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. 2019 Sep 25;9(9):CD006924.
doi: 10.1002/14651858.CD006924.pub4.

Inhaled steroids with and without regular formoterol for asthma: serious adverse events

Sadia Janjua  1 , Stefanie Schmidt, Montse Ferrer, Christopher J Cates
Affiliations

Inhaled steroids with and without regular formoterol for asthma: serious adverse events

Sadia Janjua et al. Cochrane Database Syst Rev. .

Abstract

Background: Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality. There has been much debate about whether regular (daily) long-acting beta2-agonists (LABA) are safe when used in combination with inhaled corticosteroids (ICS). This updated Cochrane Review includes results from two large trials that recruited 23,422 adolescents and adults mandated by the US Food and Drug Administration (FDA).

Objectives: To assess the risk of mortality and non-fatal serious adverse events (SAEs) in trials that randomly assign participants with chronic asthma to regular formoterol and inhaled corticosteroids versus the same dose of inhaled corticosteroid alone.

Search methods: We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data as well as FDA submissions in relation to formoterol. The date of the most recent search was February 2019.

Selection criteria: We included randomised clinical trials (RCTs) with a parallel design involving adults, children, or both with asthma of any severity who received regular formoterol and ICS (separate or combined) treatment versus the same dose of ICS for at least 12 weeks.

Data collection and analysis: We used standard methodological procedures expected by Cochrane. We obtained unpublished data on mortality and SAEs from the sponsors of the studies. We assessed our confidence in the evidence using GRADE recommendations. The primary outcomes were all-cause mortality and all-cause non-fatal serious adverse events.

Main results: We found 42 studies eligible for inclusion and included 39 studies in the analyses: 29 studies included 35,751 adults, and 10 studies included 4035 children and adolescents. Inhaled corticosteroids included beclomethasone (daily metered dosage 200 to 800 µg), budesonide (200 to 1600 µg), fluticasone (200 to 250 µg), and mometasone (200 to 800 µg). Formoterol metered dosage ranged from 12 to 48 µg daily. Fixed combination ICS was used in most of the studies. We judged the risk of selection bias, performance bias, and attrition bias as low, however most studies did not report independent assessment of causation of SAEs.DeathsSeventeen of 18,645 adults taking formoterol and ICS and 13 of 17,106 adults taking regular ICS died of any cause. The pooled Peto odds ratio (OR) was 1.25 (95% confidence interval (CI) 0.61 to 2.56, moderate-certainty evidence), which equated to one death occurring for every 1000 adults treated with ICS alone for 26 weeks; the corresponding risk amongst adults taking formoterol and ICS was also one death (95% CI 0 to 2 deaths). No deaths were reported in the trials on children and adolescents (4035 participants) (low-certainty evidence).In terms of asthma-related deaths, no children and adolescents died from asthma, but three of 12,777 adults in the formoterol and ICS treatment group died of asthma (both low-certainty evidence).Non-fatal serious adverse eventsA total of 401 adults experienced a non-fatal SAE of any cause on formoterol with ICS, compared to 369 adults who received regular ICS. The pooled Peto OR was 1.00 (95% CI 0.87 to 1.16, high-certainty evidence, 29 studies, 35,751 adults). For every 1000 adults treated with ICS alone for 26 weeks, 22 adults had an SAE; the corresponding risk for those on formoterol and ICS was also 22 adults (95% CI 19 to 25).Thirty of 2491 children and adolescents experienced an SAE of any cause when receiving formoterol with ICS, compared to 13 of 1544 children and adolescents receiving ICS alone. The pooled Peto OR was 1.33 (95% CI 0.71 to 2.49, moderate-certainty evidence, 10 studies, 4035 children and adolescents). For every 1000 children and adolescents treated with ICS alone for 12.5 weeks, 8 had an non-fatal SAE; the corresponding risk amongst those on formoterol and ICS was 11 children and adolescents (95% CI 6 to 21).Asthma-related serious adverse eventsNinety adults experienced an asthma-related non-fatal SAE with formoterol and ICS, compared to 102 with ICS alone. The pooled Peto OR was 0.86 (95% CI 0.64 to 1.14, moderate-certainty evidence, 28 studies, 35,158 adults). For every 1000 adults treated with ICS alone for 26 weeks, 6 adults had an asthma-related non-fatal SAE; the corresponding risk for those on formoterol and ICS was 5 adults (95% CI 4 to 7).Amongst children and adolescents, 9 experienced an asthma-related non-fatal SAE with formoterol and ICS, compared to 5 on ICS alone. The pooled Peto OR was 1.18 (95% CI 0.40 to 3.51, very low-certainty evidence, 10 studies, 4035 children and adolescents). For every 1000 children and adolescents treated with ICS alone for 12.5 weeks, 3 had an asthma-related non-fatal SAE; the corresponding risk on formoterol and ICS was 4 (95% CI 1 to 11).

Authors' conclusions: We did not find a difference in the risk of death (all-cause or asthma-related) in adults taking combined formoterol and ICS versus ICS alone (moderate- to low-certainty evidence). No deaths were reported in children and adolescents. The risk of dying when taking either treatment was very low, but we cannot be certain if there is a difference in mortality when taking additional formoterol to ICS (low-certainty evidence).We did not find a difference in the risk of non-fatal SAEs of any cause in adults (high-certainty evidence). A previous version of the review had shown a lower risk of asthma-related SAEs in adults taking combined formoterol and ICS; however, inclusion of new studies no longer shows a difference between treatments (moderate-certainty evidence).The reported number of children and adolescents with SAEs was small, so uncertainty remains in this age group.We included results from large studies mandated by the FDA. Clinical decisions and information provided to patients regarding regular use of formoterol and ICS need to take into account the balance between known symptomatic benefits of formoterol and ICS versus the remaining degree of uncertainty associated with its potential harmful effects.

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Conflict of interest statement

SJ: none known.

SS: none known.

MF: received payment from AstraZeneca for a lecture. None of the sponsors or funding institutions had any role in gathering, analysing, or interpreting the data, and they have no right to approve or disapprove any submitted paper.

CJC: is a Co‐ordinating Editor for the Cochrane Airways Group.

