Details about the study

The primary outcome will be yearly asthma exacerbation rates compared across the three intervention arms to the control arm. Secondary outcomes will be asthma control and asthma quality of life.   

Many studies have demonstrated the efficacy of inhaled corticosteroids (ICS) as part of rescue therapy. These studies included both ICS plus a short acting beta agonist (ICS SABA)[1-3 - see References section] as well as an ICS plus a long-acting beta agonist (ICS LABA).[4-6] Across efficacy and pragmatic trials, these approaches have reduced exacerbations from 7% to 50%. 

Recently the Global Initiative for Asthma (GINA)[7] added ICS LABA therapy for rescue therapy as the preferred approach in steps 3 and 4 as did the new US guidelines released in December, 2020.[8] Based on recent studies, GINA recently expanded ICS LABA to all steps as rescue therapy.[7]  Neither guideline has officially addressed ICS SABA rescue therapy, though a number of randomized controlled trials showed positive results.[1, 2, 9]

The PREPARE study using ICS SABA in participants of African American/Black race or Hispanic/Latinx ethnicity [3] demonstrated a 13% reduction in exacerbations, improved ACT scores by over 3 points and ASUI scores by almost 1 point at the population level (both greater than the patient MID) and decreased lost days of school or work by 20%, all statistically significant.[10]

Based on the available evidence, the iTREAT study is examining the role of rescue ICS in improving asthma control. Rescue ICS includes SMART (Single Maintenance And Reliever Therapy) or PARTICS (Patient Activated Reliever Trigger Inhaled Corticosteroids). Patients with their clinicians will decide which approach works best for them.

SMART: Patients already prescribed Symbicort or Dulera will stay on those; patients on another inhaler have their prescription changed to Symbicort. Patients are instructed to take a puff of Symbicort twice a day and as needed when they have symptoms. Patients receive 2 Symbicort inhalers. One inhaler should be used twice a day every day as a controller medicine. The other should be used INSTEAD of their reliever inhaler.

For PARTICS, patients can stay on their current controller medicine. They will receive a prescription for an extra ICS, and should use that inhaler puff for puff every time they use their reliever inhaler. If patients use a nebulizer for their reliever medicine, they take 5 puffs of their PARTICS ICS every time they use their nebulizer.

We think patients will choose SMART if they are already prescribed Symbicort or Dulera or are willing to switch to Symbicort from their current ICS. We think patients will choose PARTICS if they use a nebulizer, are unable to afford switching to Symbicort or Dulera (or their insurance will not cover the cost), or are not prescribed Symbicort or Dulera and prefer to keep taking their current ICS. 

Azithromycin (AZ), an azalide macrolide antibiotic with anti-inflammatory properties, has shown efficacy in reducing asthma exacerbations,[11, 12] though who will respond best to treatment is not clear.[13] Some individuals treated with AZ have been able to stop ICS use for prolonged periods,[14, 15] remaining symptom-free for years after completing [6-12] months of AZ.[14, 15] The mechanism of action for macrolide therapy for asthma is currently unknown. Two mechanisms have been postulated: (1) macrolides have intrinsic immunomodulatory/anti-inflammatory activity that may be more specific for neutrophil-mediated inflammation;[16] and (2) macrolides have anti-microbial activity against persistent intracellular infections, particularly mycoplasma and chlamydia organisms.[17-20] Both mechanisms may be at play in reducing asthma severity across individuals.[16] This study will attempt to determine who responds to AZ treatment.  

This study will use Asthma Symptom Monitoring (ASM), which studies show raises patients’ awareness of worsening symptoms earlier so that treatment can be adjusted in time to avoid exacerbations.[21-25]   

