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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Sepsis; Acute Respiratory Distress Syndrome
• Intervention / Treatment: Other: Inhaled Medical air; Drug: Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%)

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.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Rebecca M Baron, MD; Phone Number: 617-525-6642; Email: rbaron@bwh.harvard.edu
• Study Contact Backup: Name: Mark A Perrella, MD; Phone Number: 617-732-6809; Email: mperrella@rics.bwh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: Rebecca Baron, MD; Phone Number: 617-525-6642; Email: rbaron@bwh.harvard.edu
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Contact: Diana Barragan Bradford, MD
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University
      • Contact: Bryan D Kraft, MD; Phone Number: 314-747-3000; Email: kraft@wustl.edu
  • New York
    • Brooklyn, New York, United States, 11215
      • Recruiting
      • New York-Presbyterian Brooklyn Methodist Hospital
      • Contact: Jeremy A Weingarten, MD, MBA, MS; Phone Number: 718-780-5835; Email: jaw9031@nyp.org
      • Contact: Elizabeth M Peters, RN; Email: elp2018@med.cornell.edu
    • New York, New York, United States, 10065
      • Recruiting
      • Weill Cornell Medical College
      • Contact: Maria Plataki, MD, PhD
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Recruiting
      • Duke University Hospital
      • Contact: Karen Welty-Wolf, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Medical air; Inhaled Medical Air for up to 90 minutes daily for 3 days.	Other: Inhaled Medical air; Inhaled Medical Air for up to 90 minutes daily for 3 days.
Experimental: Inhaled Carbon Monoxide; 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%); 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.; Other Names: iCO

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 (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
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
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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in biomarkers of mitochondrial dysfunction	Mitochondrial DNA (mtDNA) plasma levels will be measured on days 1-3 and day 5 by quantitative PCR of human NADH dehydrogenase 1.	5 days
Change in biomarkers of inflammasome activation	Plasma IL-18 levels will be measured on days 1-3 and day 5 by ELISA.	5 days
Change in biomarkers of necroptosis	Plasma RIPK3 levels will be measured on days 1-3 and day 5 by ELISA.	5 days
Plasma lipid mediators (LM) and specialized pro-resolving mediators (SPMs)	Lipid mediators (LM) and specialized pro-resolving mediators (SPMs) will be measured in plasma on days 1-3 and day 5 using liquid chromatography-tandem mass spectrometry (LC-MS-MS) based methods.	5 days

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Massachusetts General Hospital; Washington University School of Medicine; National Heart, Lung, and Blood Institute (NHLBI); Duke University; Weill Medical College of Cornell University
• Investigators: Principal Investigator: Rebecca M Baron, MD, Brigham and Women's Hospital

