infiltrate on chest X-ray or chest CT (not fully explained by effusions, lobar/lung collapse or nodules) in the setting of receiving mechanical ventilation, a new suspected respiratory infection, an increase in SOFA score less than 2 at the time of randomization (baseline). Pneumonia (with sepsis, without ARDS) will be defined as a unilateral or bilateral lung infiltrate on chest X-ray or chest CT (not fully explained by effusions, lobar/lung collapse or nodules) in the setting of receiving mechanical ventilation and a new suspected respiratory infection with an increase in SOFA score of ≥ 2 over baseline at the time of randomization. Pneumonia with bilateral opacities, PaO2/FiO2 ratio ≤ 300, or an increase in SOFA score greater than or equal to 2 over baseline will continue to be considered ARDS and sepsis. 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 line 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 Severe cardiopulmonary disease classified as New York Heart Association (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 Severe airway inhalational injury Use of high frequency oscillatory ventilation Use of extracorporeal membrane oxygenation (ECMO) 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
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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
Interventional Model Description: 2:1 randomization to iCO versus placebo medical air
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inhaled Carbon Monoxide<br>Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%) for up to 90 minutes daily for 3 days. | Drug: Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%)<br>* Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%) for up to 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?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Safety Outcome: Number of pre-specified administration-related adverse events (AEs). | 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 myocardial infarction 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 | 
| Accuracy of the Coburn-Forster-Kane (CFK) equation-based personalized iCO dosing algorithm to achieve a COHb level of 6-8% | This will be assessed by comparing the measured 90-minute COHb level and the target COHb level of 6-8% daily on days 1-3. | day 1, day 2, and day 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lung injury score (LIS) on days 1-5 and 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 day 7 | PaO2/FiO2 will be measured on days 1-5 and day 7 in ventilated subjects. | 7 days | 
| Oxygenation Index (OI) on days 1-5 and day 7 | The oxygenation index will be measured on days 1-5 and 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 days 1-3 and 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 | 
| Ventilator-free days at day 28 | 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. | 28 days | 
| ICU-free days at day 28 | 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). | 28 days | 
| Hospital-free days at day 60 | 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. | 60 days | 
| Hospital mortality to day 28 and 60 | Mortality will be assessed on day 28 and day 60. | 60 days | 
| Montreal Cognitive Assessment- MoCA-Blind | The MoCA-Blind will be administered at 3 and 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. | 3 months, 6 months | 
| Hayling Sentence Completion Test | The Hayling Sentence Completion Test will be administered at 3 and 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. | 3 months, 6 months |