Figures

1
1
Study flow diagram: review update.
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
3
3
Forest plot of comparison: 1 Formoterol and ICS versus same‐dose ICS, outcome: 1.1 All‐cause mortality.
4
4
Forest plot of comparison: 1 Formoterol and ICS versus same‐dose ICS (Peto OR), outcome: 1.2 All‐cause non‐fatal serious adverse events.
5
5
Forest plot of comparison: 1 Formoterol and ICS versus same‐dose ICS (Peto OR), outcome: 1.3 Asthma mortality.
6
6
Forest plot of comparison: 1 Formoterol and ICS versus same‐dose ICS, outcome: 1.4 Asthma‐related non‐fatal serious adverse events.
7
7
Funnel plot of comparison: 1 Formoterol and ICS versus same‐dose ICS (Peto OR), outcome: 1.2 All‐cause non‐fatal serious adverse events.
1.1
1.1. Analysis
Comparison 1 Formoterol and ICS versus same‐dose ICS (Peto OR, OR, risk difference), Outcome 1 All‐cause mortality.
1.2
1.2. Analysis
Comparison 1 Formoterol and ICS versus same‐dose ICS (Peto OR, OR, risk difference), Outcome 2 All‐cause non‐fatal serious adverse events.
1.3
1.3. Analysis
Comparison 1 Formoterol and ICS versus same‐dose ICS (Peto OR, OR, risk difference), Outcome 3 Asthma mortality.
1.4
1.4. Analysis
Comparison 1 Formoterol and ICS versus same‐dose ICS (Peto OR, OR, risk difference), Outcome 4 Asthma‐related non‐fatal serious adverse events.
2.1
2.1. Analysis
Comparison 2 Formoterol and ICS versus same‐dose ICS (risk difference), Outcome 1 All‐cause mortality.
2.2
2.2. Analysis
Comparison 2 Formoterol and ICS versus same‐dose ICS (risk difference), Outcome 2 All‐cause non‐fatal serious adverse events.
2.3
2.3. Analysis
Comparison 2 Formoterol and ICS versus same‐dose ICS (risk difference), Outcome 3 Asthma mortality.
2.4
2.4. Analysis
Comparison 2 Formoterol and ICS versus same‐dose ICS (risk difference), Outcome 4 Asthma‐related non‐fatal serious adverse events.
3.1
3.1. Analysis
Comparison 3 Sensitivity analysis for adults: formoterol and ICS versus same‐dose ICS (risk difference, Peto OR), Outcome 1 Asthma mortality.
3.2
3.2. Analysis
Comparison 3 Sensitivity analysis for adults: formoterol and ICS versus same‐dose ICS (risk difference, Peto OR), Outcome 2 Asthma‐related non‐fatal serious adverse events.
4.1
4.1. Analysis
Comparison 4 Formoterol and ICS versus same‐dose ICS (fixed‐effect versus random‐effects), Outcome 1 All‐cause mortality.
4.2
4.2. Analysis
Comparison 4 Formoterol and ICS versus same‐dose ICS (fixed‐effect versus random‐effects), Outcome 2 All‐cause non‐fatal serious adverse events.
4.3
4.3. Analysis
Comparison 4 Formoterol and ICS versus same‐dose ICS (fixed‐effect versus random‐effects), Outcome 3 Asthma mortality.
4.4
4.4. Analysis
Comparison 4 Formoterol and ICS versus same‐dose ICS (fixed‐effect versus random‐effects), Outcome 4 Asthma‐related non‐fatal serious adverse events.
5.1
5.1. Analysis
Comparison 5 Subgroup analysis for different LABA + ICS combinations, Outcome 1 All‐cause serious adverse events.
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O'Byrne 2001 {published data only}
    1. Barnes PJ, O'Byrne PM, Rodriguez Roisin R, Runnerstrom E, Sandstrom T, Svensson K, et al. Treatment of mild persistent asthma with low doses of inhaled budesonide alone or in combination with formoterol. Thorax 2000;55(Suppl 3):A4.
    1. Grosser D, Smith B. Low‐dose budesonide improved asthma control in mild asthma: adding formoterol improved control in corticosteroid‐treated patients. ACP Journal Club 2002;137(1):19. - PubMed
    1. Jonsson B, Berggren F, Svensson K, O'Byrne PM. An economic evaluation of combination treatment with budesonide and formoterol in patients with mild‐to‐moderate persistent asthma. Respiratory Medicine 2004;98(11):1146‐54. - PubMed
    1. Jönsson BG, Berggren FE, Svensson K, O'Byrne PM. Budesonide and formoterol in mild persistent asthma compared with doubling the dose of budesonide ‐ a cost‐effectiveness analysis. European Respiratory Journal 2001;18(Suppl 33):517s.
    1. Jönsson BG, Berggren FE, Svensson K, O'Byrne PM. Economic results of adding formoterol to budesonide in mild persistent asthma. European Respiratory Journal 2001;18(Suppl 33):331s.
Paggiaro 2016 {published data only}
    1. Paggiaro P, Corradi M, Latorre M, Raptis H, Muraro A, Gessner C, et al. High strength extrafine pMDI beclometasone/formoterol (200/6 μg) is effective in asthma patients not adequately controlled on medium‐high dose of inhaled corticosteroids. BMC Pulmonary Medicine 2016;16(1):180. - PMC - PubMed
    1. Paggiaro P, Corradi M, Raptis H, Baronio R, Gessner C, Siergiejko Z, et al. High dose extrafine beclomethasone/formoterol via metered dose inhaler is effective and safe in asthmatics not controlled on medium‐high dose of inhaled corticosteroids [Abstract]. European Respiratory Journal 2014;44 (Suppl 58):P901.
Pauwels 1997 {published data only}
    1. Juniper EF, Svensson K, O'Byrne PM, Barnes PJ, Bauer CA, Lofdahl CGA, et al. Asthma quality of life during 1 year of treatment with budesonide with or without formoterol. European Respiratory Journal 1999;14(5):1038‐43. - PubMed
    1. Pauwels R. Additive effects of inhaled formoterol and budesonide in reducing asthma exacerbations. [Review]. Allergy 1998;53(42 Suppl):20‐3. - PubMed
    1. Pauwels RA, Lofdahl CG, Postma DS, Tattersfield AE, O'Byrne P, Barnes PJ, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. New England Journal of Medicine 1997;337(20):1405‐11. [0028‐4793: (Print)] - PubMed
    1. Tattersfield AE, Postma DS, Barnes PJ, Svensson K, Bauer CA, O'Byrne PM, et al. Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group. American Journal of Respiratory and Critical Care Medicine 1999;160(2):594‐9. - PubMed
Pearlman 2013 {published data only}
    1. Pearlman DS, LaForce C, Kaiser K. Fluticasone propionate/formoterol fumarate combination therapy has superior efficacy to both fluticasone and formoterol alone [Abstract]. European Respiratory Journal 2011;55:727s. Abstract P3990.
    1. Pearlman DS, LaForce CF, Kaiser K. Fluticasone/formoterol combination therapy compared with monotherapy in adolescent and adult patients with mild to moderate asthma. Clinical Therapeutics 2013;35(7):431‐7. - PubMed
Pearlman 2017 {published data only}
    1. Pearlman DS, Eckerwall G, McLaren J, Lamarca R, Puu M, Gilbert I, et al. Efficacy and safety of budesonide/formoterol pMDI vs budesonide pMDI in asthmatic children (6‐<12 years). Annals of Allergy, Asthma and Immunology 2017;118(4):489‐99. - PubMed
