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. 2023 Aug 21;8(8):CD013797.
doi: 10.1002/14651858.CD013797.pub2.

Addition of long-acting beta2 agonists or long-acting muscarinic antagonists versus doubling the dose of inhaled corticosteroids (ICS) in adolescents and adults with uncontrolled asthma with medium dose ICS: a systematic review and network meta-analysis

Yuji Oba  1 , Sumayya Anwer  2 , Tarang Patel  1 , Tinashe Maduke  1 , Sofia Dias  2
Affiliations

Addition of long-acting beta2 agonists or long-acting muscarinic antagonists versus doubling the dose of inhaled corticosteroids (ICS) in adolescents and adults with uncontrolled asthma with medium dose ICS: a systematic review and network meta-analysis

Yuji Oba et al. Cochrane Database Syst Rev. .

Abstract

Background: Inhaled corticosteroids (ICS) are the mainstay treatment for persistent asthma. Escalating treatment is required when asthma is not controlled with ICS therapy alone, which would include, but is not limited to, adding a long-acting beta2-agonist (LABA) or a long-acting muscarinic antagonist (LAMA) or doubling the dose of ICS.

Objectives: To assess the efficacy and safety of adding a LABA or LAMA to ICS therapy versus doubling the dose of ICS in adolescents and adults whose asthma is not well controlled on medium-dose (MD)-ICS using a network meta-analysis (NMA), and to provide a ranking of these treatments according to their efficacy and safety.

Search methods: We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, Global Health, ClinicalTrials.gov, and the World Health Organization ICTRP for pre-registered randomised controlled trials (RCTs) from January 2008 to 19 December 2022.

Selection criteria: We searched for studies including adolescents and adults with uncontrolled asthma who had been treated with or were eligible for MD-ICS, comparing it to high-dose (HD)-ICS, ICS/LAMA, or ICS/LABA. We excluded cluster- and cross-over RCTs. Studies were of at least 12 weeks duration.

Data collection and analysis: We conducted a systematic review and network meta-analysis according to a previously published protocol. We used Cochrane's Screen4ME workflow to assess search results. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. The primary outcome is asthma exacerbations (moderate and severe).

Main results: We included 38,276 participants from 35 studies (median duration 24 weeks (range 12 to 78); mean age 44.1; 38% male; 69% white; mean forced expiratory volume in one second 2.1 litres and 68% of predicted). MD- and HD-ICS/LABA likely reduce and MD-ICS/LAMA possibly reduces moderate to severe asthma exacerbations compared to MD-ICS (hazard ratio (HR) 0.70, 95% credible interval (CrI) 0.59 to 0.82; moderate certainty; HR 0.59, 95% CrI 0.46 to 0.76; moderate certainty; and HR 0.56, 95% CrI 0.38 to 0.82; low certainty, respectively), whereas HD-ICS probably does not (HR 0.94, 95% CrI 0.70 to 1.24; moderate certainty). There is no clear evidence to suggest that any combination therapy or HD-ICS reduces severe asthma exacerbations compared to MD-ICS (low to moderate certainty). This study suggests no clinically meaningful differences in the symptom or quality of life score between dual combinations and monotherapy (low to high certainty). MD- and HD-ICS/LABA increase or likely increase the odds of Asthma Control Questionnaire (ACQ) responders at 6 and 12 months compared to MD-ICS (odds ratio (OR) 1.47, 95% CrI 1.23 to 1.76; high certainty; and OR 1.59, 95% CrI 1.31 to 1.94; high certainty at 6 months; and OR 1.61, 95% CrI 1.22 to 2.13; moderate certainty and OR 1.55, 95% CrI 1.20 to 2.00; high certainty at 12 months, respectively). MD-ICS/LAMA probably increases the odds of ACQ responders at 6 months (OR 1.32, 95% CrI 1.11 to 1.57; moderate certainty). No data were available at 12 months. There is no clear evidence to suggest that HD-ICS increases the odds of ACQ responders or improves the symptom or qualify of life score compared to MD-ICS (very low to high certainty). There is no evidence to suggest that ICS/LABA or ICS/LAMA reduces asthma-related or all-cause serious adverse events (SAEs) compared to MD-ICS (very low to high certainty). HD-ICS results in or likely results in little or no difference in the included safety outcomes compared to MD-ICS as well as HD-ICS/LABA compared to MD-ICS/LABA. The pairwise meta-analysis shows that MD-ICS/LAMA likely reduces all-cause adverse events (AEs) and results in a slight reduction in treatment discontinuation due to AEs compared to MD-ICS (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.77 to 0.96; 4 studies, 2238 participants; moderate certainty; and RR 0.51, 95% CI 0.26 to 0.99; 4 studies, 2239 participants; absolute risk reduction 10 fewer per 1000 participants; moderate certainty, respectively). The NMA evidence is in agreement with the pairwise evidence on treatment discontinuation due to AEs, but very uncertain on all-cause AEs, due to imprecision and heterogeneity.

Authors' conclusions: The review findings suggest that MD- or HD-ICS/LABA and MD-ICS/LAMA reduce moderate to severe asthma exacerbations and increase the odds of ACQ responders compared to MD-ICS whereas HD-ICS probably does not. The evidence is generally stronger for MD- and HD-ICS/LABA than for MD-ICS/LAMA primarily due to a larger evidence base. There is no evidence to suggest that ICS/LABA, ICS/LAMA, or HD-ICS/LABA reduces severe asthma exacerbations or SAEs compared to MD-ICS. MD-ICS/LAMA likely reduces all-cause AEs and results in a slight reduction in treatment discontinuation due to AEs compared to MD-ICS. The above findings may assist in deciding on a treatment option during the stepwise approach of asthma management. Longer-term safety of higher than medium-dose ICS needs to be addressed in phase 4 or observational studies given that the median duration of included studies was six months.

Trial registration: ClinicalTrials.gov NCT00565266.

PubMed Disclaimer

Conflict of interest statement

Y. Oba has provided consultation and received honoraria from Genentech unrelated to the current review. This author, who is a Cochrane Editor, was not involved in the editorial process.

T Patel: none known.

S Anwer: none known.

T Maduke: none known.

S Dias: none known.

Figures

1
1
2
2
Network diagram for severe exacerbations Nodes colours denote the treatment group. Nodes are scaled proportional to the number of patients who received a particular treatment. The widths of the lines joining two nodes are weighted according to the number of studies that provide evidence on that comparison. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; LD: low dose; MD: medium dose.
3
3
Plot of hazard ratios (HRs) relative for severe exacerbations Hazard ratios less than one favour the first named treatment. CrI: credible interval; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; LD: low dose; MD: medium dose
4
4
Forest plot for threshold analysis for severe exacerbations (random‐effects model) Treatment codes: 1 = MD‐ICS, 2 = HD‐ICS, 3 = LD‐ICS/LABA, 4 = MD‐ICS/LAMA, 5 = MD‐ICS/LABA, 6 = HD‐ICS/LABA. The optimum treatment for this analysis was MD‐ICS/LAMA. HD: high dose; HR: hazard ratio; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; LD: low dose; MD: medium dose.
5
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Network diagram for moderate to severe exacerbations Nodes colours denote the treatment group. Nodes are scaled proportional to the number of patients who received a particular treatment. The widths of the lines joining two nodes are weighted according to the number of studies that provide evidence on that comparison. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; LD: low dose; MD: medium dose.
6
6
Plot of hazard ratios (HRs) relative for moderate to severe exacerbations Hazard ratios less than one favour the first named treatment. CrI: credible interval; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; LD: low dose; MD: medium dose.
7
7
Forest plot for threshold analysis for moderate to severe exacerbations (random‐effects model) Treatment Codes: 1 = MD‐ICS, 2 = HD‐ICS, 3 = LD‐ICS/LABA, 4 = MD‐ICS/LAMA, 5 = MD‐ICS/LABA, 6 = HD‐ICS/LABA. The optimum treatment for this analysis was LD‐ICS/LABA. HD: high dose; HR: hazard ratio; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; LD: low dose; MD: medium dose.
8
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Network diagram for change from baseline ACQ score at 3 months Nodes colours denote the treatment group. Nodes are scaled proportional to the number of patients who received a particular treatment. The widths of the lines joining two nodes are weighted according to the number of studies that provide evidence on that comparison. ACQ: Asthma Control Questionnaire; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LD: low dose; MD: medium dose.
9
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Plot of relative effects for the change from baseline ACQ score at 3 months using a fixed‐effect model Mean differences less than zero favour the first named treatment. ACQ: Asthma Control Questionnaire; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonistLD: low dose; MD: medium dose
10
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Network diagram for change from baseline ACQ score at 6 months Nodes colours denote the treatment group. Nodes are scaled proportional to the number of patients who received a particular treatment. The widths of the lines joining two nodes are weighted according to the number of studies that provide evidence on that comparison. ACQ: Asthma Control Questionnaire; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; MD: medium dose.
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Plot of relative effects for the change from baseline in ACQ score at 6 months using the fixed‐effect model Mean differences less than zero favour the first named treatment. ACQ: Asthma Control Questionnaire; CrI: credible interval; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; MD: mean difference; MD: medium dose.
12
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Network diagram for change from baseline ACQ score at 12 months Nodes colours denote the treatment group. Nodes are scaled proportional to the number of patients who received a particular treatment. The widths of the lines joining two nodes are weighted according to the number of studies that provide evidence on that comparison. ACQ: Asthma Control Questionnaire; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; MD: medium dose.
13
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Plot of relative effects for the change from baseline ACQ score at 12 months using a fixed‐effect (FE) and a random‐effects (RE) model Mean differences (MD) less than zero favour the first named treatment. ACQ: Asthma Control Questionnaire; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; MD: medium dose.
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Network diagram for change from baseline AQLQ score at 3 months Nodes colours denote the treatment group. Nodes are scaled proportional to the number of patients who received a particular treatment. The widths of the lines joining two nodes are weighted according to the number of studies that provide evidence on that comparison. AQLQ: Asthma Quality of Life Questionnaire; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; MD: medium dose.
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Plot of relative effects for the change from baseline AQLQ score at 3 months using a fixed‐effect model Mean differences (MDs) greater than zero favour the first named treatment. AQLQ: Asthma Quality of Life Questionnaire; CrI: credible interval; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; MD: medium dose.
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Network diagram for change from baseline AQLQ score at 6 months Nodes colours denote the treatment group. Nodes are scaled proportional to the number of patients who received a particular treatment. The widths of the lines joining two nodes are weighted according to the number of studies that provide evidence on that comparison. AQLQ: Asthma Quality of Life Questionnaire; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LD: low dose; MD: medium dose.
17
17
Plot of relative effects for the change from baseline AQLQ score at 6 months using fixed‐ (FE) and random‐effects (RE) model Mean differences (MDs) greater than zero favour the first named treatment. AQLQ: Asthma Quality of Life Questionnaire; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LD: low dose; MD: medium dose.
18
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Network diagram for ACQ response at 6 months Nodes colours denote the treatment group. Nodes are scaled proportional to the number of patients who received a particular treatment. The widths of the lines joining two nodes are weighted according to the number of studies that provide evidence on that comparison. ACQ: Asthma Control Questionnaire; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; MD: medium dose.
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Plot of odds ratios relative for ACQ responders at 6 months (fixed‐effect model) Odds ratios (ORs) greater than one favour the first named treatment. ACQ: Asthma Control Questionnaire; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; MD: medium dose.
20
20
Network diagram for ACQ response at 12 months Nodes colours denote the treatment group. Nodes are scaled proportional to the number of patients who received a particular treatment. The widths of the lines joining two nodes are weighted according to the number of studies that provide evidence on that comparison. ACQ: Asthma Control Questionnaire; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; MD: medium dose.
21
21
Plot of odds ratios for ACQ responders at 12 months for the fixed‐effect model Odds ratios (ORs) greater than one favour the first named treatment. ACQ: Asthma Control Questionnaire; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; MD: medium dose.
22
22
Network diagram for asthma‐related SAEs Nodes colours denote the treatment group. Nodes are scaled proportional to the number of patients who received a particular treatment. The widths of the lines joining two nodes are weighted according to the number of studies that provide evidence on that comparison. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; LD: low dose; MD: medium dose; SAE: serious adverse event.
23
23
Plots of odds ratios relative for asthma‐related SAEs for fixed‐effect and random‐effects models Odds ratios (ORs) less than one favour the first named treatment. CrI: credible interval; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; LD: low dose; MD: medium dose; SAE: serious adverse event.
24
24
Network diagram for all‐cause SAEs Nodes colours denote the treatment group. Nodes are scaled proportional to the number of patients who received a particular treatment. The widths of the lines joining two nodes are weighted according to the number of studies that provide evidence on that comparison. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; LD: low dose; MD: medium dose; SAE: serious adverse event.
25
25
Plots of odds ratios for all‐cause SAEs for the fixed‐effect (FE) and random‐effects (RE) models Odds ratios (ORs) less than one favour the first named treatment. CrI: credible interval; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; LD: low dose; MD: medium dose; SAE: serious adverse event.
26
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Network diagram for all‐cause AEs Nodes colours denote the treatment group. Nodes are scaled proportional to the number of patients who received a particular treatment. The widths of the lines joining two nodes are weighted according to the number of studies that provide evidence on that comparison. AE: adverse event; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; LD: low dose; MD: medium dose.
27
27
Plots of odds ratios for all‐cause AEs (fixed‐effect model) Odds ratios (ORs) less than one favour the first named treatment. AE: adverse event; CrI: credible interval; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; LD: low dose; MD: medium dose.
28
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Network diagram for dropouts due to AEs Nodes colours denote the treatment group. Nodes are scaled proportional to the number of patients who received a particular treatment. The widths of the lines joining two nodes are weighted according to the number of studies that provide evidence on that comparison. AE: adverse event; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; LD: low dose; MD: medium dose.
29
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Plots of odds ratios for dropouts due to AEs (fixed‐effect (FE) and random‐effects (RE) models) Odds ratios (ORs) less than one favour the first named treatment. AE: adverse event; CrI: credible interval; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta2 agonist; LAMA: long‐acting muscarinic antagonist; LD: low dose; MD: medium dose.
1.1
1.1. Analysis
Comparison 1: Exacerbations, Outcome 1: Severe exacerbations
1.2
1.2. Analysis
Comparison 1: Exacerbations, Outcome 2: Moderate to severe exacerbations
2.1
2.1. Analysis
Comparison 2: Severe exacerbations (high‐ and low‐risk subgroups), Outcome 1: HD‐ICS vs MD‐ICS
2.2
2.2. Analysis
Comparison 2: Severe exacerbations (high‐ and low‐risk subgroups), Outcome 2: MD‐ICS/LAMA vs MD‐ICS
2.3
2.3. Analysis
Comparison 2: Severe exacerbations (high‐ and low‐risk subgroups), Outcome 3: MD‐ICS/LABA vs MD‐ICS
2.4
2.4. Analysis
Comparison 2: Severe exacerbations (high‐ and low‐risk subgroups), Outcome 4: HD‐ICS/LABA vs MD‐ICS
2.5
2.5. Analysis
Comparison 2: Severe exacerbations (high‐ and low‐risk subgroups), Outcome 5: MD‐ICS/LABA vs HD‐ICS
2.6
2.6. Analysis
Comparison 2: Severe exacerbations (high‐ and low‐risk subgroups), Outcome 6: HD‐ICS/LABA vs HD‐ICS
2.7
2.7. Analysis
Comparison 2: Severe exacerbations (high‐ and low‐risk subgroups), Outcome 7: MD‐ICS/LABA vs LD‐ICS/LABA
2.8
2.8. Analysis
Comparison 2: Severe exacerbations (high‐ and low‐risk subgroups), Outcome 8: HD‐ICS/LABA vs MD‐ICS/LABA
2.9
2.9. Analysis
Comparison 2: Severe exacerbations (high‐ and low‐risk subgroups), Outcome 9: ICS/LAMA vs ICS
2.10
2.10. Analysis
Comparison 2: Severe exacerbations (high‐ and low‐risk subgroups), Outcome 10: ICS/LABA vs ICS
3.1
3.1. Analysis
Comparison 3: Moderate to severe exacerbations (high‐ and low‐risk subgroups), Outcome 1: HD‐ICS vs MD‐ICS
3.2
3.2. Analysis
Comparison 3: Moderate to severe exacerbations (high‐ and low‐risk subgroups), Outcome 2: MD‐ICS/LAMA vs MD‐ICS
3.3
3.3. Analysis
Comparison 3: Moderate to severe exacerbations (high‐ and low‐risk subgroups), Outcome 3: MD‐ICS/LABA vs MD‐ICS
3.4
3.4. Analysis
Comparison 3: Moderate to severe exacerbations (high‐ and low‐risk subgroups), Outcome 4: HD‐ICS/LABA vs MD‐ICS
3.5
3.5. Analysis
Comparison 3: Moderate to severe exacerbations (high‐ and low‐risk subgroups), Outcome 5: MD‐ICS/LABA vs HD‐ICS
3.6
3.6. Analysis
Comparison 3: Moderate to severe exacerbations (high‐ and low‐risk subgroups), Outcome 6: HD‐ICS/LABA vs HD‐ICS
3.7
3.7. Analysis
Comparison 3: Moderate to severe exacerbations (high‐ and low‐risk subgroups), Outcome 7: MD‐ICS/LABA vs LD‐ICS/LABA
3.8
3.8. Analysis
Comparison 3: Moderate to severe exacerbations (high‐ and low‐risk subgroups), Outcome 8: HD‐ICS/LABA vs MD‐ICS/LABA
3.9
3.9. Analysis
Comparison 3: Moderate to severe exacerbations (high‐ and low‐risk subgroups), Outcome 9: ICS/LABA vs ICS
4.1
4.1. Analysis
Comparison 4: Change from baseline in ACQ, Outcome 1: Change from baseline in ACQ at 3 months
4.2
4.2. Analysis
Comparison 4: Change from baseline in ACQ, Outcome 2: Change from baseline in ACQ at 6 months
4.3
4.3. Analysis
Comparison 4: Change from baseline in ACQ, Outcome 3: Change from baseline in ACQ at 12 months
5.1
5.1. Analysis
Comparison 5: Change from baseline in AQLQ, Outcome 1: Change from baseline in AQLQ at 3 months
5.2
5.2. Analysis
Comparison 5: Change from baseline in AQLQ, Outcome 2: Change from baseline in AQLQ at 6 months
6.1
6.1. Analysis
Comparison 6: ACQ responder, Outcome 1: ACQ responder at 6 months
6.2
6.2. Analysis
Comparison 6: ACQ responder, Outcome 2: ACQ responder at 12 months
7.1
7.1. Analysis
Comparison 7: Safety outcomes, Outcome 1: Asthma‐related SAEs
7.2
7.2. Analysis
Comparison 7: Safety outcomes, Outcome 2: All‐cause SAEs
7.3
7.3. Analysis
Comparison 7: Safety outcomes, Outcome 3: All‐cause AEs
7.4
7.4. Analysis
Comparison 7: Safety outcomes, Outcome 4: Dropouts due to adverse events
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Update of

  • doi: 10.1002/14651858.CD013797

References

References to studies included in this review

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    1. Kerstjens HA, Casale TB, Bleecker ER, Meltzer EO, Pizzichini E, Schmidt O, et al. Tiotropium or salmeterol as add-on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, placebo-controlled, parallel-group, active-comparator, randomised trials. Lancet Respiratory Medicine 2015;3(5):367-76. [DOI: 10.1016/S2213-2600(15)00031-4] [PMID: ] - DOI - PubMed
Kerstjens 2015b   {published data only}
    1. Kerstjens HA, Casale TB, Bleecker ER, Meltzer EO, Pizzichini E, Schmidt O, et al. Tiotropium or salmeterol as add-on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, placebo-controlled, parallel-group, active-comparator, randomised trials. Lancet Respiratory Medicine 2015;3(5):367-76. [DOI: 10.1016/S2213-2600(15)00031-4] [PMID: ] - DOI - PubMed
Kerstjens 2020 {published data only}
    1. Kerstjens HAM, Maspero J, Chapman KR, Zyl-Smit RN, Hosoe M, Tanase AM, et al. Once-daily, single-inhaler mometasone-indacaterol-glycopyrronium versus mometasone-indacaterol or twice-daily fluticasone-salmeterol in patients with inadequately controlled asthma (IRIDIUM): a randomised, double-blind, controlled phase 3 study. Lancet Respiratory Medicine 2020;8(10):1000-12. [DOI: 10.1016/S2213-2600(20)30190-9] [PMID: ] - DOI - PubMed
Kerwin 2011 {published and unpublished data}
    1. Kerwin E, Prazma CM, Sutton L, Stempel DA. Safety and efficacy of long-term treatment with fluticasone propionate and salmeterol via DISKUS versus fluticasone propionate alone. Clinical Research and Regulatory Affairs 2011;28(1):14-21. [DOI: 10.3109/10601333.2010.544315] - DOI
Kerwin 2020 {published data only}
    1. Kerwin E, Pascoe S, Bailes Z, Nathan R, Bernstein D, Dahl R, et al. A phase IIb, randomised, parallel-group study: the efficacy, safety and tolerability of once-daily umeclidinium in patients with asthma receiving inhaled corticosteroids. Respiratory Research 2020;21(1):148. [DOI: 10.1186/s12931-020-01400-5] [PMID: ] - DOI - PMC - PubMed
Lee 2020 {published data only}
    1. Lee LA, Bailes Z, Barnes N, Boulet LP, Edwards D, Fowler A, et al. Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial. Lancet Respiratory Medicine 2021;9(1):69-84. [DOI: 10.1016/S2213-2600(20)30389-1] [PMID: ] - DOI - PubMed
Lin 2015 {published data only}
    1. Lin J, Kang J, Lee SH, Wang C, Zhou X, Crawford J, et al. Fluticasone furoate/vilanterol 200/25 mcg in Asian asthma patients: a randomized trial. Respiratory Medicine 2015;109(1):44-53. [DOI: 10.1016/j.rmed.2014.10.012] [PMID: ] - DOI - PubMed
Lotvall 2014 {published and unpublished data}
    1. Lötvall J, Bleecker ER, Busse WW, O'Byrne PM, Woodcock A, Kerwin EM, et al. Efficacy and safety of fluticasone furoate 100 μg once-daily in patients with persistent asthma: a 24-week placebo and active-controlled randomised trial. Respiratory Medicine 2014;108(1):41-9. [DOI: 10.1016/j.rmed.2013.11.009] [PMID: ] - DOI - PubMed
Mansfield 2017 {published data only}
    1. Mansfield L, Yiu G, Sakov A, Liu S, Caracta C. A 6-month safety and efficacy study of fluticasone propionate and fluticasone propionate/salmeterol multidose dry powder inhalers in persistent asthma. Allergy & Asthma Proceedings 2017;38(4):264-76. [DOI: 10.2500/aap.2017.38.4061] [PMID: ] - DOI - PubMed
Murphy 2015 {published data only}
    1. Murphy KR, Dhand R, Trudo F, Uryniak T, Aggarwal A, et al. Therapeutic equivalence of budesonide/formoterol delivered via breath-actuated inhaler vs pMDI. Respiratory Medicine 2015;109(2):170-9. [DOI: 10.1016/j.rmed.2014.12.009] [PMID: ] - DOI - PubMed
Nathan 2010 {published data only}
    1. Nathan RA, Nolte H, Pearlman DS. Twenty-six-week efficacy and safety study of mometasone furoate/formoterol 200/10 microg combination treatment in patients with persistent asthma previously receiving medium-dose inhaled corticosteroids. Allergy & Asthma Proceedings 2010;31(4):269-79. [DOI: 10.2500/aap.2010.31.3364] [PMID: ] - DOI - PubMed
O'Byrne 2014 {published data only}
    1. O'Byrne PM, Bleecker ER, Bateman ED, Busse WW, Woodcock A, Forth R, et al. Once-daily fluticasone furoate alone or combined with vilanterol in persistent asthma. European Respiratory Journal 2014;43(3):773-82. [DOI: 10.1183/09031936.00064513] [PMID: ] - DOI - PMC - PubMed
Paggiaro 2016b {published data only}
    1. Paggiaro P, Halpin DM, Buhl R, Engel M, Zubek VB, Blahova Z, et al. The effect of tiotropium in symptomatic asthma despite low- to medium-dose inhaled corticosteroids: a randomized controlled trial. Journal of Allergy and Clinical Immunology: In Practice 2016;4(1):104-13. [DOI: 10.1016/j.jaip.2015.08.017] [PMID: ] - DOI - PubMed
Papi 2007 {published data only}
    1. Papi A, Paggiaro P, Nicolini G, Vignola AM, Fabbri LM. Beclomethasone/formoterol vs fluticasone/salmeterol inhaled combination in moderate to severe asthma. Allergy 2007 Oct;62(10):1182-8. [DOI: 10.1111/j.1398-9995.2007.01493.x] [PMID: ] - DOI - PubMed
Pedersen 2017 {published data only}
    1. Pedersen SE, Prasad N, Goehring UM, Andersson H, Postma DS. Control of moderate-to-severe asthma with randomized ciclesonide doses of 160, 320 and 640 μg/day. Journal of Asthma and Allergy 2017;10:35-46. [DOI: 10.2147/JAA.S111712] [PMID: ] - DOI - PMC - PubMed
Pertseva 2013 {published data only}
    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. [DOI: 10.1185/03007995.2013.825592] [PMID: ] - DOI - PubMed
Peters 2008 {published data only}
    1. Peters SP, Prenner BM, Mezzanotte WS, Martin P, O'Brien CD. Long-term safety and asthma control with budesonide/formoterol versus budesonide pressurized metered-dose inhaler in asthma patients. Allergy & Asthma Proceedings 2008;29(5):499-516. [DOI: 10.2500/aap.2008.29.3147] [PMID: ] - DOI - PubMed
Peters 2016 {published data only}
    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. [DOI: 10.1056/NEJMoa1511190] [PMID: ] - DOI - PubMed
Sher 2017 {published data only}
    1. Sher LD, Yiu G, Sakov A, Liu S, Caracta CF. Fluticasone propionate and fluticasone propionate/salmeterol multidose dry powder inhalers compared with placebo for persistent asthma. Allergy & Asthma Proceedings 2017;38(5):343-53. [DOI: 10.2500/aap.2017.38.4069] [PMID: ] - DOI - PubMed
Spector 2012 {published data only}
    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. [DOI: 10.3109/02770903.2011.633788] [PMID: ] - DOI - PubMed
Stempel 2016 {published data only}
    1. Stempel DA, Raphiou IH, Kral KM, Yeakey AM, Emmett AH, Prazma CM, et al. Serious asthma events with fluticasone plus salmeterol versus fluticasone alone. New England Journal of Medicine 2016;374(19):1822-30. [DOI: 10.1056/NEJMoa1511049] [PMID: ] - DOI - PubMed
Stirbulov 2012 {published data only}
    1. Stirbulov R, Fritscher CC, Pizzichini E, Pizzichini MM. 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. Brazilian Journal of Pulmonology 2012;38(4):431-7. [DOI: 10.1590/s1806-37132012000400004] [PMID: ] - DOI - PubMed
van Zyl‐Smit 2020 {published data only}
    1. Zyl-Smit RN, Krüll M, Gessner C, Gon Y, Noga O, Richard A, et al. Once-daily mometasone plus indacaterol versus mometasone or twice-daily fluticasone plus salmeterol in patients with inadequately controlled asthma (PALLADIUM): a randomised, double-blind, triple-dummy, controlled phase 3 study. Lancet Respiratory Medicine 2020;8(10):987-99. [DOI: 10.1016/S2213-2600(20)30178-8] [PMID: ] - DOI - PubMed
Weinstein 2010 {published data only}
    1. Weinstein SF, Corren J, Murphy K, Nolte H, White M. Twelve-week efficacy and safety study of mometasone furoate/formoterol 200/10 microg and 400/10 microg combination treatments in patients with persistent asthma previously receiving high-dose inhaled corticosteroids. Allergy & Asthma Proceedings 2010;31(4):280-9. [DOI: 10.2500/aap.2010.31.3381] [PMID: ] - DOI - PubMed
Woodcock 2013 {published data only}
    1. Woodcock A, Bleecker ER, Lötvall J, O'Byrne PM, Bateman ED, Medley H, et al. Efficacy and safety of fluticasone furoate/vilanterol compared with fluticasone propionate/salmeterol combination in adult and adolescent patients with persistent asthma: a randomized trial. Chest 2013;144(4):1222-9. [DOI: 10.1378/chest.13-0178] [PMID: ] - DOI - PMC - PubMed
Woodcock 2014 {published data only}
    1. Woodcock A, Lötvall J, Busse WW, Bateman ED, Stone S, Ellsworth A, et al. Efficacy and safety of fluticasone furoate 100 μg and 200 μg once daily in the treatment of moderate-severe asthma in adults and adolescents: a 24-week randomised study. BMC Pulmonary Medicine 2014;14:113. [DOI: 10.1186/1471-2466-14-113] [PMID: ] - DOI - PMC - PubMed
Zangrilli 2011 {published data only}
    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 & Immunology 2011;107(3):258-65. [DOI: 10.1016/j.anai.2011.05.024] [PMID: ] - DOI - PubMed

