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

Sepsis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04870125
• Other study ID #: 2021P000745
• Secondary ID: 1R61HL153011-01
• Status: Recruiting
• Phase: Phase 1
• Start date: December 6, 2023
• Est. completion date: September 2025

Study information

• Verified date: December 2023
• Source: Brigham and Women's Hospital
• Contact: Rebecca M Baron, MD
• Phone: 617-525-6642
• Email: rbaron[@]bwh.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: September 2025
• Est. primary completion date: June 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome
• Pneumonia
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Newborn
• Sepsis
• Syndrome
• Toxemia

Intervention

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:
• Inhaled Medical air
Inhaled Medical Air for up to 90 minutes daily for 3 days.

Locations

Country	Name	City	State
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	New York-Presbyterian Brooklyn Methodist Hospital	Brooklyn	New York
United States	Duke University Hospital	Durham	North Carolina
United States	Weill Cornell Medical College	New York	New York
United States	Washington University	Saint Louis	Missouri

Sponsors (6)

Lead Sponsor	Collaborator
Brigham and Women's Hospital	Duke University, Massachusetts General Hospital, National Heart, Lung, and Blood Institute (NHLBI), Washington University School of Medicine, Weill Medical College of Cornell University

Country where clinical trial is conducted

United States, 

References & Publications (12)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Change in biomarkers of inflammasome activation	Plasma IL-18 levels will be measured on days 1-3 and day 5 by ELISA.	5 days
Other	Change in biomarkers of necroptosis	Plasma RIPK3 levels will be measured on days 1-3 and day 5 by ELISA.	5 days
Other	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Hospital mortality to day 28 and 60	Mortality will be assessed on day 28 and day 60.	60 days
Secondary	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
Secondary	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