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

Francis H Y Green, Richard Leigh, Morenike Fadayomi, Gurkeet Lalli, Andrea Chiu, Grishma Shrestha, Sharif G ElShahat, David Evan Nelson, Tamer Y El Mays, Cora A Pieron, John H Dennis, Francis H Y Green, Richard Leigh, Morenike Fadayomi, Gurkeet Lalli, Andrea Chiu, Grishma Shrestha, Sharif G ElShahat, David Evan Nelson, Tamer Y El Mays, Cora A Pieron, John H Dennis

Abstract

Background: A major challenge in treating acute asthma exacerbations is the need to open constricted airways rapidly enough to reestablish ventilation and allow delivery of conventional medication to diseased airways. The solution requires a new approach that considers both biophysical and pharmacological aspects of treatments used in acute asthma. The result of testing several formulations was S-1226: carbon dioxide-enriched air delivered in nebulized perflubron, a synthetic surfactant. These agents act synergistically to rapidly reopen closed airways within seconds. The bronchodilator effect is independent of β-adrenergic and cholinergic mediated-signaling pathways, offering a unique mechanism of action. S-1226 has a low toxicity profile and was effective in treating bronchoconstriction in animal models of asthma. The goal of the present study was to evaluate the safety and tolerability of S-1226 in healthy human subjects.

Methods: The phase I study was a single-center, randomized, double-blind, placebo-controlled, sequential, single-ascending-dose study conducted in Canada. Thirty-six subjects were distributed into three cohorts. Within each cohort, subjects were randomized to receive a single dose of S-1226 or a matching placebo administered over a 2-minute nebulization period. S-1226 was formulated with perflubron and 4 %, 8 %, or 12 % CO2. The dose of CO2 was sequentially escalated by cohort. The safety and tolerability of S-1226 were evaluated through assessment of adverse events, vital signs, 12-lead electrocardiograms, clinical laboratory parameters, and physical examinations.

Results: S-1226 was safe and well tolerated at all three CO2 levels (4 %, 8 %, and 12 %). A total of 28 adverse events were reported, and all were judged mild in severity. Twenty-four adverse events occurred in the S-1226 cohort, of which five were considered remotely related and six possibly related to S-1226.

Conclusions: S-1226 is a novel drug being developed for the treatment of acute asthma exacerbations. It consists of CO2-enriched air and perflubron and has potential to offer rapid and potent bronchodilation. The results of the study indicate that S-1226 is safe and well tolerated. All adverse events were mild, reversible, and likely due to known side effects of CO2 inhalation.

Trial registration: ClinicalTrials.gov NCT02616770 . Registered on 25 November 2015.

Keywords: Asthma; Biophysical drug; CO2; Perflubron; Phase I; S-1226; Safety.

Figures

Fig. 1
Fig. 1
2010 Consolidated Standards of Reporting Trials (CONSORT) flow diagram. Participant enrollment, allocation, and analysis in S-1226 (4 %, 8 %, and 12 % CO2) and placebo treatment groups. PFOB perflubron
Fig. 2
Fig. 2
Flow diagram of related adverse events (AEs) in S-1226 (4 %, 8 %, and 12 % CO2) and placebo treatment groups based on their relationship to the drug (possibly or remotely). ECG electrocardiogram, WBC white blood cell

