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Open Access 01-12-2022 | Bronchial Asthma | Study protocol

Symptom-driven inhaled corticosteroid/long-acting beta-agonist therapy for adult patients with asthma who are non-adherent to daily maintenance inhalers: a study protocol for a pragmatic randomized controlled trial

Authors: James G. Krings, Kaitlyn M. Wojcik, Vanessa Chen, Tejas C. Sekhar, Kelly Harris, Abigail Zulich, Kaharu Sumino, Ross Brownson, Eric Lenze, Mario Castro

Published in: Trials | Issue 1/2022

Abstract

Background

While inhaled corticosteroids (ICS) are considered the essential foundation of most asthma therapy, ICS inhaler nonadherence is a notoriously common problem and a significant cause of asthma-related morbidity. Partially acknowledging the problem of nonadherence, international organizations recently made paradigm-shifting recommendations that all patients with mild-to-moderate persistent asthma be considered for symptom-driven ICS-containing inhalers rather than relying on adherence to traditional maintenance ICS inhalers and symptom-driven short-acting beta-agonists (SABA). With this new approach, asthma patients are at least exposed to the important anti-inflammatory effects of ICS-containing inhalers when their symptom reliever inhaler is deployed due to acute symptoms.

Methods

This study will (Part 1) complete a pragmatic randomized controlled trial to evaluate if an inhaler strategy that utilizes symptom-driven ICS inhalers is particularly beneficial in maintenance ICS inhaler non-adherent asthma patients, and (Part 2) use a dissemination and implementation (D&I) science conceptual framework to better understand patients’ and providers’ views of inhaler nonadherence. This study, which will have an option of taking place entirely remotely, will use a Food and Drug Administration (FDA)-approved electronic sensor (Hailie® sensor) to monitor inhaler adherence and includes semi-structured interviews guided by the Consolidated Framework for Implementation Research (CFIR).

Discussion

This study is assessing the problem of nonadherence using a D&I implementation science research lens while testing a new inhaler approach to potentially ameliorate the detrimental consequences of maintenance inhaler nonadherence. We hypothesize that the use of a symptom-driven ICS/LABA management strategy, as compared to traditional maintenance ICS treatment and symptom-driven SABA, will lead to improved adherence to an asthma treatment strategy, decreased asthma-related morbidity, less cumulative ICS exposure, and greater patient satisfaction with an inhaler approach.

Trial registration

ClinicalTrials.gov NCT05111262. Registered on November 8, 2021.

Available only for authorised users

To T, Stanojevic S, Moores G, Gershon AS, Bateman ED, Cruz AA, et al. Global asthma prevalence in adults: findings from the cross-sectional world health survey. BMC Public Health. 2012;12(1):204.PubMedPubMedCentralCrossRef

Masoli M, Fabian D, Holt S, Beasley R. The global burden of asthma: executive summary of the GINA Dissemination Committee Report. Allergy. 2004;59(5):469–78.PubMedCrossRef

Reddel HK, FitzGerald JM, Bateman ED, Bacharier LB, Becker A, Brusselle G, et al. GINA 2019: a fundamental change in asthma management. Eur Respir J. 2019;53(6):1901046.PubMedCrossRef

Slejko JF, Ghushchyan VH, Sucher B, Globe DR, Lin SL, Globe G, et al. Asthma control in the United States, 2008-2010: Indicators of poor asthma control. J Allergy Clin Immunol. 2014;133(6):1579–87.PubMedCrossRef

Meltzer EO, Blaiss MS, Nathan RA, Doherty DE, Murphy KR, Stoloff SW. Asthma burden in the United States: Results of the 2009 Asthma Insight and Management survey. Allergy Asthma Proc. 2012;33(1):36–46.PubMedCrossRef

Fuhlbrigge A, Reed ML, Stempel DA, Ortega HO, Fanning K, Stanford RH. The status of asthma control in the U.S. adult population. Allergy Asthma Proc. 2009;30(5):529–33.PubMedCrossRef

Fuhlbrigge AL, Adams RJ, Guilbert TW, Grant E, Lozano P, Janson SL, et al. The burden of asthma in the United States: level and distribution are dependent on interpretation of the national asthma education and prevention program guidelines. Am J Respir Crit Care Med. 2002;166(8):1044–9.PubMedCrossRef

Zahran HS, Bailey CM, Damon SA, Garbe PL, Breysse PN. Vital Signs: Asthma in Children - United States, 2001-2016. MMWR Morb Mortal Wkly Rep. 2018;67(5):149–55.PubMedPubMedCentralCrossRef

AsthmaStats 2019. CDC. 2019.

