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

NCT ID: NCT04870125

Last Updated: 2026-01-12

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-12-06
• Study Completion Date: 2026-03-31

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.

Conditions

Acute Respiratory Distress Syndrome; Sepsis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: EXPERIMENTAL

Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%)

Intervention Type: DRUG

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.

Medical air

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

Group Type: PLACEBO_COMPARATOR

Inhaled Medical air

Intervention Type: OTHER

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

Interventions

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.

Intervention Type: DRUG

Inhaled Medical air

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

Intervention Type: OTHER

Other Intervention Names

iCO

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Weill Medical College of Cornell University

OTHER

Sponsor Role: collaborator

Massachusetts General Hospital

OTHER

Sponsor Role: collaborator

Duke University

OTHER

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: collaborator

Brigham and Women's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Rebecca Baron

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Rebecca M Baron, MD

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

Locations

Massachusetts General Hospital

Boston, Massachusetts, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Washington University

St Louis, Missouri, United States

New York-Presbyterian Brooklyn Methodist Hospital

Brooklyn, New York, United States

Weill Cornell Medical College

New York, New York, United States

Duke University Hospital

Durham, North Carolina, United States

Countries

United States

References

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Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

1R61HL153011-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2021P000745

Identifier Type: -

Identifier Source: org_study_id