The SYGMA programme of phase 3 trials to evaluate the efficacy and safety of budesonide/formoterol given 'as needed' in mild asthma: study protocols for two randomised controlled trials

Paul M O'Byrne, J Mark FitzGerald, Nanshan Zhong, Eric Bateman, Peter J Barnes, Christina Keen, Gun Almqvist, Kristine Pemberton, Carin Jorup, Stefan Ivanov, Helen K Reddel, Paul M O'Byrne, J Mark FitzGerald, Nanshan Zhong, Eric Bateman, Peter J Barnes, Christina Keen, Gun Almqvist, Kristine Pemberton, Carin Jorup, Stefan Ivanov, Helen K Reddel

Abstract

Background: In many patients with mild asthma, the low frequency of symptoms and the episodic nature of exacerbations make adherence to regular maintenance treatment difficult. This often leads to over-reliance on short-acting β2-agonist (SABA) reliever medication and under-treatment of the underlying inflammation, with poor control of asthma symptoms and increased risk of exacerbations. The use of budesonide/formoterol 'as needed' in response to symptoms may represent an alternative treatment option for patients with mild asthma.

Methods/design: The SYmbicort Given as needed in Mild Asthma (SYGMA) programme consists of two 52-week, double-blind, randomised, multicentre, parallel-group, phase 3 trials of patients aged 12 years and older with a clinical diagnosis of asthma for at least 6 months, who would qualify for treatment with regular inhaled corticosteroids (ICS). SYGMA1 aims to recruit 3750 patients who will be randomised to placebo twice daily (bid) plus as-needed budesonide/formoterol 160/4.5 μg, placebo bid plus as-needed terbutaline 0.4 mg, or budesonide 200 μg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate the superiority of as-needed budesonide/formoterol over as-needed terbutaline for asthma control, as measured by well-controlled asthma weeks; a secondary objective is to establish the noninferiority of as-needed budesonide/formoterol versus maintenance budesonide plus as-needed terbutaline using the same outcome measure. SYGMA2 aims to recruit 4114 patients who will be randomised to placebo bid plus as-needed budesonide/formoterol 160/4.5 μg, or budesonide 200 μg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate the noninferiority of as-needed budesonide/formoterol over budesonide bid plus as-needed terbutaline as measured by the annualised severe exacerbation rate. In both studies, use of all blinded study inhalers will be recorded electronically using Turbuhaler® Usage Monitors.

Discussion: Given the known risks of mild asthma, and known poor adherence with regular inhaled corticosteroids, the results of the SYGMA programme will help to determine the efficacy and safety of as-needed budesonide/formoterol therapy in mild asthma. Patient recruitment is complete, and completion of the phase 3 studies is planned in 2017.

Trial registration: ClinicalTrials.gov identifiers: NCT02149199 SYGMA1 and NCT02224157 SYGMA2. Registered on 16 May 2014 and 19 August 2014, respectively.

Keywords: As-needed; Asthma control; Budesonide/formoterol; Exacerbations; Mild asthma; Prn; Rescue inhaler; SYGMA.

Figures

Fig. 1
Fig. 1
SYGMA1 study design. bid twice daily, E enrolment, EM electronic monitoring twice daily (eDiary), FU follow-up phone call, TUM Turbuhaler® Usage Monitor, recording use of each blinded study inhalers. †Corresponds to the terbutaline Turbuhaler® 0.4 mg, with regards to the dose delivered
Fig. 2
Fig. 2
SYGMA2 study design. bid twice daily, E enrolment, FU follow-up phone call, TUM Turbuhaler® Usage Monitor, recording use of each blinded study inhalers. †Corresponds to the terbutaline Turbuhaler® 0.4 mg, with regards to the dose delivered

References

    1. Dusser D, Montani D, Chanez P, de Blic J, Delacourt C, Deschildre A, et al. Mild asthma: an expert review on epidemiology, clinical characteristics and treatment recommendations. Allergy. 2007;62(6):591–604. doi: 10.1111/j.1398-9995.2007.01394.x.
    1. Global Strategy for Asthma Management and Prevention. Updated 2015. Global Initiative for Asthma. 2015. . Accessed 13 Oct 2015.
    1. 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. doi: 10.1016/S0140-6736(03)12891-7.
    1. Patel M, Pilcher J, Pritchard A, Perrin K, Travers J, Shaw D, et al. Efficacy and safety of maintenance and reliever combination budesonide-formoterol inhaler in patients with asthma at risk of severe exacerbations: a randomised controlled trial. Lancet Respir Med. 2013;1(1):32–42. doi: 10.1016/S2213-2600(13)70007-9.
    1. Barnes CB, Ulrik CS. Asthma and adherence to inhaled corticosteroids: current status and future perspectives. Respir Care. 2015;60(3):455–68. doi: 10.4187/respcare.03200.
    1. 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. doi: 10.1056/NEJM200008033430504.
    1. Why asthma still kills: The National Review of Asthma Deaths (NRAD). Royal College of Physicians. 2014. . Accessed 13 Oct 2015.
    1. Suissa S, Ernst P, Kezouh A. Regular use of inhaled corticosteroids and the long term prevention of hospitalisation for asthma. Thorax. 2002;57(10):880–4. doi: 10.1136/thorax.57.10.880.
    1. 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):1185-91.e2. doi: 10.1016/j.jaci.2011.09.011.
    1. Rabe KF, Adachi M, Lai CK, Soriano JB, Vermeire PA, Weiss KB, et al. Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys. J Allergy Clin Immunol. 2004;114(1):40–7. doi: 10.1016/j.jaci.2004.04.042.
    1. Papi A, Canonica GW, Maestrelli P, Paggiaro P, Olivieri D, Pozzi E, et al. Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med. 2007;356(20):2040–52. doi: 10.1056/NEJMoa063861.
    1. Calhoun WJ, Ameredes BT, King TS, Icitovic N, Bleecker ER, Castro M, 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. 2012;308(10):987–97. doi: 10.1001/2012.jama.10893.
    1. 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(4):748–55. doi: 10.1183/09031936.06.00128005.
    1. Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet. 2006;368(9537):744–53. doi: 10.1016/S0140-6736(06)69284-2.
    1. Papi A, Caramori G, Adcock IM, Barnes PJ. Rescue treatment in asthma. More than as-needed bronchodilation. Chest. 2009;135(6):1628–33. doi: 10.1378/chest.08-2536.
    1. Beasley R, Weatherall M, Shirtcliffe P, Hancox R, Reddel HK. Combination corticosteroid/beta-agonist inhaler as reliever therapy: a solution for intermittent and mild asthma? J Allergy Clin Immunol. 2014;133(1):39–41. doi: 10.1016/j.jaci.2013.10.053.
    1. Global Strategy for Asthma Management and Prevention. Updated 2012. Global Initiative for Asthma. 2012. . Accessed 13 Oct 2015.
    1. Gradinarsky L, Lööf T, editors. Inhalation adherence monitoring using smart electronic add-on device. MobiHealth: 4th International Conference on Wireless Mobile Communication and Healthcare – ‘Transforming healthcare through innovations in mobile and wireless technologies’. Athens: European Union Digital Library; 2014.
    1. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med. 2004;170(8):836–44. doi: 10.1164/rccm.200401-033OC.
    1. Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009;180(1):59–99. doi: 10.1164/rccm.200801-060ST.
    1. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319–38. doi: 10.1183/09031936.05.00034805.
    1. Pilcher J, Shirtcliffe P, Patel M, McKinstry S, Cripps T, Weatherall M, et al. Three-month validation of a turbuhaler electronic monitoring device: implications for asthma clinical trial use. BMJ Open Resp Res. 2015;2:e000097. doi: 10.1136/bmjresp-2015-000097.
    1. Barbour RS. The role of qualitative research in broadening the ‘evidence base’ for clinical practice. J Eval Clin Pract. 2000;6(2):155–63. doi: 10.1046/j.1365-2753.2000.00213.x.
    1. O’Byrne P, Cuddy L, Taylor DW, Birch S, Morris J, Syrotuik J. Efficacy and cost benefit of inhaled corticosteroids in patients considered to have mild asthma in primary care practice. Can Respir J. 1996;3(3):169–75. doi: 10.1155/1996/105967.
    1. NCT00463866. Local Phase 4 Pan-European SMART Study. 2015. . Accessed 16 June 2015.
    1. NCT00315744. Viapaed Study in children and adolescents with asthma. 2015. . Accessed 16 June 2015.
    1. Patel M, Perrin K, Pritchard A, Williams M, Wijesinghe M, Weatherall M, et al. Accuracy of patient self-report as a measure of inhaled asthma medication use. Respirology. 2013;18(3):546–52. doi: 10.1111/resp.12059.
    1. O’Byrne PM, Barnes PJ, Rodriguez-Roisin R, Runnerstrom E, Sandstrom T, Svensson K, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med. 2001;164(8 Pt 1):1392–7. doi: 10.1164/ajrccm.164.8.2104102.
    1. Fuhlbrigge A, Peden D, Apter AJ, Boushey HA, Camargo CA, Jr, Gern J, et al. Asthma outcomes: exacerbations. J Allergy Clin Immunol. 2012;129(3 Suppl):S34–48. doi: 10.1016/j.jaci.2011.12.983.
    1. de Vries F, Setakis E, Zhang B, van Staa TP. Long-acting {beta}2-agonists in adult asthma and the pattern of risk of death and severe asthma outcomes: a study using the GPRD. Eur Respir J. 2010;36(3):494–502. doi: 10.1183/09031936.00124209.
    1. Shahidi N, Fitzgerald JM. Current recommendations for the treatment of mild asthma. J Asthma Allergy. 2010;3:169–76. doi: 10.2147/JAA.S14420.
    1. Foster JM, Smith L, Bosnic-Anticevich SZ, Usherwood T, Sawyer SM, Rand CS, et al. Identifying patient-specific beliefs and behaviours for conversations about adherence in asthma. Intern Med J. 2012;42(6):e136–44. doi: 10.1111/j.1445-5994.2011.02541.x.
    1. Beasley R, Pavord I, Papi A, Reddel HK, Harrison T, Marks G et al. Description of randomised controlled trial of ICS/LABA reliever therapy in mild asthma. Eur Respir J. 2015. In press.
    1. Reddel HK, Busse WW, Pedersen S, Tan WC, Chen Y-Z, Jorup C, et al. Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: a post-hoc efficacy analysis of the START study. Lancet. 2016. doi:10.1016/S0140-6736(16)31399-X.
    1. Global Strategy for Asthma Management and Prevention. Updated 2016. Global Initiative for Asthma. 2016. . Accessed 7 Oct 2016
    1. CPMP. Committee for Proprietary Medicinal Products. London; 2000. . Accessed 7 Oct 2016.
    1. Pocock SJ, Stone GW. The primary outcome fails—What next? N Engl J Med. 2016;375(9):861–70. doi: 10.1056/NEJMra1510064.
    1. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012;40(6):1324–43. doi: 10.1183/09031936.00080312.

Source: PubMed

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