Publications and helpful links

General Publications

• Rhodes MA, Carraway MS, Piantadosi CA, Reynolds CM, Cherry AD, Wester TE, Natoli MJ, Massey EW, Moon RE, Suliman HB. Carbon monoxide, skeletal muscle oxidative stress, and mitochondrial biogenesis in humans. Am J Physiol Heart Circ Physiol. 2009 Jul;297(1):H392-9. doi: 10.1152/ajpheart.00164.2009. Epub 2009 May 22.
• Fredenburgh LE, Kraft BD, Hess DR, Harris RS, Wolf MA, Suliman HB, Roggli VL, Davies JD, Winkler T, Stenzler A, Baron RM, Thompson BT, Choi AM, Welty-Wolf KE, Piantadosi CA. Effects of inhaled CO administration on acute lung injury in baboons with pneumococcal pneumonia. Am J Physiol Lung Cell Mol Physiol. 2015 Oct 15;309(8):L834-46. doi: 10.1152/ajplung.00240.2015. Epub 2015 Aug 28.
• Hausberg M, Somers VK. Neural circulatory responses to carbon monoxide in healthy humans. Hypertension. 1997 May;29(5):1114-8. doi: 10.1161/01.hyp.29.5.1114.
• Mayr FB, Spiel A, Leitner J, Marsik C, Germann P, Ullrich R, Wagner O, Jilma B. Effects of carbon monoxide inhalation during experimental endotoxemia in humans. Am J Respir Crit Care Med. 2005 Feb 15;171(4):354-60. doi: 10.1164/rccm.200404-446OC. Epub 2004 Nov 19.
• Peterson JE, Stewart RD. Predicting the carboxyhemoglobin levels resulting from carbon monoxide exposures. J Appl Physiol. 1975 Oct;39(4):633-8. doi: 10.1152/jappl.1975.39.4.633.
• Stewart RD, Peterson JE, Baretta ED, Bachand RT, Hosko MJ, Herrmann AA. Experimental human exposure to carbon monoxide. Arch Environ Health. 1970 Aug;21(2):154-64. doi: 10.1080/00039896.1970.10667214. No abstract available.
• Zevin S, Saunders S, Gourlay SG, Jacob P, Benowitz NL. Cardiovascular effects of carbon monoxide and cigarette smoking. J Am Coll Cardiol. 2001 Nov 15;38(6):1633-8. doi: 10.1016/s0735-1097(01)01616-3.
• Ren X, Dorrington KL, Robbins PA. Respiratory control in humans after 8 h of lowered arterial PO2, hemodilution, or carboxyhemoglobinemia. J Appl Physiol (1985). 2001 Apr;90(4):1189-95. doi: 10.1152/jappl.2001.90.4.1189.
• Pecorella SR, Potter JV, Cherry AD, Peacher DF, Welty-Wolf KE, Moon RE, Piantadosi CA, Suliman HB. The HO-1/CO system regulates mitochondrial-capillary density relationships in human skeletal muscle. Am J Physiol Lung Cell Mol Physiol. 2015 Oct 15;309(8):L857-71. doi: 10.1152/ajplung.00104.2015. Epub 2015 Jul 17.
• Fredenburgh LE, Perrella MA, Barragan-Bradford D, Hess DR, Peters E, Welty-Wolf KE, Kraft BD, Harris RS, Maurer R, Nakahira K, Oromendia C, Davies JD, Higuera A, Schiffer KT, Englert JA, Dieffenbach PB, Berlin DA, Lagambina S, Bouthot M, Sullivan AI, Nuccio PF, Kone MT, Malik MJ, Porras MAP, Finkelsztein E, Winkler T, Hurwitz S, Serhan CN, Piantadosi CA, Baron RM, Thompson BT, Choi AM. A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS. JCI Insight. 2018 Dec 6;3(23):e124039. doi: 10.1172/jci.insight.124039.
• Rosas IO, Goldberg HJ, Collard HR, El-Chemaly S, Flaherty K, Hunninghake GM, Lasky JA, Lederer DJ, Machado R, Martinez FJ, Maurer R, Teller D, Noth I, Peters E, Raghu G, Garcia JGN, Choi AMK. A Phase II Clinical Trial of Low-Dose Inhaled Carbon Monoxide in Idiopathic Pulmonary Fibrosis. Chest. 2018 Jan;153(1):94-104. doi: 10.1016/j.chest.2017.09.052. Epub 2017 Oct 31.
• Bathoorn E, Slebos DJ, Postma DS, Koeter GH, van Oosterhout AJ, van der Toorn M, Boezen HM, Kerstjens HA. Anti-inflammatory effects of inhaled carbon monoxide in patients with COPD: a pilot study. Eur Respir J. 2007 Dec;30(6):1131-7. doi: 10.1183/09031936.00163206. Epub 2007 Aug 22.

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2023
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: April 26, 2021
• First Submitted That Met QC Criteria: April 28, 2021
• First Posted (Actual): May 3, 2021

Study Record Updates

• Last Update Posted (Actual): December 26, 2023
• Last Update Submitted That Met QC Criteria: December 19, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Sepsis; Toxemia; Syndrome; Pneumonia; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Gasotransmitters; Carbon Monoxide
• Other Study ID Numbers: 2021P000745; 1R61HL153011-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will submit de-identified datasets and associated documentation from the clinical trial to the NHLBI data repository Biological Specimen and Data Repository Information Coordinating Center (BioLINCC).
• IPD Sharing Time Frame: According to NHLBI guidelines
• IPD Sharing Access Criteria: According to NHLBI guidelines
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No