A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS

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.

Keywords: Clinical Trials; Drug therapy; Pulmonology; Respiration.

Conflict of interest statement

Conflict of interest: LEF has received clinical trial support for an unrelated study from Asahi Kasei Pharma America (AKPA). DRH is a consultant for Philips Respironics and Ventec Life Support; receives publishing royalties from Jones and Bartlett, McGraw-Hill, and UpToDate; and is managing editor of Respiratory Care (Daedalus Enterprises) and an inter-professional member of the Pulmonary Disease Board of the American Board of Internal Medicine. BDK has received grants from Karius Inc., Savara Pharmaceuticals, and Defense Advanced Research Projects Agency, as well as personal fees from La Jolla Pharmaceutical Company. RSH is an employee at Vertex Pharmaceuticals as of December 2017. JDD is a consultant for Teleflex Medical. PFN has received personal fees from Third Pole Inc. CNS has received personal fees from Corbus Pharmaceuticals, Inflammation Research Foundation, and FASEB Journal, as well as grants from Solutex. CNS is an inventor on patents related to resolvins and other pro-resolving mediators (both composition of matter and use of) that are licensed by Partners–Brigham and Women’s Hospital (Partners-BWH) for clinical development. BTT has served as a consultant on ARDS clinical trial design for Bayer, Boehringer Ingelheim, and GlaxoSmithKline. AMKC is a cofounder of and SAB member for Proterris Inc. and served as a consultant for Teva Pharmaceuticals. AMKC has a use patent on CO, which belongs to University of Pittsburgh, Johns Hopkins University, Yale University, and Proterris Inc.

Figures

Figure 1. CONSORT diagram.

CONSORT subject flow diagram shows the number of subjects screened, enrolled, randomized, and included in the primary analysis. One hundred forty-five patients were screened, and 12 participants were enrolled. In cohort 1, 4 subjects were randomized to 100 ppm iCO and 2 subjects were randomized to placebo air. In cohort 2, 4 subjects were randomized to 200 ppm iCO and 2 subjects were randomized to placebo air. The primary safety endpoint analysis included all subjects treated with at least one dose of iCO or placebo.

Figure 2. Arterial blood gas parameters before and after treatment with iCO versus placebo air.

Arterial blood was drawn from participants before treatment (Pre) and 90 minutes following treatment (Post) with placebo air (day 1, n = 4; day 2, n = 4; day 3, n = 2; day 4, n = 1), iCO 100 ppm (day 1, n = 4; day 2, n = 4; day 3, n = 2; day 5, n = 2), or iCO 200 ppm (day 1, n = 2; day 2, n = 4; day 3, n = 2; day 4, n = 4; day 5, n = 1). Pre- and post-treatment values of PaO2 (A), SaO2 (B), PaCO2 (C), and pH (D) for each participant on each day of treatment. Error bars represent the median and interquartile range.

Figure 3. Mean carboxyhemoglobin levels in participants treated with iCO versus placebo air on days 1–5.

Arterial blood was drawn from participants for measurement of baseline carboxyhemoglobin (COHb) level prior to treatment. If baseline COHb was A–E) COHb levels for iCO-treated and placebo-treated participants on each day of treatment. COHb levels were measured in triplicate for each subject at each time point and mean value obtained. (A) Day 1, n = 4 iCO 100 ppm, n = 2 iCO 200 ppm, n = 4 placebo. (B) Day 2, n = 4 iCO 100 ppm, n = 4 iCO 200 ppm, n = 4 placebo. (C) Day 3, n = 2 iCO 100 ppm, n = 2 iCO 200 ppm, n = 2 placebo. (D) Day 4, n = 4 iCO 200 ppm, n = 1 placebo. (E) Day 5, n = 2 iCO 100 ppm, n = 1 iCO 200 ppm. Data are mean and SD for each group on each day of treatment. COHb levels were significantly different between treatment groups and over time on days 1–3 by 2-way ANOVA followed by Tukey’s post hoc test (Supplemental Table 6). Arrows indicate duration of treatment.

Figure 4. Coburn-Forster-Kane equation accurately predicts COHb levels in ARDS patients.

The Coburn-Forster-Kane (CFK) equation was used to predict COHb levels at 60, 75, and 90 minutes using the measured COHb level at baseline and 20 minutes in subjects treated with 100 ppm (day 1, n = 4; day 2, n = 4; day 3, n = 2; day 5, n = 2) (A and C) or 200 ppm (day 1, n = 2; day 2, n = 4; day 3, n = 2; day 4, n = 4; day 5, n = 1) (B and D) iCO. Accuracy of the CFK equation in predicting COHb levels was analyzed by Spearman’s correlation and Bland-Altman plots using measured vs. predicted COHb levels and modeled using linear regression. (A) Correlation between predicted and measured COHb levels using the 20-minute COHb level and CFK equation in 100 ppm iCO–treated subjects in cohort 1 (Spearman’s r = 0.8614, P < 0.0001; goodness-of-fit R2 = 0.7186, P < 0.0001). (B) Correlation between predicted and measured COHb levels using the 20-minute COHb level and CFK equation in 200 ppm iCO–treated subjects in cohort 2 (Spearman’s r = 0.916, P < 0.0001; goodness-of-fit R2 = 0.9204, P < 0.0001). (C and D) Bland-Altman plots demonstrate excellent agreement between measured and predicted COHb levels in 100 ppm iCO–treated subjects in cohort 1 (C) and 200 ppm iCO–treated subjects in cohort 2 (D).

Figure 5. Secondary respiratory and systemic outcomes.

Mean and SD for (A) PaO2/FiO2, (B) oxygenation index (OI), (C) lung injury score (LIS), (D) lactate, and (E) sequential organ failure assessment (SOFA) score for subjects treated with placebo air (n = 4), iCO 100 ppm (n = 4), or iCO 200 ppm (n = 4) at baseline, study days 1, 2, 3, 4, 5, and 7.

Figure 6. Circulating mtDNA levels are decreased in iCO-treated subjects compared with placebo-treated subjects.

Plasma levels of (A) mtDNA, (B) RIPK3, and (C) IL-18 were measured in subjects before treatment on day 1 and after treatment on day 2 in subjects (n = 10) completing 2 days of treatment. Mean changes in mtDNA, RIPK3, and IL-18 in iCO-treated subjects (100 ppm and 200 ppm) were compared with changes in placebo-treated subjects in a pairwise manner using t tests. Box plots show 25th, median, and 75th percentiles.