A phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover, single-dose clinical trial of a new class of bronchodilator for acute asthma

Veronica Swystun, Francis H Y Green, John H Dennis, Emmanouil Rampakakis, Gurkeet Lalli, Morenike Fadayomi, Andrea Chiu, Grishma Shrestha, Sharif Galal El Shahat, David Evan Nelson, Tamer Y El Mays, Cora A Pieron, Richard Leigh, Veronica Swystun, Francis H Y Green, John H Dennis, Emmanouil Rampakakis, Gurkeet Lalli, Morenike Fadayomi, Andrea Chiu, Grishma Shrestha, Sharif Galal El Shahat, David Evan Nelson, Tamer Y El Mays, Cora A Pieron, Richard Leigh

Abstract

Background: This study evaluates a novel bronchodilator, S1226, for its efficacy in reversing allergen-induced bronchoconstriction in subjects with mild, allergic asthma. S1226 is a new class of bronchodilator that is an aerosol/vapor/gas mixture combining pharmacological and biophysical principles for a novel mode of action. It contains a potent bronchodilator gas (carbon dioxide or CO2) and nebulized perflubron (a synthetic surfactant possessing mucolytic properties). It has demonstrated rapid reversal of allergen-induced bronchoconstriction in an ovine study model.

Methods: This was a phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover single-dose clinical trial to evaluate the safety, tolerability, and efficacy of S1226 (8% CO2) administered by nebulization following an allergen-induced early asthmatic response in 12 subjects with mild, allergic asthma. Primary safety endpoints were adverse events, vital signs, pulse oximetry, and spirometry. Efficacy endpoints included bronchodilator response (measured as the forced expiratory volume in 1 s or FEV1) over time, the area under the curve of FEV1 for the early asthmatic response over time, and achievement of responder status, defined as a 12% improvement after the allergen challenge.

Results: No significant safety issues were observed. All adverse events were non-serious, mild, and transient. There was a statistically significant decrease in peripheral blood oxygenation levels over time in the placebo group following allergen inhalation, whereas blood oxygenation was maintained at normal levels in the S1226-treated subjects (P = 0.028). This effect was greatest 5 min after start of treatment (P < 0.001). The recovery rate was faster but not significantly so (P = 0.272) for S1226 compared to the placebo at earlier time points (5, 10, and 15 min), as assessed by ≥12% reversal of FEV1. The recovery of FEV1 over time was significantly greater (P = 0.04) with S1226 compared to the placebo.

Conclusions: S1226 was safe, tolerated well, and provided bronchodilation and improved blood oxygenation in subjects with mild atopic asthma following allergen-induced bronchoconstriction. Additional studies to optimize the therapeutic response are indicated.

Trial registration: ClinicalTrials.gov, NCT02334553 . Registered on 12 November 2014.

Keywords: Asthma; Carbon dioxide (CO2); Clinical trial; Novel bronchodilator; Perflubron; S1226.

Conflict of interest statement

Ethics approval and consent to participate

The study was conducted at the Respiratory Clinical Trials Centre, University of Calgary, AB, Canada. All procedures were conducted in accordance with the standard operating procedures for the Respiratory Clinical Trials Centre. The study is registered with NCT02334553). The study follows the Consolidated Standards of Reporting Trials (CONSORT) 2010 checklist (see Additional file 5).

This study was conducted in accordance with the Declaration of Helsinki. The Conjoint Health Research Ethics Board of the University of Calgary approved the study protocol, amendments, and consent form (REB14–1581). Written informed consent was obtained from all subjects.

Consent for publication

Not applicable.

Competing interests

FHYG and JHD are founders, shareholders, management, and board members of SolAeroMed Inc., a biotechnology company with patent rights for S1226. GL, MF, AC, TYEM, CAP, and RL are shareholders in SolAeroMed Inc. VS, ER, GS, SG, and DEN have no conflicts of interest to declare.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Study design from enrollment to analysis following the CONSORT guidelines
Fig. 2
Fig. 2
Oxygen saturation measured by pulse oximetry, placebo vs S1226. The absolute change between pre-dose and post-dose %SpO2 levels was significantly different (P = 0.028) for the S1226 group compared with the placebo group over time. %SpO2 significantly decreased 5 min post-treatment following the allergen challenge for the placebo *P < 0.001 but not for S1226 (P = 0.267). Error bars show standard errors. PA pre-allergen
Fig. 3
Fig. 3
Change in FEV1 over time. Baseline adjusted FEV1 over time for S1226 was significantly higher than placebo (P = 0.043). Error bars show the standard deviation
Fig. 4
Fig. 4
Time to achieve 12% reversal (response) in FEV1 following S1226 or the placebo (P = 0.272)

