Laura E Fredenburgh1, Mark A Perrella1,2, Diana Barragan-Bradford1, Dean R Hess3,4, Elizabeth Peters5, Karen E Welty-Wolf6, Bryan D Kraft6, R Scott Harris7, Rie Maurer8, Kiichi Nakahira5, Clara Oromendia9, John D Davies10, Angelica Higuera1, Kristen T Schiffer5, Joshua A Englert1, Paul B Dieffenbach1, David A Berlin5, Susan Lagambina11, Mark Bouthot11, Andrew I Sullivan11, Paul F Nuccio11, Mamary T Kone7, Mona J Malik6, Maria Angelica Pabon Porras5, Eli Finkelsztein5, Tilo Winkler3, Shelley Hurwitz8, Charles N Serhan12, Claude A Piantadosi6, Rebecca M Baron1, B Taylor Thompson7, Augustine Mk Choi5. 1. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. 2. Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. 3. Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. 4. Department of Respiratory Care, Massachusetts General Hospital, Boston, Massachusetts, USA. 5. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA. 6. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. 7. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. 8. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. 9. Department of Healthcare Policy and Research, Division of Biostatistics and Epidemiology, Weill Cornell Medicine, New York, New York, USA. 10. Department of Respiratory Care, Duke University Medical Center, Durham, North Carolina, USA. 11. Department of Respiratory Care, Brigham and Women's Hospital, Boston, Massachusetts, USA. 12. Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Abstract
BACKGROUND:Acute respiratory distress syndrome (ARDS) is a prevalent disease with significant mortality for which no effective pharmacologic therapy exists. Low-dose inhaled carbon monoxide (iCO) confers cytoprotection in preclinical models of sepsis and ARDS. METHODS: We conducted a phase I dose escalation trial to assess feasibility and safety of low-dose iCO administration in patients with sepsis-induced ARDS. Twelve participants were randomized to iCO or placebo air 2:1 in two cohorts. Four subjects each were administered iCO (100 ppm in cohort 1 or 200 ppm in cohort 2) or placebo for 90 minutes for up to 5 consecutive days. Primary outcomes included the incidence of carboxyhemoglobin (COHb) level ≥10%, prespecified administration-associated adverse events (AEs), and severe adverse events (SAEs). Secondary endpoints included the accuracy of the Coburn-Forster-Kane (CFK) equation to predict COHb levels, biomarker levels, and clinical outcomes. RESULTS: No participants exceeded a COHb level of 10%, and there were no administration-associated AEs or study-related SAEs. CO-treated participants had a significant increase in COHb (3.48% ± 0.7% [cohort 1]; 4.9% ± 0.28% [cohort 2]) compared with placebo-treated subjects (1.97% ± 0.39%). The CFK equation was highly accurate at predicting COHb levels, particularly in cohort 2 (R2 = 0.9205; P < 0.0001). Circulating mitochondrial DNA levels were reduced in iCO-treated participants compared with placebo-treated subjects. CONCLUSION: Precise administration of low-dose iCO is feasible, well-tolerated, and appears to be safe in patients with sepsis-induced ARDS. Excellent agreement between predicted and observed COHb should ensure that COHb levels remain in the target range during future efficacy trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT02425579. FUNDING: NIH grants P01HL108801, KL2TR002385, K08HL130557, and K08GM102695.
RCT Entities:
BACKGROUND: Acute respiratory distress syndrome (ARDS) is a prevalent disease with significant mortality for which no effective pharmacologic therapy exists. Low-dose inhaled carbon monoxide (iCO) confers cytoprotection in preclinical models of sepsis and ARDS. METHODS: We conducted a phase I dose escalation trial to assess feasibility and safety of low-dose iCO administration in patients with sepsis-induced ARDS. Twelve participants were randomized to iCO or placebo air 2:1 in two cohorts. Four subjects each were administered iCO (100 ppm in cohort 1 or 200 ppm in cohort 2) or placebo for 90 minutes for up to 5 consecutive days. Primary outcomes included the incidence of carboxyhemoglobin (COHb) level ≥10%, prespecified administration-associated adverse events (AEs), and severe adverse events (SAEs). Secondary endpoints included the accuracy of the Coburn-Forster-Kane (CFK) equation to predict COHb levels, biomarker levels, and clinical outcomes. RESULTS: No participants exceeded a COHb level of 10%, and there were no administration-associated AEs or study-related SAEs. CO-treated participants had a significant increase in COHb (3.48% ± 0.7% [cohort 1]; 4.9% ± 0.28% [cohort 2]) compared with placebo-treated subjects (1.97% ± 0.39%). The CFK equation was highly accurate at predicting COHb levels, particularly in cohort 2 (R2 = 0.9205; P < 0.0001). Circulating mitochondrial DNA levels were reduced in iCO-treated participants compared with placebo-treated subjects. CONCLUSION: Precise administration of low-dose iCO is feasible, well-tolerated, and appears to be safe in patients with sepsis-induced ARDS. Excellent agreement between predicted and observed COHb should ensure that COHb levels remain in the target range during future efficacy trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT02425579. FUNDING: NIH grants P01HL108801, KL2TR002385, K08HL130557, and K08GM102695.
Entities:
Keywords:
Clinical Trials; Drug therapy; Pulmonology; Respiration
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