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

Ivan O. Rosas, Hilary J. Goldberg, Harold R. Collard, Souheil El-Chemaly, Kevin Flaherty, Gary M. Hunninghake, Joseph A. Lasky, David J. Lederer, Roberto Machado, Fernando J. Martinez, Rie Maurer, Danielle Teller, Imre Noth, Elizabeth Peters, Ganesh Raghu, Joe G.N. Garcia, Augustine M.K. Choi

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)94-104
Number of pages11
JournalChest
Volume153
Issue number1
DOIs
StatePublished - Jan 1 2018
Externally publishedYes

Fingerprint

Idiopathic Pulmonary Fibrosis
Phase II Clinical Trials
Carbon Monoxide
Matrix Metalloproteinase 7
Therapeutics
Hospitalization
Respiratory Function Tests
Controlled Clinical Trials
Registries
Fibrosis
Placebos
Quality of Life
Clinical Trials
Oxygen
Lung
Incidence
Serum

Keywords

  • carbon monoxide
  • idiopathic pulmonary fibrosis
  • inhaled therapy
  • IPF
  • MMP7

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Rosas, I. O., Goldberg, H. J., Collard, H. R., El-Chemaly, S., Flaherty, K., Hunninghake, G. M., ... Choi, A. M. K. (2018). A Phase II Clinical Trial of Low-Dose Inhaled Carbon Monoxide in Idiopathic Pulmonary Fibrosis. Chest, 153(1), 94-104. https://doi.org/10.1016/j.chest.2017.09.052

A Phase II Clinical Trial of Low-Dose Inhaled Carbon Monoxide in Idiopathic Pulmonary Fibrosis. / Rosas, Ivan O.; Goldberg, Hilary J.; Collard, Harold R.; El-Chemaly, Souheil; Flaherty, Kevin; Hunninghake, Gary M.; Lasky, Joseph A.; Lederer, David J.; Machado, Roberto; Martinez, Fernando J.; Maurer, Rie; Teller, Danielle; Noth, Imre; Peters, Elizabeth; Raghu, Ganesh; Garcia, Joe G.N.; Choi, Augustine M.K.

In: Chest, Vol. 153, No. 1, 01.01.2018, p. 94-104.

Research output: Contribution to journalArticle

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 2018, 'A Phase II Clinical Trial of Low-Dose Inhaled Carbon Monoxide in Idiopathic Pulmonary Fibrosis', Chest, vol. 153, no. 1, pp. 94-104. https://doi.org/10.1016/j.chest.2017.09.052
Rosas IO, Goldberg HJ, Collard HR, El-Chemaly S, Flaherty K, Hunninghake GM et al. A Phase II Clinical Trial of Low-Dose Inhaled Carbon Monoxide in Idiopathic Pulmonary Fibrosis. Chest. 2018 Jan 1;153(1):94-104. https://doi.org/10.1016/j.chest.2017.09.052
Rosas, Ivan O. ; Goldberg, Hilary J. ; Collard, Harold R. ; El-Chemaly, Souheil ; Flaherty, Kevin ; Hunninghake, Gary M. ; Lasky, Joseph A. ; Lederer, David J. ; Machado, Roberto ; Martinez, Fernando J. ; Maurer, Rie ; Teller, Danielle ; Noth, Imre ; Peters, Elizabeth ; Raghu, Ganesh ; Garcia, Joe G.N. ; Choi, Augustine M.K. / A Phase II Clinical Trial of Low-Dose Inhaled Carbon Monoxide in Idiopathic Pulmonary Fibrosis. In: Chest. 2018 ; Vol. 153, No. 1. pp. 94-104.
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AU - El-Chemaly, Souheil

AU - Flaherty, Kevin

AU - Hunninghake, Gary M.

AU - Lasky, Joseph A.

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AU - Martinez, Fernando J.

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AU - Teller, Danielle

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N2 - 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.

AB - 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.

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