Pertseva 2013 {published data only}
    1. Pertseva T, Dissanayake S, Kaiser K. Efficacy and safety of fluticasone/formoterol compared to fluticasone alone in patients with asthma [Abstract]. European Respiratory Journal 2012;56:392s. Abstract P2191.
    1. Pertseva T, Dissanayake S, Kaiser K. Superiority of fluticasone propionate/formoterol fumarate versus fluticasone propionate alone in patients with moderate‐to‐severe asthma: a randomised controlled trial. Current Medical Research and Opinion 2013;29(10):1357‐69. - PubMed
Peters 2008 {published and unpublished data}
    1. AstraZeneca SD‐039‐0728. Titratable dosing in moderate to severe asthmatics [A 52‐week, randomized, double‐blind, single‐dummy, parallel‐group, multicenter Phase III study comparing the long‐term safety of SYMBICORT® pMDI 160/4.5 mcg × 4 actuations twice daily to SYMBICORT® pMDI 160/4.5 mcg × 2 actuations twice daily and budesonide HFA pMDI 160 mcg × 4 actuations twice daily in adult and adolescent subjects with asthma]. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=964 (first received 1 August 2003).
    1. Lawrance R, Ambrose H, Goldman M. Effect of gly16arg beta2‐adrenergic receptor variation on the long‐term safety of formoterol (FM) in combination with budesonide (BUD) and of BUD alone, delivered via one pressurized metered‐dose inhaler (pMDI) in patients with moderate to severe asthma [Abstract]. American Thoracic Society International Conference; 2007 May 18‐23; San Francisco. Poster #420.
    1. O'Brien CD, Peters SP, Prenner BM, Martin P. Long‐term safety of budesonide/formoterol pressurized metered‐dose inhaler (BUD/FM pMDI) in asthma patients: adverse events and asthma exacerbations [Abstract]. American Thoracic Society International Conference; 2007 May 18‐23; San Francisco. Poster #L57.
    1. O'Brien CD, Peters SP, Prenner BM, Martin P. Resource use with budesonide/formoterol pressurized metered‐dose inhaler (BUD/FM pMDI) versus BUD pMDI in asthma patients [Abstract]. American Thoracic Society International Conference; 2007 May 18‐23; San Francisco. Poster #L58.
    1. Peters SP, Prenner BM, Martin P, O'Brien CD. Long‐term effects on lung function of budesonide (BUD) and formoterol (FM) in one pressurized metered‐dose inhaler (BUD/FM pMDI) and BUD pMDI in patients with asthma [Abstract]. American Thoracic Society International Conference; 2007 May 18‐23; San Francisco. Poster #K5.
Peters 2016 {published data only}
    1. NCT01444430. A 6 month safety study comparing Symbicort with inhaled corticosteroid only in asthmatic adults and adolescents [A 26 week, randomized, double‐blind, parallel‐group, active controlled, multicenter, multinational safety study evaluating the risk of serious asthma‐related events during treatment with Symbicort®, a fixed combination of inhaled corticosteroid (ICS) (budesonide) and a long acting β2‐agonist (LABA) (formoterol) as compared to treatment with ICS (budesonide) alone in adult and adolescent (≥12 years of age) patients with asthma]. clinicaltrials.gov/show/nct01444430 (first received 1 December 2011).
    1. Peters SP, Bleecker ER, Canonica GW, Park YB, Ramirez R, Hollis S, et al. Serious asthma events with budesonide plus formoterol vs. budesonide alone. New England Journal of Medicine 2016;375(9):850‐60. - PubMed
Ploszczuk 2014 {published data only}
    1. EudraCT 2010‐024635‐16. A double‐blind, double dummy, randomised, parallel group, multi‐centre study to compare the efficacy and safety of Flutiform pMDI with fluticasone pMDI and with Seretide pMDI in paediatric subjects aged 5 to less than 12 years with moderate to severe persistent reversible asthma. https://www.clinicaltrialsregister.eu/ctr‐search/trial/2010‐024635‐16/re... 13/06/2016 (first received 03/05/2018). [EudraCT 2010‐024635‐16]
    1. NCT01511367. Comparison of Flutiform, Fluticasone, and Seretide in treatment of moderate to severe asthma in paediatric patients. https://www.clinicaltrialsregister.eu/ctr‐search/trial/2010‐024635‐16/re... 18/01/2012 (first received 03/05/2018). [NCT01511367]
    1. Ploszczuk A, Bosheva M, Spooner K, McIver T. Efficacy and safety of fluticasone propionate/formoterol fumarate in paediatric asthma patients: a randomised controlled trial. Therapeutic Advances in Respiratory Disease 2018;12:1‐15. - PMC - PubMed
    1. Ploszczuk A, Bosheva M, Spooner K, McIver T, Dissanayake S. Efficacy and safety of fluticasone propionate/formoterol in paediatric patients with asthma. European Respiratory Journal 2014;44(Suppl 58):P1167.
    1. Ploszczuk A, Bosheva M, Spooner K, McIver T, Dissanayake S. Efficacy and safety of fluticasone propionate/formoterol in paediatric patients with asthma. Thorax 2014;69 DBP(Suppl 2):A177.
Pohunek 2006 {published data only}
    1. AstraZeneca SD‐039‐0688. Efficacy and safety of Symbicort® (budesonide/formoterol 80/4.5 µg, 2 inhalations b.i.d.) compared to Pulmicort® (budesonide 100 mcg, 2 inhalations b.i.d.) and Pulmicort (budesonide 100 µg, 2 inhalations b.i.d.) plus Oxis® (formoterol 4.5 µg, 2 inhalations b.i.d.) all delivered via Turbuhaler® in steroid using asthmatic children: a double‐blind, double‐dummy, randomised, parallel‐group, phase III, multicentre 12‐week study. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=1003 (first received 1 March 2002).
    1. Pohunek P, Kuna P, Boeck K. Budesonide/formoterol improves lung function compared with budesonide alone in children with asthma [Abstract]. European Respiratory Journal 2004;24(Suppl 48):379s.
    1. Pohunek P, Kuna P, Jorup C, Boeck K. Budesonide/formoterol improves lung function compared with budesonide alone in children with asthma. Pediatric Allergy and Immunology 2006; Vol. 17, issue 6:458‐65. - PubMed
    1. Pohunek P, Matulka M, Rybnicek O, Kopriva F, Honomichlova H, Svobodova T. Dose‐related efficacy and safety of formoterol (Oxis) Turbuhaler compared with salmeterol Diskhaler in children with asthma. Pediatric Allergy and Immunology 2004;15(1):32‐9. - PubMed
Price 2002 {published data only}
    1. Price D, Dutchman D, Mawson A, Bodalia B, Duggan S, Todd P. Early asthma control and maintenance with eformoterol following reduction of inhaled corticosteroid dose. Thorax 2002;57(9):791‐8. [0040‐6376: (Print)] - PMC - PubMed
    1. Price MJ, Briggs AH. Development of an economic model to assess the cost effectiveness of asthma management strategies. Pharmacoeconomics 2002;20(3):183‐94. - PubMed
