A Phase II Clinical Trial of Low-Dose Inhaled Carbon Monoxide in Idiopathic Pulmonary Fibrosis

Abstract

Background: Preclinical studies have demonstrated that low-dose carbon monoxide (CO) can abrogate experimental lung fibrosis. To test the therapeutic role of inhaled CO, we designed a clinical study in patients with idiopathic pulmonary fibrosis (IPF).

Methods: We conducted a multicenter, phase IIa, double-blinded, sham-controlled, clinical trial. Patients with IPF were randomized to treatment with inhaled CO at 100 to 200 parts per million or to inhaled 21% oxygen for 2 h daily, twice weekly, for 12 weeks. The primary study end point was the difference in change in matrix metalloproteinase-7 (MMP7) serum concentration after 12 weeks of treatment. Secondary end points included pulmonary function test measures, 6-min walk distance, rates of adverse events, acute exacerbation, hospitalization and death, and quality of life measures.

Results: Fifty-eight subjects were randomized to treatment with inhaled CO (n = 29) or placebo (n = 29). Despite modest increases in CO blood levels, the change in MMP7 concentrations after 12 weeks of treatment did not significantly differ between the study arms (MMP7 difference at week 12, -0.90 ng/mL; 95% CI, -4.18 to 2.38 ng/mL). No differences were observed in physiologic measures, incidence of acute exacerbations, hospitalization, death, or patient-reported outcomes. Importantly, no differences in distribution of adverse events were noted between the treatment arms.

Conclusions: Inhaled CO is well tolerated and can be safely administered to patients with IPF in the ambulatory setting; however, inhaled CO did not result in significant changes in study end points. Our findings support testing the efficacy of inhaled therapies in future IPF clinical trials.

Trial registry: ClinicalTrials.gov; No.: NCT01214187; URL: www.clinicaltrials.gov.

Keywords: IPF; MMP7; carbon monoxide; idiopathic pulmonary fibrosis; inhaled therapy.

Copyright © 2017. Published by Elsevier Inc.

Figures

Figure 1

Administration of CO or placebo: certified medical grade CO gas (single-use cylinder units with predetermined CO gas concentrations of 100 or 200 ppm) or oxygen (21%) was delivered through a tight-fitting CPAP facemask at 15 L/min. The mask was connected to tubing with a one-way expiratory valve to prevent accumulation and rebreathing of exhaled gas. ASCO = ASCO Power Technologies; CO = carbon monoxide; ppm = parts per million.

Figure 2

Flowchart of study enrollment: a total of 65 subjects were screened and 58 subjects were randomized in 1:1 fashion to receive inhaled CO or placebo. See Figure 1 legend for expansion of abbreviation.

Figure 3

Max COHB during drug administration by treatment group: when all doses were averaged, the Max mean change in COHB levels was significantly higher in the treatment group than placebo (P = .02). No significant differences in co-oximetry levels were observed at any individual time point between the two study arms. COHB = carboxyhemoglobin; Max = maximum.

Figure 4

Primary end point, MMP-7 serum concentration, during the study period by treatment group: although MMP-7 levels overall significantly increased over time combining the two groups (P = .006), there was no significant difference observed in the primary study end point of reduction in serum MMP-7 levels between the carbon monoxide-treated group and placebo after the 12-wk dosing period. MMP-7 = matrix metalloproteinase-7.

Figure 5

A-D, Secondary end points, (A) FVC, (B) TLC, (C) Dlco, and (D) 6-min walk distance: no significant differences were observed in measures diffusing capacity for carbon monoxide of pulmonary function or 6-min walk distance between the two treatment arms after the 12-wk dosing period or after 12-mo of follow-up. Dlco = diffusing capacity for carbon monoxide; TLC = total lung capacity.

Figure 6

Self-reported outcomes: no significant differences were observed in scores on the St. George’s Respiratory Questionnaire between the two treatment arms after the 12-wk dosing period or after 12-mo of follow-up.