References

    1. Global Asthma Network. Global asthma report 2014. . Accessed 3 May 2016.
    1. World Health Organization. Global surveillance, prevention and control of chronic respiratory diseases: a comprehensive approach. 2007. . Accessed 26 Jan 2016.
    1. Statistics Canada. Asthma. 2011. . Accessed 26 Jan 2016.
    1. Public Health Agency of Canada. Fast facts about asthma: data compiled from the 2011 survey on living with chronic diseases in Canada. 2011. . Accessed 3 May Jan 2016.
    1. Ismaila AS, Sayani AP, Marin M, Su Z. Clinical, economic, and humanistic burden of asthma in Canada: a systematic review. BMC Pulm Med. 2013;13:70. doi: 10.1186/1471-2466-13-70.
    1. Global Initiative for Asthma (GINA). 2016 GINA report: global strategy for asthma management and prevention. . Accessed 13 May 2016.
    1. Rowe BH, Sevcik W, Villa-Roel C. Management of severe acute asthma in the emergency department. Curr Opin Crit Care. 2011;17(4):335–41. doi: 10.1097/MCC.0b013e328348bf09.
    1. Wener RR, Bel EH. Severe refractory asthma: an update. Eur Respir Rev. 2013;22(129):227–35. doi: 10.1183/09059180.00001913.
    1. Green FH, Williams DJ, James A, McPhee LJ, Mitchell I, Mauad T. Increased myoepithelial cells of bronchial submucosal glands in fatal asthma. Thorax. 2010;65(1):32–8. doi: 10.1136/thx.2008.111435.
    1. Brenner B, Corbridge T, Kazzi A. Intubation and mechanical ventilation of the asthmatic patient in respiratory failure. Proc Am Thor Soc. 2009;6(4):371–9. doi: 10.1513/pats.P09ST4.
    1. Skov P, Valbjørn O, Danish Climate Study Group (DISG) The “sick” building syndrome in the office environment: the Danish town hall study. Environ Int. 1987;13(4–5):339–49. doi: 10.1016/0160-4120(87)90190-5.
    1. Guyenet PG, Bayliss DA. Neural control of breathing and CO2 homeostasis. Neuron. 2015;87(5):946–61. doi: 10.1016/j.neuron.2015.08.001.
    1. Fisher HK, Hansen TA. Site of action of inhaled 6 per cent carbon dioxide in the lungs of asthmatic subjects before and after exercise. Am Rev Respir Dis. 1976;114(5):861–70.
    1. Brackett CN, Cohen JJ, Schwartz WB. Carbon dioxide titration curve of normal man: effects of increasing degrees of acute hypercapnia on acid-base equilibrium. N Engl J Med. 1965;272(1):6–12. doi: 10.1056/NEJM196501072720102.
    1. Dripps RD, Comroe JH. The respiratory and circulatory response of normal man to inhalation of 7.6 and 10.4 percent CO2 with a comparison of maximal ventilation produced by severe muscular exercise, inhalation of CO2 and maximal voluntary hyperventilation. Am J Physiol. 1947;149(1):43–51.
    1. Astin TW, Barer GR, Shaw JW, Warren PM. The action of carbon dioxide on constricted airways. J Physiol. 1973;235(3):607–23. doi: 10.1113/jphysiol.1973.sp010407.
    1. Duane SF, Weir EK, Stewart RM, Niewoehner DE. Distal airway responses to changes in oxygen and carbon dioxide tensions. Respir Physiol. 1979;38(3):303–11. doi: 10.1016/0034-5687(79)90056-2.
    1. Twort CH, Cameron IR. Effects of PCO2, pH and extracellular calcium on contraction of airway smooth muscle from rats. Respir Physiol. 1986;66(3):259–67. doi: 10.1016/0034-5687(86)90078-2.
    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(7):513–20. doi: 10.1139/y11-052.
    1. van den Elshout FJ, van Herwaarden CL, Folgering HT. Effects of hypercapnia and hypocapnia on respiratory resistance in normal and asthmatic subjects. Thorax. 1991;46(1):28–32. doi: 10.1136/thx.46.1.28.
    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(1):47–63. doi: 10.1081/BIO-200046659.
    1. Hirschl RB, Croce M, Gore D, Wiedemann H, Davis K, Zwischenberger J, et al. Prospective, randomized, controlled pilot study of partial liquid ventilation in adult acute respiratory distress syndrome. Am J Respir Crit Care Med. 2002;165(6):781–7. doi: 10.1164/ajrccm.165.6.2003052.
    1. Riess JG, Krafft MP. Fluorocarbon emulsions as in vivo oxygen delivery systems: background and chemistry. In: Winslow RM, editor. Blood substitutes. Oxford, UK: Academic Press; 2006. pp. 259–75.
    1. Al-Saiedy MR, Nelson DE, Amrein M, Leigh R, Green F. The role of an artificial surfactant in mucous plug clearance in vitro [abstract] 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(2):117–27. doi: 10.1016/j.prrv.2005.03.010.
    1. Leach CL, Greenspan JS, Rubenstein SD, Shaffer TH, Wolfson MR, Jackson JC, et al. Partial liquid ventilation with perflubron in premature infants with severe respiratory distress syndrome. N Engl J Med. 1996;335(11):761–7. doi: 10.1056/NEJM199609123351101.
    1. von der Hardt K, Kandler MA, Brenn G, Scheuerer K, Schoof E, Dötsch J, et al. Comparison of aerosol therapy with different perfluorocarbons in surfactant-depleted animals. Crit Care Med. 2004;32(5):1200–6. doi: 10.1097/01.CCM.0000124876.31138.F6.
    1. Kandler MA, von der Hardt K, Schoof E, Dötsch J, Rascher W. Persistent improvement of gas exchange and lung mechanics by aerosolized perfluorocarbon. Am J Respir Crit Care Med. 2001;164(1):31–5. doi: 10.1164/ajrccm.164.1.2010049.
    1. El Mays T, Choudhury P, Leigh R, Koumoundouros E, Van der Velden J, Shrestha G, Pieron C, Dennis J, Green FHY, Snibson K. Nebulized perflubron and carbon dioxide rapidly dilate constricted airways in an ovine model of allergic asthma. Respir Res. 2014;15:98.
    1. Maresh CM, Armstrong LE, Kavouras SA, Allen GJ, Casa DJ, Whittlesey M, et al. Physiological and psychological effects associated with high carbon dioxide levels in healthy men. Aviat Space Environ Med. 1997;68(1):41–5.
    1. Gellhorn E, Spiesman IG. The influence of hyperpnea and of variations of O2- and CO2-tension in the inspired air upon hearing. Am J Physiol. 1935;112:519–28.
    1. Sechzer P, Egbert L, Linde H, Cooper D, Price H. Effect of carbon dioxide inhalation on arterial pressure, ECG and plasma catecholamines and 17-OH corticosteroids in normal man. J Appl Physiol. 1960;15:454–8.
    1. Schmetterer L, Lexer, Findl O, Graselli U, Eichler HG, Wolzt M. The effect of inhalation of different mixtures of O2 and CO2 on ocular fundus pulsations. Exp Eye Res. 1996;63:351–5. doi: 10.1006/exer.1996.0125.
    1. Reickert CA, Pranikoff T, Overbeck MC, Kazerooni EA, Massey KD, Bartlett RH, et al. The pulmonary and systemic distribution and elimination of perflubron from adult patients treated with partial liquid ventilation. Chest. 2001;119:515–22. doi: 10.1378/chest.119.2.515.
    1. Alliance Pharmaceutical Corp. U.S. Food and Drug Administration New Drug Application NDA 20-091: Imagent GI (perflubron). 1993. Obtained by U.S. Freedom of Information Act request.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa