Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
권호 표지
DOI QR코드

DOI QR Code

A Pilot Randomized Trial of As-Needed Budesonide-Formoterol for Stepping Down Controller Treatment in Moderate Asthma with Complete Remission

  • Received : 2022.03.27
  • Accepted : 2022.05.09
  • Published : 2022.07.31
Download PDF
⟨ Previous Next ⟩

Abstract

Background: The use of low-dose inhaled corticosteroid-formoterol as reliever monotherapy has recently been recommended in the asthma treatment guidelines. However, the efficacy of this treatment strategy has not yet been determined during the stepping-down period in moderate asthma. This study aimed to evaluate the feasibility of reducing treatment to as-needed budesonide-formoterol (BFM) in moderate asthma with complete remission. Methods: We randomly assigned 31 patients (8 males and 23 females with a mean age of 57.2 years) with complete remission of asthma by inhaled BFM (160/4.5 ㎍) twice daily to receive BFM (160/4.5 ㎍) as needed (16 patients), or budesonide (BUD) (200 ㎍) twice daily (15 patients). The study was an open-label study done for 48 weeks, with the primary outcome as the cumulative percentages of patients with treatment failure (asthma exacerbation or loss of asthma control or lack of satisfaction after using medications) in the two groups. Results: Six patients (42%) using as-needed BFM had treatment failure, as compared with three patients (21.4%) using BUD maintenance (hazards ratio for as-needed BFM, 1.77; 95% confidential interval, 0.44-7.12; p=0.41). The changes in forced expiratory volume in 1 second were -211.3 mL with as-needed BFM versus -97.8 mL with BUD maintenance (difference, 113.5 mL; p=0.75) and the change in fractional exhaled nitric oxide was significantly higher in both groups, at 8.68 parts per billion (ppb) in the as-needed BFM group and 2.5 ppb. in the BUD maintenance group (difference, 6.18 ppb; p=0.049). Conclusion: Compared with BUD maintenance, there were no significant differences in treatment failure rate in patients who received as-needed BFM during the stepping down period in moderate asthma. However, they showed reduced lung function and relapsed airway inflammation. The results are limited by imprecision, and further large RCTs are needed.

Keywords

Acknowledgement

The authors thank the patients who participated in the trial, as well as investigators and staff at our sites.

References

  1. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention, updated 2020 [Internet]. Fontana: Global Initiative for Asthma; 2020 [cited 2020 Jan 1]. Available from: http://www.ginasthma.org.
  2. British guideline on the management of asthma [Internet]. London: British Thoracic Society; 2019 [cited 2020 Jan 1]. Available from: https://www.brit-thoracic.org.uk/quality-improvement/guidelines/asthma/.
  3. Mori K, Fujisawa T, Inui N, Hashimoto D, Enomoto N, Nakamura Y, et al. Step-down treatment from medium-dosage of budesonide/formoterol in controlled asthma. Respir Med 2016;119:1-6. https://doi.org/10.1016/j.rmed.2016.08.007
  4. Nakwan N, Perkleang T, Tamsawai T, Taptawee P, Usaha S. A 12-week, randomized, parallel-group, phase III study comparing the efficacy of once-daily budesonide/formoterol turbuhaler (160/4.5 mug/d) with twice-daily budesonide (400 mug/d) during the step-down period in well-controlled asthma. Turk Thorac J 2018;19:66-72.
  5. Kim SH, Lee T, Jang AS, Park CS, Jung JW, Kim MH, et al. Pragmatic randomized controlled trial for stepping down asthma controller treatment in patients controlled with low-dose inhaled corticosteroid and long-acting beta2-agonist: step-down of intervention and grade in moderate asthma study. J Allergy Clin Immunol Pract 2021;9:3638-46. https://doi.org/10.1016/j.jaip.2021.04.042
  6. Bateman ED, Reddel HK, O'Byrne PM, Barnes PJ, Zhong N, Keen C, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med 2018;378:1877-87. https://doi.org/10.1056/NEJMoa1715275
  7. O'Byrne PM, FitzGerald JM, Bateman ED, Barnes PJ, Zhong N, Keen C, et al. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J Med 2018; 378:1865-76. https://doi.org/10.1056/NEJMoa1715274
  8. Beasley R, Holliday M, Reddel HK, Braithwaite I, Ebmeier S, Hancox RJ, et al. Controlled trial of budesonide-formoterol as needed for mild asthma. N Engl J Med 2019;380: 2020-30. https://doi.org/10.1056/NEJMoa1901963
  9. Hardy J, Baggott C, Fingleton J, Reddel HK, Hancox RJ, Harwood M, et al. Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, superiority, randomised controlled trial. Lancet 2019;394:919-28. https://doi.org/10.1016/s0140-6736(19)31948-8
  10. FitzGerald JM, O'Byrne PM, Bateman ED, Barnes PJ, Zheng J, Ivanov S, et al. Safety of as-needed budesonide-formoterol in mild asthma: data from the two phase III SYGMA studies. Drug Saf 2021;44:467-78. https://doi.org/10.1007/s40264-020-01041-z
  11. FitzGerald JM, Arnetorp S, Smare C, Gibson D, Coulton K, Hounsell K, et al. The cost-effectiveness of as-needed budesonide/formoterol versus low-dose inhaled corticosteroid maintenance therapy in patients with mild asthma in the UK. Respir Med 2020;171:106079. https://doi.org/10.1016/j.rmed.2020.106079
  12. Sadatsafavi M, FitzGerald JM, O'Byrne PM, Soliman M, Sriskandarajah N, Vicente C, et al. The cost-effectiveness of as-needed budesonide-formoterol versus low-dose inhaled corticosteroid maintenance therapy in patients with mild asthma in Canada. Allergy Asthma Clin Immunol 2021;17:108. https://doi.org/10.1186/s13223-021-00610-w
  13. Niyatiwatchanchai N, Chaiwong W, Pothirat C. The validity and reliability of the Thai version of the asthma control test. Asian Pac J Allergy Immunol 2021 Jan 2 [Epub]. https://doi.org/10.12932/AP-130820-0940.
  14. Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999;14:902-7. https://doi.org/10.1034/j.1399-3003.1999.14d29.x
  15. Juniper EF, Bousquet J, Abetz L, Bateman ED; GOAL Committee. Identifying 'well-controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire. Respir Med 2006;100:616-21. https://doi.org/10.1016/j.rmed.2005.08.012
  16. Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med 2005; 99:553-8. https://doi.org/10.1016/j.rmed.2004.10.008
  17. Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med 2011; 184:602-15. https://doi.org/10.1164/rccm.9120-11ST
  18. Price DB, Rigazio A, Campbell JD, Bleecker ER, Corrigan CJ, Thomas M, et al. Blood eosinophil count and prospective annual asthma disease burden: a UK cohort study. Lancet Respir Med 2015;3:849-58. https://doi.org/10.1016/S2213-2600(15)00367-7
  19. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014;43:343-73. https://doi.org/10.1183/09031936.00202013
  20. Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, et al. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol 2004;113:59-65. https://doi.org/10.1016/j.jaci.2003.09.008
  21. Schatz M, Sorkness CA, Li JT, Marcus P, Murray JJ, Nathan RA, et al. Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists. J Allergy Clin Immunol 2006;117:549-56. https://doi.org/10.1016/j.jaci.2006.01.011
  22. Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med 1995;152:1107-36. https://doi.org/10.1164/ajrccm.152.3.7663792
  23. Makela MJ, Christensen HN, Karlsson A, Rastogi S, Kettunen K. Health care resource utilization and characteristics of patients with eosinophilic asthma in secondary health care in Finland. Eur Clin Respir J 2018;5:1458560. https://doi.org/10.1080/20018525.2018.1458560
  24. Kieser M, Wassmer G. On the use of the upper confidence limit for the variance from a pilot sample for sample size determination. Biom J 1996;38:941-9. https://doi.org/10.1002/bimj.4710380806
  25. Whitehead AL, Julious SA, Cooper CL, Campbell MJ. Estimating the sample size for a pilot randomised trial to minimise the overall trial sample size for the external pilot and main trial for a continuous outcome variable. Stat Methods Med Res 2016;25:1057-73. https://doi.org/10.1177/0962280215588241
  26. Menzies-Gow A, Bafadhel M, Busse WW, Casale TB, Kocks JW, Pavord ID, et al. An expert consensus framework for asthma remission as a treatment goal. J Allergy Clin Immunol 2020;145:757-65. https://doi.org/10.1016/j.jaci.2019.12.006
  27. Denlinger LC, Phillips BR, Ramratnam S, Ross K, Bhakta NR, Cardet JC, et al. Inflammatory and comorbid features of patients with severe asthma and frequent exacerbations. Am J Respir Crit Care Med 2017;195:302-13. https://doi.org/10.1164/rccm.201602-0419OC
  28. Kerstjens HA, Brand PL, de Jong PM, Koeter GH, Postma DS. Influence of treatment on peak expiratory flow and its relation to airway hyperresponsiveness and symptoms. The Dutch CNSLD Study Group. Thorax 1994;49:1109-15. https://doi.org/10.1136/thx.49.11.1109
  29. Brozek JL, Kraft M, Krishnan JA, Cloutier MM, Lazarus SC, Li JT, et al. Long-acting beta2-agonist step-off in patients with controlled asthma. Arch Intern Med 2012;172:1365-75. https://doi.org/10.1001/archinternmed.2012.3250
  30. Kharitonov SA, Yates DH, Chung KF, Barnes PJ. Changes in the dose of inhaled steroid affect exhaled nitric oxide levels in asthmatic patients. Eur Respir J 1996;9:196-201. https://doi.org/10.1183/09031936.96.09020196
  31. Kharitonov SA, Yates DH, Barnes PJ. Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med 1996;153:454-7. https://doi.org/10.1164/ajrccm.153.1.8542158
  32. Lonnkvist K, Anderson M, Hedlin G, Svartengren M. Exhaled NO and eosinophil markers in blood, nasal lavage and sputum in children with asthma after withdrawal of budesonide. Pediatr Allergy Immunol 2004;15:351-8. https://doi.org/10.1111/j.1399-3038.2004.00165.x
  33. Haahtela T, Tamminen K, Malmberg LP, Zetterstrom O, Karjalainen J, Yla-Outinen H, et al. Formoterol as needed with or without budesonide in patients with intermittent asthma and raised NO levels in exhaled air: a SOMA study. Eur Respir J 2006;28:748-55. https://doi.org/10.1183/09031936.06.00128005
  34. Bose S, Bime C, Henderson RJ, Blake KV, Castro M, DiMango E, et al. Biomarkers of type 2 airway inflammation as predictors of loss of asthma control during step-down therapy for well-controlled disease: the Long-Acting Beta-Agonist Step-Down Study (LASST). J Allergy Clin Immunol Pract 2020;8:3474-81. https://doi.org/10.1016/j.jaip.2020.06.067
  35. Boulet LP. Perception of the role and potential side effects of inhaled corticosteroids among asthmatic patients. Chest 1998;113:587-92. https://doi.org/10.1378/chest.113.3.587
  36. Sovani MP, Whale CI, Oborne J, Cooper S, Mortimer K, Ekstrom T, et al. Poor adherence with inhaled corticosteroids for asthma: can using a single inhaler containing budesonide and formoterol help? Br J Gen Pract 2008;58: 37-43. https://doi.org/10.3399/bjgp08X263802