    1. Price MJ, Sondhi S, Yan S, Nyth A, House K. Salmeterol/fluticasone propionate combination inhaler is more cost effective than fluticasone propionate in patients with asthma. European Respiratory Society 9th Annual Congress; 1999 Oct 9‐13; Madrid. 1999:#2459.
Samson 2012 {published data only}
    1. Samson MA, Panganiban SC. Effectiveness and safety of budesonide alone versus budesonide/formoterol in decreasing the number of severe exacerbations: a randomised controlled trial. Respirology 2012;4:152.
SD‐039‐0714 {unpublished data only}
    1. AstraZeneca SD‐039‐0714. Efficacy and safety of budesonide/formoterol Turbuhaler® (160/4.5 mg b.i.d. delivered dose) compared to budesonide Turbuhaler® (200 mg b.i.d. metered dose) in steroid‐using asthmatic adolescent patients: a double‐blind, double dummy, randomised, parallel group, phase III, multi‐centre study. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=999 (first received 14 November 2008).
SD‐039‐0718 {unpublished data only}
    1. AstraZeneca SD‐039‐0718. Symbicort in asthmatic children ‐ SEEDLING [A 12 week randomized, double‐blind, double‐dummy, placebo‐controlled trial of Symbicort TM (40/4.5 mcg) versus its mono‐products (budesonide and formoterol) in asthmatic children aged six to eleven years ‐ SEEDLING 40/4.5]. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=968 (first received14 November 2008).
    1. Pearlman DS, Murphy KR, Uryniak T, O'Brien CD, Mezzanotte WS, Denver M. Safety of budesonide/formoterol pressurized metered dose inhaler (BUD/FM pMDI) in children with asthma previously treated with inhaled corticosteroids (ICSs) [Abstract]. American Thoracic Society International Conference; 2008 May 16‐21; Toronto #A710 (#K67).
SD‐039‐0719 {unpublished data only}
    1. AstraZeneca SD‐039‐0719. Long‐term safety of Symbicort in asthmatic children ‐ SAPLING [A six‐month, randomized, open‐label safety study of SYMBICORT® (160/4.5 μg) compared to PULMICORT Turbuhaler® in asthmatic children aged 6 to 11 years]. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=967 (first received 14 November 2008).
    1. Berger WE, Bleecker ER, O'Dowd L, Miller CJ, Mezzanotte W. Efficacy and safety of budesonide/formoterol pressurized metered‐dose inhaler: randomized controlled trial comparing once‐ and twice‐daily dosing in patients with asthma. Allergy and Asthma Proceedings 2010;31(1):49‐59. - PubMed
    1. Berger WE, Leflein JG, Geller DE, Parasuraman B, Miller CJ, O'Brien CD, et al. The safety and clinical benefit of budesonide/formoterol pressurized metered‐dose inhaler versus budesonide alone in children. Allergy and Asthma Proceedings 2010;31(1):26‐39. - PubMed
    1. Berger WE, Leflein JG, Uryniak T, O'Brien CD, O'Dowd L. Long‐term efficacy and resource utilization after treatment with budesonide and formoterol administered via one pressurized metered‐dose inhaler (pMDI) compared with budesonide dry powder inhaler (DPI) alone in children with asthma. Journal of Allergy and Clinical Immunology 2008;121(2 Suppl 1):S8.
    1. Leflein JG, Berger WE, Uryniak T, Vervaet P, O'Dowd L, O'Brien CD. Long‐term safety and systemic effects of budesonide and formoterol administered via one pressurized metered‐dose inhaler (pMDI) in children with asthma. Journal of Allergy and Clinical Immunology 2008;121(2 Suppl 1):S155.
SD‐039‐0725 {unpublished data only}
    1. AstraZeneca SD‐039‐0725. Efficacy of Symbicort pMDI administered once daily in children and adolescents during 12 weeks ‐ SPROUT [A twelve‐week, randomized, double‐blind, double‐dummy, active‐controlled study of SYMBICORT® pMDI administered once daily in children and adolescents 6 to 15 years of age with asthma ‐ SPROUT]. https://astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=966 (first received 1 April 2003).
    1. Eid NS, Noonan MJ, Chipps B, Parasuraman B, Miller CJ, O'Brien CD. Once‐ vs twice‐daily budesonide/formoterol in 6‐ to 15‐year‐old patients with stable asthma. Pediatrics 2010;126(3):e565‐75. - PubMed
SD‐039‐0726 {unpublished data only}
    1. AstraZeneca SD‐039‐0726. Efficacy of Symbicort pMDI administered once daily in adolescents and adults during 12 weeks ‐ STEM [A twelve‐week, randomized, double‐blind, double‐dummy, placebo‐ and active‐controlled study of SYMBICORT® pMDI administered once daily in adults and adolescents with asthma ‐ STEM]. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=965 (first received 1 April 2003).
Spector 2012 {published data only}
    1. AstraZeneca D589BL00003. Phase4/Symbicort® versus Pulmicort Flexhaler® in African Americans (Titan) [A 12‐week, randomized, double‐blind, double‐dummy, multi‐center, phase IV study comparing the efficacy and safety of SYMBICORT® pMDI 160/4.5 μg × 2 actuations twice daily versus budesonide inhalation powder DPI 180 μg × 2 inhalations twice daily, in adult and adolescent (≥12 years) African American subjects with asthma]. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=1614 (first received 1 June 2008). [D589BL00003]
    1. Spector SL, Martin UJ, Uryniak T, O'Brien CD. Budesonide/formoterol pressurized metered‐dose inhaler versus budesonide: a randomized controlled trial in black patients with asthma. Journal of Asthma 2012;49(1):70‐7. [1532‐4303: (Electronic)] - PubMed
    1. Spector SL, Martin UJ, Uryniak T, O'Brien CD. Effect of budesonide/formoterol pressurized metered‐dose inhaler versus budesonide dry powder inhaler on asthma control in black adolescents and adults with moderate to severe persistent asthma [Abstract]. Annals of Allergy, Asthma and Immunology 2010;105(Suppl):5.
    1. Spector SL, O'Brien CD, Uryniak T, Martin UJ. Safety and tolerability of a budesonide/formoterol (BUD/FM) pressurized metered‐dose inhaler (pMDI) in black adolescents and adults with moderate to severe persistent asthma [Abstract]. Chest 2010;138(4):705A.
Stirbulov 2012 {published data only}
    1. NCT01676987. Evaluation of the efficacy and safety of a fixed‐dose, single‐capsule budesonide‐formoterol combination in uncontrolled asthma [Evaluation of the efficacy and safety of a fixed‐dose, single‐capsule budesonide‐formoterol combination in uncontrolled asthma: a randomized, double‐blind, multicenter, controlled clinical trial]. clinicaltrials.gov/ct2/show/NCT01676987 (first received 1 April 2009).
    1. Pizzichini MM, Stirbulov R, Fristcher CC, Pizzichini E. Efficacy and safety of a combination of budesonide/formoterol in a single capsule in uncontrolled asthma [Abstract]. American Journal of Respiratory and Critical Care Medicine 2012;185:A3970.
    1. Stirbulov R, Fritscher CC, Pizzichini MMM. Evaluation of the efficacy and safety of a fixed‐dose, single‐capsule budesonide‐formoterol combination in uncontrolled asthma: a randomized, double‐blind, multicenter, controlled clinical trial. Jornal Brasileiro de Pneumologia: Publicacao Oficial da Sociedade Brasileira de Pneumologia e Tisilogia 2012;38(4):431‐7. - PubMed
Tal 2002 {published data only}
    1. AstraZeneca SD‐039‐0353. Efficacy and safety of budesonide/formoterol Turbuhaler® in a fixed combination in steroid‐using asthmatic children. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=1019 (first received 1 November 1998).
    1. Tal A, Simon G, Vermeulen JH. Symbicort® budesonide and formoterol in a single inhaler is effective and well tolerated in children with asthma. Annual Thoracic Society 97th International Conference; 2001 May 18‐23; San Francisco. 2001.
    1. Tal A, Simon G, Vermeulen JH, Petru V, Cobos N, Everard ML, et al. Budesonide/formoterol in a single inhaler versus inhaled corticosteroids alone in the treatment of asthma. Pediatric Pulmonology 2002;34(5):342‐50. - PubMed
    1. Tal A, Simon G, Vermeulen JH, Petru V, Cobos N, Everard ML, et al. Rapid and sustained improvements in lung function and symptom control with budesonide/formoterol in adolescent asthma. European Respiratory Journal 2001;18(Suppl 33):494s.
    1. Tal A, Simon G, Vermeulen JH, Petru V, Cobos N, Everard ML, et al. Symbicort budesonide and formoterol in a single inhaler is more effective that budesonide alone in children with asthma. International Paediatric Respiratory and Allergy Congress; 2001 April 1‐4; Prague. 2001:84‐5.
Weinstein 2010 {published data only}
    1. NCT00381485. Effects of mometasone furoate/formoterol combination versus mometasone furoate alone in persistent asthmatics (Study P04431AM2) (COMPLETED) [A 12‐week efficacy and safety study of two doses of mometasone furoate/formoterol combination formulation compared with mometasone furoate monotherapy, in persistent asthmatics previously treated with high‐dose inhaled glucocorticosteroids]. clinicaltrials.gov/ct2/show/NCT00381485 (first received 27 September 2006). [NCT00381485]
    1. Nolte H, White M, Weinstein SF, Nathan RA, Gates D, Meltzer EO. Evaluation of diary data on asthma control factors managed with combined mometasone furoate and formoterol fumarate in patients with severe asthma. Respirology 2012;17 (Suppl 2):1‐16.
    1. Weinstein S, Murphy K, Corren J, Nolte H, White M. Efficacy and safety of medium and high doses of mometasone furoate/formoterol (MF/F) combination treatment in subjects with severe persistent asthma [Abstract]. Journal of Allergy and Clinical Immunology 2010;125(2 Suppl 1):AB196. [0091‐6749]
    1. Weinstein S, Murphy K, Corren J, Nolte H, White M. Efficacy and safety of medium and high doses of mometasone furoate/formoterol combination treatment in subjects with severe asthma. European Respiratory Society https://www.ers‐education.org/home/browse‐all‐content.aspx?idParent=86111 2010;36(Suppl 54):5482.
    1. Weinstein S, Murphy K, Nolte H. Efficacy and safety of two doses of mometasone furoate/formoterol combination treatment in subjects with severe asthma. World Allergy Organization. 2012:S79‐80.
Weinstein 2019 {published data only}
    1. NCT01471340. A serious asthma outcome study with mometasone furoate/formoterol versus mometasone furoate in asthmatics 12 years and over (P06241) (SPIRO) [A 26‐week randomized, double‐blinded, active controlled study comparing the safety of mometasone furoate/formoterol fumarate MDI fixed dose combination versus mometasone furoate MDI monotherapy in adolescents and adults with persistent asthma (protocol no. P06241 also known as P202)]. clinicaltrials.gov/ct2/show/NCT01471340 (first received 16 November 2011).
    1. Weinstein CLJ, Ryan N, Shekar T, Gates D, Lane SJ, Agache I, et al. Serious asthma events with mometasone furoate plus formoterol compared with mometasone furoate. Journal of Allergy and Clinical Immunology 2019;143(4):1395‐1402. [DOI: 10.1016/j.jaci.2018.10.065] - DOI - PubMed
Zangrilli 2011 {published data only}
    1. NCT00419757. An efficacy study comparing SYMBICORT® pressurised metered dose Iinhaler (pMDI) with budesonide hydrofluoroalkanes (HFA) pMDI, in hispanic subjects with ICS dependent asthma [A 12‐week, randomised, double blind, active‐controlled, multi‐centre, phase IIIB study comparing the efficacy and safety of SYMBICORT® pMDI 160/4.5 mg x 2 actuations twice daily versus budesonide HFA pMDI 160 mg x 2 actuations twice daily, in adult/adolescent (> 12 Yrs) Hispanic subjects with asthma]. clinicaltrials.gov/ct2/show/NCT00419757 (first received 9 January 2007). [NCT00419757]
    1. Zangrilli J, Mansfield LE, Uryniak T, O'Brien CD. Efficacy of budesonide/formoterol pressurized metered‐dose inhaler versus budesonide pressurized metered‐dose inhaler alone in Hispanic adults and adolescents with asthma: a randomized, controlled trial. Annals of Allergy, Asthma and Immunology 2011;107:258‐65. - PubMed
Zetterstrom 2001 {published data only}
    1. AstraZeneca SD‐039‐0349. Efficacy and safety of a fixed combination of budesonide/formoterol Turbuhaler® in inhaled steroid‐using asthmatic adults. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=1020 (first received 1 October 1998).
    1. Buhl R, Zetterstrom O, Mellem H, Perpina M, Hedman J, O'Neill S, et al. Improved asthma control with budesonide/formoterol via a single inhaler compared with budesonide alone, in moderate persistent asthma. European Respiratory Journal 2001;18(Suppl 33):48s. - PubMed
    1. Zetterstrom O, Buhl R, Mellem H. Efficacy and safety of Symbicort® budesonide and formoterol in a single inhaler in adults with asthma. Annual Thoracic Society 97th International Conference; 2001 May 18‐23; San Francisco. 2001.
    1. Zetterstrom O, Buhl R, Mellem H, Perpina M, Hedman J, O'Neill S, et al. Improved asthma control with budesonide/formoterol in a single inhaler, compared with budesonide alone. European Respiratory Journal 2001;18(2):262‐8. - PubMed
    1. Zetterström O, Buhl R, Mellem H, Perpiñá M, Hedman J, O'Neill S, et al. Efficacy and safety of a new single inhaler product containing both budesonide and formoterol in adult asthma. European Respiratory Journal 2000;16(Suppl 31):455s. Abstract P3198.

