Clinical trial NCT04870125: Safety Study of Inhaled Carbon Monoxide to Treat Pneumonia and Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)
Official title: A Phase Ib Trial of Inhaled Carbon Monoxide for the Treatment of Pneumonia and Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Acute Respiratory Distress Syndrome
Sepsis
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: Weill Medical College of Cornell University
name: Massachusetts General Hospital
name: Duke University
name: National Heart, Lung, and Blood Institute (NHLBI)
name: Washington University School of Medicine
First posted: 2021-05-03
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 2:1 randomization to iCO versus placebo medical air
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Primary Safety Outcome: Number of pre-specified administration-related adverse events (AEs).
timeFrame: 7 days
measure: Accuracy of the Coburn-Forster-Kane (CFK) equation-based personalized iCO dosing algorithm to achieve a COHb level of 6-8%
timeFrame: day 1, day 2, and day 3
Secondary outcomes:
measure: Lung injury score (LIS) on days 1-5 and day 7
timeFrame: 7 days
measure: PaO2/FiO2 ratio on days 1-5 and day 7
timeFrame: 7 days
measure: Oxygenation Index (OI) on days 1-5 and day 7
timeFrame: 7 days
measure: Dead Space Fraction (Vd/Vt) on days 1-3 and day 7
timeFrame: 7 days
measure: Sequential Organ Failure Assessment (SOFA) score on days 1-5, 7, 14, 28
timeFrame: 28 days
measure: Ventilator-free days at day 28
timeFrame: 28 days
measure: ICU-free days at day 28
timeFrame: 28 days
measure: Hospital-free days at day 60
timeFrame: 60 days
measure: Hospital mortality to day 28 and 60
timeFrame: 60 days
measure: Montreal Cognitive Assessment- MoCA-Blind
timeFrame: 3 months, 6 months
measure: Hayling Sentence Completion Test
timeFrame: 3 months, 6 months
Other outcomes:
measure: Change in biomarkers of mitochondrial dysfunction
timeFrame: 5 days
measure: Change in biomarkers of inflammasome activation
timeFrame: 5 days
measure: Change in biomarkers of necroptosis
timeFrame: 5 days
measure: Plasma lipid mediators (LM) and specialized pro-resolving mediators (SPMs)
timeFrame: 5 days
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Brooklyn
country: United States
facility: New York-Presbyterian Brooklyn Methodist Hospital
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Durham
country: United States
facility: Duke University Hospital
state: North Carolina
Study officials:
affiliation: Brigham and Women's Hospital
name: Rebecca M Baron, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
citation: 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.