10.

Williams LK, Pladevall M, Xi H, Peterson EL, Joseph C, Lafata JE, et al. Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma. J Allergy Clin Immunol. 2004;114(6):1288–93.PubMedCrossRef

11.

Bender BG, Bender SE. Patient-identified barriers to asthma treatment adherence: responses to interviews, focus groups, and questionnaires. Immunol Allergy Clin North Am. 2005;25(1):107–30.PubMedCrossRef

12.

Rand CS, Wise RA. Measuring Adherence to Asthma Medication Regimens. Am J Respir Crit Care Med. 1994;149(2_pt_2):S69–76.PubMedCrossRef

13.

Normansell R, Kew KM, Stovold E. Interventions to improve adherence to inhaled steroids for asthma. Cochrane Database Syst Rev. 2017, 2017;4.

14.

Barnes CB, Ulrik CS. Asthma and Adherence to Inhaled Corticosteroids: Current Status and Future Perspectives. Respir Care. 2015;60(3):455–68.PubMedCrossRef

15.

Blake K, v. Improving adherence to asthma medications. Curr Opin Pulm Med. 2017;23(1):62–70.PubMedCrossRef

16.

Bender B, Milgrom H, Rand C. Nonadherence in Asthmatic Patients: Is there a Solution to the Problem ? Ann Allergy Asthma Immunol. 1997;79(3):177–87.PubMedCrossRef

17.

Halm EA, Mora P, Leventhal H. No symptoms, no asthma: the acute episodic disease belief is associated with poor self-management among inner-city adults with persistent asthma. Chest. 2006; [cited 2022 Oct 2];129(3):573–80. Available from: https://pubmed.ncbi.nlm.nih.gov/16537854/.

18.

Horne R, Chapman SCE, Parham R, Freemantle N, Forbes A, Cooper V. Understanding Patients’ Adherence-Related Beliefs about Medicines Prescribed for Long-Term Conditions: A Meta-Analytic Review of the Necessity-Concerns Framework. PLoS One. 2013; [cited 2022 Oct 2];8(12). Available from: /pmc/articles/PMC3846635/.

19.

Matsunaga K, Hamada K, Oishi K, Yano M, Yamaji Y, Hirano T. Factors Associated with Physician-Patient Discordance in the Perception of Asthma Control. J Allergy Clin Immunol Pract. 2019; [cited 2022 Oct 2];7(8):2634–41. Available from: https://pubmed.ncbi.nlm.nih.gov/31100555/.

20.

Nelsen LM, Kosinski M, Rizio AA, Jacques L, Schatz M, Stanford RH, et al. A structured review evaluating content validity of the Asthma Control Test, and its consistency with U.S. guidelines and patient expectations for asthma control. 2020 [cited 2022 Oct 2];59(3):628–37. Available from: https://www.tandfonline.com/doi/abs/10.1080/02770903.2020.1861624

21.

O’Byrne P, Fabbri LM, Pavord ID, Papi A, Petruzzelli S, Lange P. Asthma progression and mortality: the role of inhaled corticosteroids. Eur Respir J. 2019;54(1):1900491.PubMedPubMedCentralCrossRef

22.

Blais L, Suissa S, Boivin JF, Ernst P. First treatment with inhaled corticosteroids and the prevention of admissions to hospital for asthma. Thorax. 1998;53(12):1025–9.PubMedPubMedCentralCrossRef

23.

Pauwels RA, Pedersen S, Busse WW, Tan WC, Chen YZ, Ohlsson SV, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003;361(9363):1071–6.PubMedCrossRef

24.

Haahtela T, Järvinen M, Kava T, Kiviranta K, Koskinen S, Lehtonen K, et al. Comparison of a β ₂ -Agonist, Terbutaline, with an Inhaled Corticosteroid, Budesonide, in Newly Detected Asthma. N Engl J Med. 1991;325(6):388–92.PubMedCrossRef

25.

Gamble J, Stevenson M, McClean E, Heaney LG. The Prevalence of Nonadherence in Difficult Asthma. Am J Respir Crit Care Med. 2009;180(9):817–22.PubMedCrossRef

26.

Levy ML. The national review of asthma deaths: what did we learn and what needs to change? Breathe. 2015;11(1):14–24.PubMedPubMedCentralCrossRef

27.

Engelkes M, Janssens HM, de Jongste JC, Sturkenboom MCJM, Verhamme KMC. Medication adherence and the risk of severe asthma exacerbations: a systematic review. Eur Respir J. 2015;45(2):396–407.PubMedCrossRef

28.

Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-Dose Inhaled Corticosteroids and the Prevention of Death from Asthma. N Engl J Med. 2000;343(5):332–6.PubMedCrossRef

29.

Williams LK, Peterson EL, Wells K, Ahmedani BK, Kumar R, Burchard EG, et al. Quantifying the proportion of severe asthma exacerbations attributable to inhaled corticosteroid nonadherence. J Allergy Clin Immunol. 2011;128(6):1185–1191.e2.PubMedPubMedCentralCrossRef

30.

Becker AB, Abrams EM. Asthma guidelines: the Global Initiative for Asthma in relation to national guidelines. Curr Opin Allergy Clin Immunol. 2017;17(2):99–103.PubMedCrossRef

31.

Reddy AP, Gupta MR. Management of Asthma: The Current US and European Guidelines; 2014. p. 81–103.

32.

Federal Register: Request for Information on “Update on Selected Topics in Asthma Management 2020: A Report From the National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC) Expert Panel Report 4 (EPR-4) Working Group”. [cited 2022 Apr 10]. Available from: https://www.federalregister.gov/documents/2019/12/02/2019-26017/request-for-information-on-update-on-selected-topics-in-asthma-management-2020-a-report-from-the

33.

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(20):1865–76.PubMedCrossRef

34.

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(20):1877–87.PubMedCrossRef

35.

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(21):2020–30.PubMedCrossRef

36.

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(10202):919–28.PubMedCrossRef

37.

What’s new in pulmonary and critical care medicine - UpToDate. [cited 2022 Apr 10]. Available from: https://www.uptodate.com/contents/whats-new-in-pulmonary-and-critical-care-medicine

38.

Dy T, Lewis EM, Murugan V, Gehlert S, Taylor J, Garbutt J, et al. Caregiver and pediatric provider perspectives on symptom-based inhaled corticosteroid therapy in asthma. Respir Med. 2018;137:201–5.PubMedCrossRef

39.

Fehrenbach H, Wagner C, Wegmann M. Airway remodeling in asthma: what really matters. Cell Tissue Res. 2017;367(3):551–69.PubMedPubMedCentralCrossRef

40.

Al-Muhsen S, Johnson JR, Hamid Q. Remodeling in asthma. J Allergy Clin Immunol. 2011;128(3):451–62.PubMedCrossRef

41.

Castro-Rodriguez JA, Saglani S, Rodriguez-Martinez CE, Oyarzun MA, Fleming L, Bush A. The relationship between inflammation and remodeling in childhood asthma: A systematic review. Pediatr Pulmonol. 2018;53(6):824–35.PubMedCrossRef

42.

Kaye L, Theye B, Smeenk I, Gondalia R, Barrett MA, Stempel DA. Changes in medication adherence among patients with asthma and COPD during the COVID-19 pandemic. J Allergy Clin Immunol Pract. 2020;8(7):2384–5.PubMedPubMedCentralCrossRef

43.

de Keyser HEH, Kaye L, Anderson WC, Gondalia R, Theye B, Szefler SJ, et al. Electronic medication monitors help determine adherence subgroups in asthma. Respir Med. 2020;164:105914.PubMedCrossRef

44.

Anderson WC, Gondalia R, Hoch HE, Kaye L, Barrett M, Szefler SJ, et al. Assessing asthma control: comparison of electronic-recorded short-acting beta-agonist rescue use and self-reported use utilizing the asthma control test. J Asthma. 2021;58(2):271–5.PubMedCrossRef

45.

Chen J, Kaye L, Tuffli M, Barrett MA, Jones-Ford S, Shenouda T, et al. Passive Monitoring of Short-Acting Beta-Agonist Use via Digital Platform in Patients With Chronic Obstructive Pulmonary Disease: Quality Improvement Retrospective Analysis. JMIR Form Res. 2019;3(4):e13286.PubMedPubMedCentralCrossRef

46.

Anderson WC, Gondalia R, Hoch HE, Kaye L, Szefler SJ, Stempel DA. Screening for inhalation technique errors with electronic medication monitors. J Allergy Clin Immunol Pract. 2019;7(6):2065–7.PubMedCrossRef

47.

Kenyon CC, Gruschow SM, Quarshie WO, Griffis H, Leach MC, Zorc JJ, et al. Controller adherence following hospital discharge in high risk children: A pilot randomized trial of text message reminders. J Asthma. 2019;56(1):95–103.PubMedCrossRef

48.

Hoch H, Kempe A, Brinton J, Szefler S. Feasibility of medication monitoring sensors in high risk asthmatic children. J Asthma. 2019;56(3):270–2.PubMedCrossRef

49.

Sumino K, Locke ER, Magzamen S, Gylys-Colwell I, Humblet O, Nguyen HQ, et al. Use of a Remote Inhaler Monitoring Device to Measure Change in Inhaler Use with Chronic Obstructive Pulmonary Disease Exacerbations. J Aerosol Med Pulm Drug Deliv. 2018;31(3):191–8.PubMedCrossRef

50.

Merchant RK, Inamdar R, Quade RC. Effectiveness of Population Health Management Using the Propeller Health Asthma Platform: A Randomized Clinical Trial. J Allergy Clin Immunol Pract. 2016;4(3):455–63.PubMedCrossRef

51.

van Sickle D, Magzamen S, Truelove S, Morrison T. Remote Monitoring of Inhaled Bronchodilator Use and Weekly Feedback about Asthma Management: An Open-Group, Short-Term Pilot Study of the Impact on Asthma Control. PLoS One. 2013;8(2):e55335.PubMedPubMedCentralCrossRef

52.

Su JG, Barrett MA, Henderson K, Humblet O, Smith T, Sublett JW, et al. Feasibility of Deploying Inhaler Sensors to Identify the Impacts of Environmental Triggers and Built Environment Factors on Asthma Short-Acting Bronchodilator Use. Environ Health Perspect. 2017;125(2):254–61.PubMedCrossRef

53.

van Noord JA, Smeets JJ, Raaijmakers JAM, Bommer AM, Maesen FPV. Salmeterol versus formoterol in patients with moderately severe asthma: onset and duration of action. Eur Respir J. 1996;9(8):1684–8.PubMedCrossRef

54.

Lindberg A, Szalai Z, Pullerits T, Radeczky E. Fast onset of effect of budesonide/formoterol versus salmeterol/fluticasone and salbutamol in patients with chronic obstructive pulmonary disease and reversible airway obstruction. Respirology. 2007;12(5):732–9.PubMedCrossRef

55.

Cote C, Pearle JL, Sharafkhaneh A, Spangenthal S. Faster onset of action of formoterol versus salmeterol in patients with chronic obstructive pulmonary disease: A multicenter, randomized study. Pulm Pharmacol Ther. 2009;22(1):44–9.PubMedCrossRef

56.

Weinstein AG. The potential of asthma adherence management to enhance asthma guidelines. Ann Allergy Asthma Immunol. 2011;106(4):283–91.PubMedCrossRef

57.

Vasbinder E, Belitser S, Souverein P, van Dijk L, Vulto AG, van den Bemt PMLA. Non-adherence to inhaled corticosteroids and the risk of asthma exacerbations in children. Patient Prefer Adherence. 2016;531.

58.

Bender BG. Nonadherence to Asthma Treatment: Getting Unstuck. J Allergy Clin Immunol Pract. 2016;4(5):849–51.PubMedCrossRef

59.

Heaney L, Lindsay J. Nonadherence in difficult asthma – facts, myths, and a time to act. Patient Prefer Adherence. 2013;329.

60.

Cochrane MG, Bala MV, Downs KE, Mauskopf J, Ben-Joseph RH. Inhaled Corticosteroids for Asthma Therapy. Chest. 2000;117(2):542–50.PubMedCrossRef

61.

Baddar S, Jayakrishnan B, Al-Rawas OA. Asthma control: importance of compliance and inhaler technique assessments. J Asthma. 2014;51(4):429–34.PubMedCrossRef

62.

McDonald VM, Yorke J. herence in severe asthma: time to get it right. Eur Respir J. 2017;50(6):1702191.PubMedCrossRef

63.

Moorman JE, Akinbami LJ, Bailey CM, Zahran HS, King ME, Johnson CA, et al. National surveillance of asthma: United States, 2001-2010. Vital Health Stat. 2012;3(35):1–58.

64.

Nurmagambetov T, Kuwahara R, Garbe P. The Economic Burden of Asthma in the United States, 2008–2013. Ann Am Thorac Soc. 2018;15(3):348–56.PubMedCrossRef

65.

Nunes C, Pereira AM, Morais-Almeida M. Asthma costs and social impact. Asthma Res Pract. 2017;3(1):1.PubMedPubMedCentralCrossRef

66.

Kozyrskyj AL, Kendall GE, Jacoby P, Sly PD, Zubrick SR. Association Between Socioeconomic Status and the Development of Asthma: Analyses of Income Trajectories. Am J Public Health. 2010;100(3):540–6.PubMedPubMedCentralCrossRef

67.

Cope SF, Ungar WJ, Glazier RH. Socioeconomic factors and asthma control in children. Pediatr Pulmonol. 2008;43(8):745–52.PubMedPubMedCentralCrossRef

68.

Hedlund U. Socio-economic status is related to incidence of asthma and respiratory symptoms in adults. Eur Respir J. 2006;28(2):303–410.PubMedCrossRef

69.

Latry P, Pinet M, Labat A, Magand J, Peter C, Robinson P, et al. Adherence to anti-inflammatory treatment for asthma in clinical practice in France. Clin Ther. 2008;30:1058–68.PubMedCrossRef

70.

Mendes ES, Rebolledo P, Campos M, Wanner A. Immediate Antiinflammatory Effects of Inhaled Budesonide in Patients with Asthma. Ann Am Thorac Soc. 2014;11(5):706–11.PubMedCrossRef

71.

Lazarus SC. On-Demand versus Maintenance Inhaled Treatment in Mild Asthma. N Engl J Med. 2018;378(20):1940–2.PubMedCrossRef

Title: Symptom-driven inhaled corticosteroid/long-acting beta-agonist therapy for adult patients with asthma who are non-adherent to daily maintenance inhalers: a study protocol for a pragmatic randomized controlled trial
Authors: James G. Krings
Kaitlyn M. Wojcik
Vanessa Chen
Tejas C. Sekhar
Kelly Harris
Abigail Zulich
Kaharu Sumino
Ross Brownson
Eric Lenze
Mario Castro
Publication date: 01-12-2022
Publisher: BioMed Central
Keyword: Bronchial Asthma
Published in: Trials / Issue 1/2022
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-022-06916-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Symptom-driven inhaled corticosteroid/long-acting beta-agonist therapy for adult patients with asthma who are non-adherent to daily maintenance inhalers: a study protocol for a pragmatic randomized controlled trial

Abstract

Background

Methods

Discussion

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Discussion

Trial registration

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