References to studies excluded from this review

Ankerst 2003 {published data only}
    1. Ankerst J, Persson G, Weibull E. Tolerability of a high dose of budesonide/formoterol in a single inhaler in patients with asthma. Pulmonary Pharmacology and Therapeutics 2003;16(3):147‐51. - PubMed
Antilla 2014 {published data only}
    1. Antilla M, Castro F, Cruz A, Rubin A, Rosario N, Stelmach R. Efficacy and safety of the single‐capsule combination of fluticasone/formoterol in patients with persistent asthma: a non‐inferiority trial. Jornal Brasileiro de Pneumologia: Publicacao Oficial da Sociedade Brasileira de Pneumologia e Tisilogia 2014;40(6):599‐608. - PMC - PubMed
AstraZeneca 2005 {published data only}
    1. AstraZeneca D5890C00010. Efficacy & safety of Symbicort Turbuhaler 160/4.5 µg twice daily & Pulmicort Turbuhaler 200 µg twice daily + Theolong tablet 200 mg twice daily in Japanese asthmatic patients [An 8‐week, randomised, double blind, parallel‐group, multi‐centre, phase III study comparing the efficacy and safety of Symbicort® Turbuhaler® 160/4.5 µg twice daily and Pulmicort® Turbuhaler® 200 µg twice daily + Theolong® tablet 200 mg twice daily in Japanese patients with asthma]. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=572 (first received 1 October 2005).
AstraZeneca 2005a {published data only}
    1. AstraZeneca D5890L00001. SHARE ‐ Symbicort and health economics in a real life evaluation [Symbicort and health economics in a real life evaluation – SHARE – a randomised, open‐label, parallel‐group, multicentre study to assess the asthma‐related health‐care costs, in ordinary clinical practice during 12 months]. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=1517 (first received 1 April 2004).
AstraZeneca 2005b {published data only}
    1. AstraZeneca D5890L00004. SOLO ‐ Symbicort in the treatment of persistent asthma in adolescents & adults [A comparison of Symbicort® single inhaler therapy (Symbicort® 200 Turbuhaler® 1 inhalation b.i.d. plus as needed) & conventional best practice for the treatment of persistent asthma in adolescents & adults ‐ a 26‐week, randomised, open‐label, parallel group, multicentre study]. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=1518 (first received 1 May 2004).
AstraZeneca 2005c {published data only}
    1. AstraZeneca D5890L00014. STYLE ‐ Symbicort single inhaler therapy vs. conventional therapy in treatment of persistent asthma. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=1536 (first received 1 July 2005).
AstraZeneca 2005d {published data only}
    1. AstraZeneca D5890L00005. SYMPHONIE ‐ a comparison of Symbicort single inhaler and conventional best practice for the treatment of persistent asthma in adolescents and adults [A comparison of Symbicort Single inhaler and conventional best practice for the treatment of persistent asthma in adolescents and adults ‐ a 26‐week, randomised, open, parallel group multicentre study]. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=1521 (first received 1 September 2004).
AstraZeneca 2006 {published data only}
    1. AstraZeneca D5890C00003. A comparison of the control of asthma inflammation provided by Symbicort Turbuhaler 160/4.5 mcg/inhalation bid plus as‐needed versus Symbicort Turbuhaler 320/9 ug/inhalation bid plus Pulmicort Turbuhaler 400 mcg/dose bid plus terbutaline Turbuhaler 0.4 mg/inhalation as‐needed. A 12‐month, randomised, double‐blind, parallel‐group, active controlled, multinational, phase IIIB study in adult patients with asthma, EOS. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=1512 (first received 1 May 2005).
AstraZeneca 2006a {published data only}
    1. AstraZeneca D5890L00008. MONO: Symbicort single inhaler therapy and conventional best standard treatment for the treatment of persistent asthma in adolescents and adults [A comparison of the efficacy of Symbicort® Single inhaler therapy (Symbicort Turbuhaler® 160/4.5 mg 1 inhalation b.i.d. plus as‐needed) and conventional best standard treatment for the treatment of persistent asthma in adolescents and adults. A randomized, open, parallel‐group, multicentre 26‐weeks study]. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=1523 (first received 1 September 2004).
AstraZeneca 2006b {published data only}
    1. AstraZeneca D5890L00009. SALTO ‐ Symbicort single inhaler therapy use in adolescent adults and adults with persistent asthma [A comparison of Symbicort Single inhaler therapy (Symbicort Turbohaler 160/4.5 μg, 1 inhalation b.i.d. plus as needed) and conventional best practice for the treatment of persistent asthma in adolescents and adults ‐ a 26‐week, randomised, open‐label, parallel‐group, multi‐centre study (SALTO)]. astrazenecagrouptrials.pharmacm.com/ST/Submission/View?id=1526 (first received 1 December 2004).
Balanag 2006 {published data only}
    1. Balanag VM, Yunus F, Yang PC, Jorup C. Efficacy and safety of budesonide/formoterol compared with salbutamol in the treatment of acute asthma. Pulmonary Pharmacology and Therapeutics 2006;19(2):139‐47. - PubMed
Barnes 2011 {published data only}
    1. Barnes N, Noord JA, Brindicci C, Lindemannu L, Varoli G, Perpina M, et al. Maintenance of lung function and asthma control with extrafine beclomethasone/formoterol [Abstract]. European Respiratory Society Annual Congress; 2011 Sep 24‐28; Amsterdam. 2011; Vol. 38:719s [P3956].
Barthwal 2017 {published data only}
    1. Barthwal MS, Meshram S. A randomized, double‐blind study comparing the efficacy and safety of a combination of formoterol and ciclesonide with ciclesonide alone in asthma subjects with moderate‐to‐severe airflow limitation. Lung India 2017;34(1):111‐2. - PMC - PubMed
Bateman 2003 {published data only}
    1. Bateman ED, Bantje TA, Gomes MJ, Toumbis MG, Huber RM, Naya I, et al. Combination therapy with single inhaler budesonide/formoterol compared with high dose of fluticasone propionate alone in patients with moderate persistent asthma. American Journal of Respiratory Medicine 2003;2(3):275‐81. - PubMed
Bateman 2006 {published data only}
    1. Bateman ED, Fairall L, Lombardi DM, English R. Budenoside/formoterol and formoterol provide similar rapid relief in patients with acute asthma showing refractoriness to salbutamol. Respiratory Research 2006;7:13. - PMC - PubMed
Bateman 2018 {published data only}
    1. 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. New England Journal of Medicine 2018;378(20):1877‐87. - PubMed
Beasley 2016 {published data only}
    1. Beasley R, Pavord I, Papi A, Reddel HK, Harrison T, Marks GB, et al. Description of a randomised controlled trial of inhaled corticosteroid/fast‐onset LABA reliever therapy in mild asthma. European Respiratory Journal 2016;47(3):981‐4. - PubMed
Bodzenta‐Lukaszyk 2011 {published data only}
    1. Bodzenta‐Lukaszyk A, Pulka G, Dymek A, Bumbacea D, McIver T, Schwab B, et al. Efficacy and safety of fluticasone and formoterol in a single pressurized metered dose inhaler. Respiratory Medicine 2011;105(5):674‐82. - PubMed
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Bouros 1999 {published data only}
    1. Bouros D, Bachlitzanakis N, Kottakis J, Pfister P, Polychronopoulos V, Papadakis E, et al. Formoterol and beclomethasone versus higher dose beclomethasone as maintenance therapy in adult asthma. European Respiratory Journal 1999;14(3):627‐32. - PubMed
Brusselle 2011 {published data only}
    1. Brusselle GG, Brande P, Peche R, Fonteyn B, Iacono D, Blockmans M, et al. Real‐life effectiveness of beclomethasone diproprionate/formoterol extra‐fine combination in adult patients with persistent asthma [Abstract]. European Respiratory Society Annual Congress; 2011 Sep 24‐28; Amsterdam. 2011; Vol. 38:719s. Abstract P3956.
Buhl 2004 {published data only}
    1. Buhl R, Kardos P, Richter K, Meyer‐Sabellek W, Bruggenjurgen B, Willich SN, et al. The effect of adjustable dosing with budesonide/formoterol on health‐related quality of life and asthma control compared with fixed dosing. Current Medical Research and Opinion 2004;20(8):1209‐20. - PubMed
Bumbacea 2010 {published data only}
    1. Bumbacea D, Dymek A, Mansikka H. Fluticasone propionate/formoterol fumarate combination therapy has an efficacy and safety profile similar to that of its individual components administered concurrently: a randomised controlled trial [Abstract]. Thorax 2010;65(Suppl 4):P16.
Burgess 1998 {published data only}
    1. Burgess C, Ayson M, Rajasingham S, Crane J, Della Cioppa G, Till MD. The extrapulmonary effects of increasing doses of formoterol in patients with asthma. European Journal of Clinical Pharmacology 1998;54(2):141‐7. - PubMed
Canonica 2004 {published data only}
    1. Canonica GW, Castellani P, Cazzola M, Fabbri LM, Fogliani V, Mangrella M, et al. Adjustable maintenance dosing with budesonide/formoterol in a single inhaler provides effective asthma symptom control at a lower dose than fixed maintenance dosing. Pulmonary Pharmacology and Therapeutics 2004;17(4):239‐47. - PubMed
Ceylan 2004 {published data only}
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Chawes 2014 {published data only}
    1. Chawes BL, Govoni M, Piccinno A, Kreiner‐Møller E, Vissing NH, Mortensen L, et al. A clinical pharmacology study of fixed vs. free combination of inhaled beclometasone dipropionate and formoterol fumarate dry powder inhalers in asthmatic adolescents. British Journal of Clinical Pharmacology 2014;78(5):1169‐71. - PMC - PubMed
ChiCTR1800019852 {published data only}
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Dhillon 2006 {published data only}
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FitzGerald 1999 {published data only}
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FitzGerald 2003 {published data only}
    1. FitzGerald JM, Sears MR, Boulet LP, Becker AB, McIvor AR, Ernst P, et al. Adjustable maintenance dosing with budesonide/formoterol reduces asthma exacerbations compared with traditional fixed dosing: a five‐month multicentre Canadian study. Canadian Respiratory Journal 2003;10(8):427‐34. - PubMed
Haahtela 2006 {published data only}
    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. European Respiratory Journal 2006;28(4):748‐55. - PubMed
Horio 2014 {published data only}
    1. Horio Y, Fujii K, Tsumura S, Hirosako S, Nakamura K, Hirayama S, et al. Low dose of combined budesonide/formoterol (BUD/FM) is better than medium dose of BUD monotherapy in stepping down from medium dose of BUD/FM in controlled asthmatic patients. Respirology 2014;19 (Suppl 3):68.
Ind 2004 {published data only}
    1. Ind PW, Haughney J, Price D, Rosen JP, Kennelly J. Adjustable and fixed dosing with budesonide/formoterol via a single inhaler in asthma patients: the ASSURE study. Respiratory Medicine 2004;98(5):464‐75. - PubMed
Jakopovic 2009 {published data only}
    1. Jakopovic M, Pavicic F, Redzepi G, Plestina S, Jankovic M, Franic Z, et al. Efficacy and safety of budesonide/formoterol combination therapy in asthma patients. Collegium Antropologicum 2009;33(2):587‐91. [0350‐6134] - PubMed
Kozlik‐Feldmann 1996 {published data only}
    1. Kozlik‐Feldmann R, Berg A, Berdel D, Reinhardt D. Long‐term effects of formoterol and salbutamol on bronchial hyperreactivity and beta‐adrenoceptor density on lymphocytes in children with bronchial asthma. European Journal of Medical Research 1996;1(10):465‐70. - PubMed
Lalloo 2003 {published data only}
    1. Lalloo UG, Malolepszy J, Kozma D, Krofta K, Ankerst J, Johansen B, et al. Budesonide and formoterol in a single inhaler improves asthma control compared with increasing the dose of corticosteroid in adults with mild‐to‐moderate asthma. Chest 2003;123(5):1480‐7. - PubMed
Lemanske 2010 {published data only}
    1. Lemanske RF Jr, Mauger DT, Sorkness CA, Pharm D, Jackson DJ, et al. Step‐up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. New England Journal of Medicine 2010;362(11):975‐85. - PMC - PubMed
Leuppi 2003 {published data only}
    1. Leuppi FD, Salzberg M, Meyer L, Bucher SE, Nief M, Brutsche MH, et al. An individualized, adjustable maintenance regimen of budesonide/formoterol provides effective asthma symptom control at a lower overall dose than fixed dosing. Swiss Medical Weekly 2003; Vol. 133, issue 21‐22:302‐9. - PubMed
Lotvall 2006 {published data only}
    1. Lötvall J, Langley S, Woodcock A. Inhaled steroid/long‐acting beta2 agonist combination products provide 24 hours improvement in lung function in adult asthmatic patients. Respiratory Research 2006; Vol. 7:110. - PMC - PubMed
Lundborg 2006 {published data only}
    1. Lundborg M, Wille S, Bjermer L, Tilling B, Lundgren M, Telg G, et al. Maintenance plus reliever budesonide/formoterol compared with a higher maintenance dose of budesonide/formoterol plus formoterol as reliever in asthma: an efficacy and cost‐effectiveness study. Current Medical Research and Opinion 2006;22(5):809‐21. - PubMed
Maspero 2010 {published data only}
    1. Maspero JF, Nolte H, Cherrez‐Ojeda I. Long‐term safety of mometasone furoate/formoterol combination for treatment of patients with persistent asthma. Journal of Asthma 2010;47(10):1106‐15. - PMC - PubMed
McIver 2012 {published data only}
    1. McIver T, Grothe B, Jain M, Dissanayake S. Fluticasone propionate/formoterol fumarate combination therapy has an efficacy profile similar to that of its individual components administered concurrently [Abstract]. Thorax 2012;67 (Suppl 2):A66. Abstract P6.
McIver 2012a {published data only}
    1. McIver T, Grothe B, Jain M, Dissanayake S. Fluticasone propionate/formoterol fumarate combination therapy: treatment effects in patients by baseline asthma severity across the dose range [Abstract]. Thorax 2012;67 (Suppl 2):A68. Abstract P12.
Mitchell 2003 {published data only}
    1. Mitchell C, Jenkins C, Scicchitano R, Rubinfeld A, Kottakis J. Formoterol (Foradil) and medium‐high doses of inhaled corticosteroids are more effective than high doses of corticosteroids in moderate‐to‐severe asthma. Pulmonary Pharmacology and Therapeutics 2003;16(5):299‐306. - PubMed
Molimard 2001 {published data only}
    1. Molimard M, Bourcereau J, Gros V, Bourdeix I, Leynadier F, Duroux P, et al. Comparison between formoterol 12 microg b.i.d. and on‐demand salbutamol in moderate persistent asthma. Respiratory Medicine 2001;95(1):64‐70. - PubMed
Nayak 2010 {published data only}
    1. Nayak A, LaForce C, Nathan RA, Nolte H, Weinstein SF. Mometasone furoate/formoterol administered via a pressurized metered‐dose inhaler improves proportions of SABA‐free days and nights in subjects with persistent asthma [Abstract]. Annals of Allergy, Asthma and Immunology 2010;105(5 (supplement)):A50.
NCT02571777 {published data only}
    1. NCT02571777. Study to compare the efficacy and safety of QVM149 with QMF149 in patients with asthma [A multicenter, randomised, 52‐week, double‐blind, parallel group, active controlled study to compare the efficacy and safety of QVM149 with QMF149 in patients with asthma]. clinicaltrials.gov/ct2/show/NCT02571777 (first received 8 October 2015). [7060522]
Novartis 2005 {published data only}
    1. Novartis FOR258. A 12‐month multicenter, randomized, double‐blind, double‐dummy trial to examine the long‐term tolerability of formoterol 10 µg via the multiple dose dry powder inhaler (MDDPI), both as twice daily maintenance therapy and as on‐demand use in addition to maintenance in patients with persistent asthma. https://www.novctrd.com/CtrdWeb/displaypdf.nov?trialresultid=1596 2005.
O'Byrne 2005 {published data only}
    1. O'Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma [see comment]. American Journal of Respiratory and Critical Care Medicine 2005;171(2):129‐36. - PubMed
O'Byrne 2018 {published data only}
    1. O'Byrne PM, FitzGerald JM, Bateman ED, Barnes PJ, Zhong N, Keen C, et al. Inhaled combined budesonide‐formoterol as needed in mild asthma. New England Journal of Medicine 2018;378(20):1865‐76. - PubMed
Ohta 2008 {published data only}
    1. Ohta K, Adachi M. Efficacy and safety of budesonide/formoterol comparing with budesonide and theophylline in Japanese adult patients with asthma [Abstract]. European Respiratory Society Annual Congress; 2008 Oct 4‐8; Berlin. 04/10/2008:3626.
Overbeek 2005 {published data only}
    1. Overbeek SE, Mulder PG, Baelemans SM, Hoogsteden HC, Prins JB. Formoterol added to low dose budesonide has no additional anti‐inflammatory effect in asthmatic patients. Chest 2005;128:1121‐7. - PubMed
Papi 2007 {published data only}
    1. Papi A, Paggiaro PL, Nicolini G, Vignola AM, Fabbri LM, Zarkovic J, et al. Beclomethasone/formoterol versus budesonide/formoterol combination therapy in asthma. European Respiratory Journal 2007;29(4):682‐9. - PubMed
Pauwels 2003 {published data only}
    1. Pauwels RA, Sears MR, Campbell M, Villasante C, Huang S, Lindh A, et al. Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial. European Respiratory Journal 2003; Vol. 22, issue 5:787‐94. - PubMed
Peters 2008a {published data only}
    1. Peters SP, Rosenwasser LJ, Vervaet P, O'Brien CD. Cardiac safety of budesonide (BUD)/formoterol (FM) pressurized metered dose inhaler (pMDI) pooled data from clinical studies of children, adolescents and adults with asthma [Abstract]. Journal of Allergy and Clinical Immunology 2008;121(2 Suppl 1):S155. Abstract 595.
Pleskow 2003 {published data only}
    1. Pleskow W, LaForce CF, Yegen U, Matos D, Della Cioppa G. Formoterol delivered via the dry powder Aerolizer inhaler versus albuterol MDI and placebo in mild‐to‐moderate asthma: a randomized, double‐blind, double‐dummy trial. Journal of Asthma 2003;40(5):505‐14. - PubMed
Pohl 2006 {published data only}
    1. Pohl WR, Vetter N, Zwick H, Hrubos W. Adjustable maintenance dosing with budesonide/formoterol or budesonide: double‐blind study. Respiratory Medicine 2006;100(3):551‐60. - PubMed
Rabe 2006 {published data only}
    1. Rabe KF, Pizzichini E, Stallberg B, Romero S, Balanzat AM, Atienza T, et al. Budesonide/formoterol in a single inhaler for maintenance and relief in mild‐to‐moderate asthma: a randomized, double‐blind trial. Chest 2006;129(2):246‐56. - PubMed
Rosenhall 2002 {published data only}
    1. Rosenhall L, Heinig JH, Lindqvist A, Leegaard J, Stahl E, Bergqvist PB. Budesonide/formoterol (Symbicort) is well tolerated and effective in patients with moderate persistent asthma. International Journal of Clinical Practice 2002;56(6):427‐33. - PubMed
Rosenhall 2003 {published data only}
    1. Rosenhall L, Borg S, Andersson HF, Ericsson K. Budesonide/formoterol in a single inhaler (Symbicort) reduces healthcare costs compared with separate inhalers in the treatment of asthma over 12 months. International Journal of Clinical Practice 2003;57(8):662‐7. - PubMed
Rosenhall 2003a {published data only}
    1. Rosenhall L, Elvstrand A, Tilling B, Vinge I, Jemsby P, Stahl E, et al. One‐year safety and efficacy of budesonide/formoterol in a single inhaler (Symbicort Turbuhaler) for the treatment of asthma. Respiratory Medicine 2003;97(6):702‐8. - PubMed
Rosenwasser 2008 {published data only}
    1. Rosenwasser LJ, Peters SP, Vervaet P, O'Brien CD. Tolerability of budesonide (BUD)/formoterol (FM) pressurized metered dose inhaler (pMDI) pooled adverse event (AE) data from clinical studies of children, adolescents and adults with asthma [Abstract]. Journal of Allergy and Clinical Immunology 2008;121(2 Suppl 1):S154. Abstract 591.
Saito 2011 {published data only}
    1. Saito T, Hasunuma T. Safety and tolerability of high‐dose budesonide/formoterol via Turbuhaler in Japanese patients with asthma: phase III study results. American Journal of Respiratory and Critical Care Medicine 2011;183(Meeting Abstracts):A4489.
Scicchitano 2004 {published data only}
    1. Scicchitano R, Aalbers R, Ukena D, Manjra A, Fouquert L, Centann S, et al. Efficacy and safety of budesonide/formoterol single inhaler therapy versus a higher dose of budesonide in moderate to severe asthma. Current Medical Research and Opinion 2004;20(9):1403‐18. - PubMed
Stelmach 2007 {published data only}
    1. Stelmach I, Grzelewski T, Bobrowska‐Korzeniowska M, Stelmach P, Kuna P. A randomized, double‐blind trial of the effect of anti‐asthma treatment on lung function in children with asthma. Pulmonary Pharmacology and Therapeutics 2007;20(6):691‐700. [1094‐5539: (Print)] - PubMed
UMIN000010333 {published data only}
    1. UMIN000010333. Study of step‐down therapy from formoterol/budesonide combinations in patients with asthma. upload.umin.ac.jp/cgi‐open‐bin/ctr_e/ctr_view.cgi?recptno=R000012095 (first received 27 March 2013).
van der Molen 1997 {published data only}
    1. Molen T, Postma DS, Turner MO, Jong BM, Malo JL, Chapman K, et al. Effects of the long acting beta agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids. The Netherlands and Canadian Formoterol Study Investigators. Thorax 1997;52(6):535‐9. - PMC - PubMed
Villa 2002 {published data only}
    1. Villa J, Kuna P, Egner J, Brander R. A 6‐month comparison of the safety profiles of formoterol (Oxis®) Turbuhaler® as needed and terbutaline (Bricanyl®) Turbuhaler® as needed in asthmatic children on anti‐inflammatory medication [Abstract]. American Journal of Respiratory and Critical Care Medicine 2002; Vol. 165, issue 8 Suppl:A746.
Von Berg 2003 {published data only}
    1. Berg A, Papageorgiou Saxoni F, Wille S, Carrillo T, Kattamis C, Helms PJ. Efficacy and tolerability of formoterol Turbuhaler in children. International Journal of Clinical Practice 2003;57(10):852‐6. - PubMed
Weinstein 2010a {published data only}
    1. Weinstein S, Nathan RA, Meltzer E, Nolte H, Maspero J. Treatment of persistent asthma with mometasone furoate/formoterol combination therapy is associated with a low incidence of oral candidiasis and dysphonia [Abstract]. Congress of the Asian Pacific Society of Respirology; 2010 Nov 22‐25; Manila. 2010.
White 2010 {published data only}
    1. White M, Meltzer EO, Nathan RA, Nolte H. Improved asthma control with mometasone furoate/formoterol: a new combination treatment for persistent asthma [Abstract]. Annals of Allergy, Asthma and Immunology 2010;105(5 (supplement)):A49.
Worth 2005 {published data only}
    1. Worth H. DESOLO ‐ SiT Peri‐Launch: a comparison of Symbicort single inhaler therapy and conventional best practice for the treatment of persistent asthma in adults [A comparison of Symbicort single inhaler therapy (Symbicort Turbuhaler 160/4.5 µg, 1 inhalation b.i.d. plus as needed) and conventional best practice for the treatment of persistent asthma in adults ‐ a 26‐week, randomised, open‐label, parallel‐group, multicentre study]. clinicaltrials.gov/ct2/show/NCT00252863 (first received 15 November 2005).
Zetterström 2000 {published data only}
    1. Zetterström O, Buhl R, Mellem H, Perpiñá M, Hedman J, O'Neill S, et al. Efficacy and safety of a new single inhaler product containing both budesonide and formoterol in adult asthma. European Respiratory Journal 2000;16(Suppl 31):455s. Abstract P3198.
Zetterstrom 2001a {published data only}
    1. Zetterstrom O, Buhl R, Mellem H. Efficacy and safety of Symbicort® budesonide and formoterol in a single inhaler in adults with asthma. Annual Thoracic Society 97th International Conference; 2001 May 18‐23; San Francisco. 2001.

References to ongoing studies

NCT02554786 {published data only}
    1. NCT02554786. A multicenter randomised 52 week treatment double‐blind, triple dummy parallel group study to assess the efficacy and safety of QMF149 compared to mometasone furoate in patients with asthma. clinicaltrials.gov/ct2/show/NCT02554786 (first received 18 September 2015).
NCT02741271 {published data only}
    1. NCT02741271. Study of efficacy and long‐term safety of mometasone furoate in combination with formoterol fumarate versus mometasone furoate in children (5 to 11 years of age) with persistent asthma (MK‐0887A‐087) [A phase III, randomized, active‐controlled, parallel‐group clinical trial to study the efficacy and long‐term safety of mometasone furoate/formoterol fumarate (MF/F, MK‐0887A [SCH418131]), compared with mometasone furoate (MF, MK‐0887 [SCH032088]), in children with persistent asthma]. clinicaltrials.gov/ct2/show/NCT02741271 (first received 18 April 2016).

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