1. Papi A, Canonica GW, Maestrelli P, et al. Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med. May 17 2007;356(20):2040-52. doi:10.1056/NEJMoa063861
2. Papi A, Caramori G, Adcock IM, Barnes PJ. Rescue treatment in asthma. More than as-needed bronchodilation. Chest. Jun 2009;135(6):1628-1633. doi:10.1378/chest.08-2536
3. Israel E, Cardet JC, Carroll JK, et al. Reliever-Triggered Inhaled Glucocorticoid in Black and Latinx Adults with Asthma. N Engl J Med. Feb 26 2022;386(16):1505-1518. doi:10.1056/NEJMoa2118813
4. Papi A, Corradi M, Pigeon-Francisco C, et al. Beclometasone-formoterol as maintenance and reliever treatment in patients with asthma: a double-blind, randomised controlled trial. Lancet Respir Med. Mar 2013;1(1):23-31. doi:10.1016/S2213-2600(13)70012-2
5. Kew KM, Karner C, Mindus SM, Ferrara G. Combination formoterol and budesonide as maintenance and reliever therapy versus combination inhaler maintenance for chronic asthma in adults and children. Cochrane Database Syst Rev. Dec 16 2013;(12):CD009019. doi:10.1002/14651858.CD009019.pub2
6. Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med. Nov 13 1997;337(20):1405-11. doi:10.1056/NEJM199711133372001
7. Global Initiative for Asthma. Global strategy for asthma management and prevention 2021 report. Accessed October 2, 2021. https://ginasthma.org/gina-reports/
8. Expert Panel Working Group of the National Heart Lung and Blood Institute, National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), Cloutier MM, et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. Dec 2020;146(6):1217-1270. doi:10.1016/j.jaci.2020.10.003
9. Calhoun WJ, Ameredes BT, King TS, et al. Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial. JAMA. Sep 12 2012;308(10):987-97. doi:10.1001/2012.jama.10893
10. Israel E, Cardet JC, Carroll JK, et al. A randomized, open-label, pragmatic study to assess reliever-triggered inhaled corticosteroid in African American/Black and Hispanic/Latinx adults with asthma: design and methods of the PREPARE trial. Contemporary Clinical Trials. 2021;101, 106246doi:10.1016/j.cct.2020.106246
11. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. Aug 12 2017;390(10095):659-668. doi:10.1016/S0140-6736(17)31281-3
12. Hiles SA, McDonald VM, Guilhermino M, Brusselle GG, Gibson PG. Does maintenance azithromycin reduce asthma exacerbations? An individual participant data meta-analysis. Eur Respir J. Sep 12 2019:DOI: 10.1183/13993003.01381-2019. doi:10.1183/13993003.01381-2019
13. Global Initiative for Asthma. Difficult-to-treat and severe asthma in adolescent and adult patients. Diagnosis and management. Accessed October 2, 2021. https://ginasthma.org/gina-reports/gina-2020-full-report_-final-_wms
14. Hahn DL, Grasmick M, Hetzel S, Yale S. Azithromycin for bronchial asthma in adults: an effectiveness trial. J Am Board Fam Med. Jul-Aug 2012;25(4):442-59. doi:10.3122/jabfm.2012.04.110309
15. Wagshul FA, Brown DT, Schultek NM, Hahn DL. Outcomes of Antibiotics in Adults with "Difficult to Treat" Asthma or the Overlap Syndrome. J Asthma Allergy. 2021;14:703-712. doi:10.2147/JAA.S313480
16. Steel HC, Theron AJ, Cockeran R, Anderson R, Feldman C. Pathogen- and host-directed anti-inflammatory activities of macrolide antibiotics. Mediators Inflamm. 2012;2012:584262. doi:10.1155/2012/584262
17. Kraft M, Cassell GH, Henson JE, et al. Detection of Mycoplasma pneumoniae in the airways of adults with chronic asthma. Am J Respir Crit Care Med. Sep 1998;158(3):998-1001. doi:10.1164/ajrccm.158.3.9711092
18. Wood PR, Hill VL, Burks ML, et al. Mycoplasma pneumoniae in children with acute and refractory asthma. Ann Allergy Asthma Immunol. May 2013;110(5):328-334 e1. doi:10.1016/j.anai.2013.01.022
19. Essilfie AT, Horvat JC, Kim RY, et al. Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma. Thorax. May 2015;70(5):458-67. doi:10.1136/thoraxjnl-2014-206067
20. Hansbro PM, Starkey MR, Mattes J, Horvat JC. Pulmonary immunity during respiratory infections in early life and the development of severe asthma. Ann Am Thorac Soc. Dec 2014;11 Suppl 5:S297-302. doi:10.1513/AnnalsATS.201402-086AW
21. Lang DM. New asthma guidelines emphasize control, regular monitoring. Cleveland Clinic journal of medicine. 2008;75(9):641-653. 
22. van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis c and advanced hepatic fibrosis. JAMA. 2012;308(24):2584-2593. doi:10.1001/jama.2012.144878
23. Shingo S, Zhang J, Reiss T. Correlation of airway obstruction and patient-reported endpoints in clinical studies. European Respiratory Journal. 2001;17(2):220-224. 
24. Teeter JG, Bleecker ER. Relationship between airway obstruction and respiratory symptoms in adult asthmatics. CHEST Journal. 1998;113(2):272-277. 
25. Braido F. Failure in asthma control: reasons and consequences. Scientifica. 2013;2013