References

    1. Reddel HK, Bateman ED, Becker A, Boulet LP, Cruz AA, Drazen JM, et al. A summary of the new GINA strategy: a roadmap to asthma control. Eur Respir J. 2015;46:622–639. doi: 10.1183/13993003.00853-2015.
    1. Rowe BH, Sevcik W, Villa-Roel C. Management of severe acute asthma in the emergency department. Curr Opin Crit Care. 2011;17:335–341. doi: 10.1097/MCC.0b013e328348bf09.
    1. Cheung D, Timmers MC, Zwinderman AH, Bel EH, Dijkman JH, Sterk PJ. Long-term effects of a long-acting beta 2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma. N Engl J Med. 1992;327:1198–1203. doi: 10.1056/NEJM199210223271703.
    1. O’Connor BJ, Aikman SL, Barnes PJ. Tolerance to the nonbronchodilator effects of inhaled beta 2-agonists in asthma. N Engl J Med. 1992;327:1204–1208. doi: 10.1056/NEJM199210223271704.
    1. Cockcroft DW, McParland CP, Britto SA, Swystun VA, Rutherford BC. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet. 1993;342:833–837. doi: 10.1016/0140-6736(93)92695-P.
    1. Wener RR, Bel EH. Severe refractory asthma: an update. Eur Respir Rev. 2013;22:227–235. doi: 10.1183/09059180.00001913.
    1. Al-Saiedy MR, Nelson DE, Amrein M, Leigh R, Green F. The role of an artificial surfactant in mucous plug clearance in vitro. Am J Respir Crit Care Med. 2015;191:A5997.
    1. Wolfson MR, Shaffer TH. Pulmonary applications of perfluorochemical liquids: ventilation and beyond. Paediatr Respir Rev. 2005;6:117–127. doi: 10.1016/j.prrv.2005.03.010.
    1. Riess JG. Understanding the fundamentals of perfluorocarbons and perfluorocarbon emulsions relevant to in vivo oxygen delivery. Artif Cells Blood Substit Immobil Biotechnol. 2005;33:47–63. doi: 10.1081/BIO-200046659.
    1. von der Hardt K, Kandler MA, Brenn G, Scheuerer K, Schoof E, Dotsch J, Rascher W. Comparison of aerosol therapy with different perfluorocarbons in surfactant-depleted animals. Crit Care Med. 2004;32:1200–1206. doi: 10.1097/01.CCM.0000124876.31138.F6.
    1. Kandler MA, von der Hardt K, Schoof E, Dotsch J, Rascher W. Persistent improvement of gas exchange and lung mechanics by aerosolized perfluorocarbon. Am J Respir Crit Care Med. 2001;164:31–35. doi: 10.1164/ajrccm.164.1.2010049.
    1. Fisher HK, Hansen TA. Site of action of inhaled 6 per cent carbon-dioxide in lungs of asthmatic subjects before and after exercise. Am Rev Respir Dis. 1976;114:861–870.
    1. El Mays TY, Saifeddine M, Choudhury P, Hollenberg MD, Green FH. Carbon dioxide enhances substance P-induced epithelium-dependent bronchial smooth muscle relaxation in Sprague-Dawley rats. Can J Physiol Pharmacol. 2011;89:513–520. doi: 10.1139/y11-052.
    1. El Mays T, Snibson K, Wilson R, Leigh R, Dennis J, Nelson D, Green F, Choudhury P. Investigations of mechanisms of carbon dioxide-induced bronchial smooth muscle relaxation. Am J Respir Crit Care Med. 2012;185:A2848.
    1. El Mays TY, Choudhury P, Leigh R, Koumoundouros E, Van der Velden J, Shrestha G, Pieron CA, Dennis JH, Green FH, Snibson KJ. Nebulized perflubron and carbon dioxide rapidly dilate constricted airways in an ovine model of allergic asthma. Respir Res. 2014;15:98. doi: 10.1186/s12931-014-0098-x.
    1. Green FH, Leigh R, Fadayomi M, Lalli G, Chiu A, Shrestha G, ElShahat SG, Nelson DE, El Mays TY, Pieron CA, Dennis JH. A phase I, placebo-controlled, randomized, double-blind, single ascending dose-ranging study to evaluate the safety and tolerability of a novel biophysical bronchodilator (S-1226) administered by nebulization in healthy volunteers. Trials. 2016;17:361. doi: 10.1186/s13063-016-1489-8.
    1. Green F, Leigh R, Shrestha G, Galal S, Chiu A, Fadayomi M, Pieron C, El Mays T, Nelson DE, Al-Saiedy MR, et al. Development of a new bronchodilator to enable better treatment of asthma, COPD, and CF. Am J Respir Crit Care Med. 2015;191:A5788.
    1. Diamant Z, Gauvreau GM, Cockcroft DW, Boulet LP, Sterk PJ, de Jongh FH, Dahlen B, O’Byrne PM. Inhaled allergen bronchoprovocation tests. J Allergy Clin Immunol. 2013;132:1045–1055. doi: 10.1016/j.jaci.2013.08.023.
    1. Dripps RD, Comroe JH., Jr The respiratory and circulatory response of normal man to inhalation of 7.6 and 10.4 per cent CO2 with a comparison of the maximal ventilation produced by severe muscular exercise, inhalation of CO2 and maximal voluntary hyperventilation. Am J Phys. 1947;149:43–51.
    1. Maresh CM, Armstrong LE, Kavouras SA, Allen GJ, Casa DJ, Whittlesey M, LaGasse KE. Physiological and psychological effects associated with high carbon dioxide levels in healthy men. Aviat Space Environ Med. 1997;68:41–45.
    1. Casale TB, Romero FA, Spierings EL. Intranasal noninhaled carbon dioxide for the symptomatic treatment of seasonal allergic rhinitis. J Allergy Clin Immunol. 2008;121:105–109. doi: 10.1016/j.jaci.2007.08.056.
    1. Al-Saiedy M, Nelson E, El-Mays T, Amrein M, Green F. Perflubron enhances mucin plug clearance in vitro in the presence of natural surfactant. Euro Respir J. 2013;42:686.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel