Acute Respiratory Distress Syndrome, Sepsis
Conditions
Brief summary
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
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.
Interventions
DRUGInhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%)
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.
OTHERInhaled Medical air
Inhaled Medical Air for up to 90 minutes daily for 3 days.
Sponsors
Brigham and Women's Hospital
Weill Medical College of Cornell University
Massachusetts General Hospital
Duke University
National Heart, Lung, and Blood Institute (NHLBI)
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Masking description
The study drug assignment will be blinded to the subject, clinical team, study coordinators, and other study staff with the exception of the administering study staff (respiratory therapist and physician or physician alone), who will be unblinded to the treatment assignment to ensure subject safety.
Intervention model description
2:1 randomization to iCO versus placebo medical air
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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: 1. Suspected or proven infection: Sites of infection include thorax, urinary tract, abdomen, skin, sinuses, central venous catheters, and central nervous system 2. Increase in Sequential Organ Failure Assessment (SOFA) Score ≥ 2 over baseline * 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 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: 1. Age less than 18 years 2. Greater than 168 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 line 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 \< 90 on FiO2 ≥ 0.9 12. Hemoglobin \< 7.0 g/dL 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. Severe cardiopulmonary disease classified as New York Heart Association (NYHA) class IV 18. 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 19. Burns \> 40% total body surface area 20. Severe airway inhalational injury 21. Use of high frequency oscillatory ventilation 22. Use of extracorporeal membrane oxygenation (ECMO) 23. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Safety Outcome: Number of Pre-specified Administration-related Adverse Events (AEs). | 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 myocardial infarction 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 |
| Percentage Change Measured Relative to Target COHb Level | Post exposure 90 min day 1 | This was assessed by comparing the measured 90-minute COHb level and the target COHb level of 6-8% post exposure. We present average data from the two available subjects in the CO group and report as "Mean" with standard deviation. |
| Variance of Measured Relative to Target COHb Level | Post exposure 90 min day 2 | This was assessed by comparing the measured 90-minute COHb level and the target COHb level of 6-8% post exposure. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the data from one available subject in the CO group and report as "Mean" without standard deviation, since measures of dispersion cannot be calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Lung Injury Score (LIS) on Days 1-5 Days | 5 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). The number presented is the average difference from beginning to end of treatment. We present the average of data from the 2 available subjects in each group and report as "Mean" with standard deviation. |
| Percent Change in PaO2/FiO2 Ratio Between Baseline and Day 5 | Baseline to day 5 | PaO2/FiO2 was to be measured on days 1-5 in ventilated subjects. We are providing percent change in PaO2/FiO2 ratio from baseline to day 5. We present the average of data from the 2 available subjects in each group and report as "Mean" with standard deviation. |
| Oxygenation Index (OI) on Days 1-5 Days | 5 days | The oxygenation index will be measured on days 1-5 in ventilated subjects. Oxygenation index is calculated as (FiO2 X mean airway pressure)/PaO2. We provide change in Oi from baseline. Oi is only measured when subjects are ventilated, therefore not all timepoints are available. Limited number of measurements prevents variance and measures of dispersion analyses; therefore we present the data from the subjects available in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated. |
| Dead Space Fraction (Vd/Vt) on Days 1-3 | Day 3 | The dead space fraction will be measured days 1-3 in ventilated subjects. We present change in dead space fraction between initial and final measurements that were available (measurements only taken while the subjects were intubated). We present the data from the subjects available in each group and report as "Mean" with standard deviation. |
| Sequential Organ Failure Assessment (SOFA) Score on Days 1-5. | 1-5 days | Organ failure will be assessed using the SOFA score. SOFA scores will be assessed daily on days 1-5, 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. We present changes in SOFA score over the time of hospitalization, over the time of ICU admission (up to days 3 and 5 for the enrolled subjects). We present the data from the subjects available in each group and report as "Mean" with standard deviation. |
| Ventilator-free Days at Day 28 | 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. We present data of ventilator free days for enrolled subjects. Note that one subject in the medical air group died at day 9. We present the data from the subjects available in each group and report as "Mean" with standard deviation. |
| ICU-free Days at Day 28 | 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). We present average number of ICU free days. Please note that one subject in the medical air group died at day 9. We present the data from the subjects available in each group and report as "Mean" with standard deviation. |
| Hospital-free Days at Day 60 | 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. We present hospital free days at day 60. Please note that one subject in the air group died at day 9. We present the data from the subjects available in each group and report as "Mean" with standard deviation. |
| Hospital Mortality to Day 28 and 60 | 60 days | Mortality will be assessed on day 28 and day 60. |
| Montreal Cognitive Assessment- MoCA-Blind | 3 months | Montreal Cognitive Assessment - Blind Version (MoCA-Blind) The MoCA-Blind is a remote adaptation of the Montreal Cognitive Assessment (MoCA) used as a screening assessment for detecting cognitive impairment. It is administered via telephone interview. The MoCA-Blind assesses the following cognitive domains (points): * Attention (0-6) * Language: (0-3 (Repetition (0-2) and fluency (0-1)) * Abstraction (0-2) * Memory: Delayed recall (0-5) * Orientation (0-6) The minimum score is 0 and maximum score is 22 points. Calculated as the sum of all domains. Interpretation: Higher scores indicate better cognitive functioning. Lower scores indicate worse cognitive functioning (greater cognitive impairment). A score of 18 or above is within the normal range. A limited number of measurements prevents variance and dispersion analyses; therefore, we report available group data as "means" without standard deviation where dispersion cannot be calculated. |
| Hayling Sentence Completion Test | 3 months | The Hayling Sentence Completion Test assesses executive functioning (response initiation and inhibition), administered via telephone. With 30 sentence-completion items split into 2 sections (15 each). Sections: * 1: Response initiation (time to provide a contextually appropriate word). * 2: Response inhibition (time and error score for providing an unrelated word). Scores (response time and errors) from both sections are combined and converted to an age-adjusted standardized total score. Total combined standardized score ranges from 1-10: 1. Impaired 2. Abnormal 3. Poor 4. Low Average 5. Moderate Average 6. Average 7. High Average 8. Good 9. Superior 10. Very Superior Higher scores= Better executive functioning Lower scores= Greater impairment. A limited number of measurements prevents variance and dispersion analyses; therefore, we report available group data as "means" without standard deviation where dispersion cannot be calculated. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORRebecca M Baron, MD
Brigham and Women's Hospital
Participant flow
Recruitment details
First recruited subject date was 12/6/2023 and last recruited subject was 5/22/2024. The study treatment was 3 days and follow up during 14 days during hospitalization and up to 6 months follow up. Screening was conducted in Intensive Care Units and qualifying subjects were consented by study physicians at Brigham and Women's Hospital. One subject consented but then withdrew from the study prior to any protocol procedures.
Pre-assignment details
After consent. Subjects were randomized to either placebo or inhaled CO. Study procedures started the following day after randomization.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Baseline Critical Illness Category ARDS with Sepsis | 1 Participants |
| Baseline Critical Illness Category Pneumonia without ARDS or sepsis | 0 Participants |
| Baseline Critical Illness Category Pneumonia with sepsis, without ARDS | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 1 / 2 |
| other Total, other adverse events | 0 / 2 | 0 / 2 |
| serious Total, serious adverse events | 1 / 2 | 1 / 2 |
Outcome results
None listed