References to studies excluded from this review

Amar 2016 {published data only}
    1. Amar NJ, Moss MH, Kerwin EM, Li J, Small CJ. Safety and efficacy of beclomethasone dipropionate delivered by breath-actuated or metered-dose inhaler for persistent asthma. Allergy & Asthma Proceedings 2016;37(5):359-69. [DOI: 10.2500/aap.2016.37.3983] [PMID: ] - DOI - PubMed
Antilla 2014 {published data only}
    1. Antilla M, Castro F, Cruz Á, Rubin A, Rosário N, Stelmach R. Efficacy and safety of the single-capsule combination of fluticasone/formoterol in patients with persistent asthma: a non-inferiority trial. Brazilian Journal of Pulmonology 2014;40(6):599-608. [DOI: 10.1590/S1806-37132014000600003] [PMID: ] - DOI - PMC - PubMed
Barnes 2013 {published data only}
    1. Barnes N, Noord JA, Brindicci C, Lindemann L, Varoli G, Perpiña M, et al. Stepping-across controlled asthmatic patients to extrafine beclometasone/formoterol combination. Pulmonary Pharmacology and Therapeutics 2013;26(5):555-61. [DOI: 10.1016/j.pupt.2013.01.011] [PMID: ] - DOI - PubMed
Bateman 2011 {published data only}
    1. Bateman ED, Kornmann O, Schmidt P, Pivovarova A, Engel M, Fabbri LM. Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma. Journal of Allergy and Clinical Immunology 2011;128(2):315-22. [DOI: 10.1016/j.jaci.2011.06.004] [PMID: ] - DOI - PubMed
Berger 2010 {published data only}
    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 & Asthma Proceedings 2010;31(1):49-59. [DOI: 10.2500/aap.2010.31.3309] [PMID: ] - DOI - PubMed
Bernstein 2018 {published data only}
    1. Bernstein D, Andersen L, Forth R, Jacques L, Yates L. Once-daily fluticasone furoate/vilanterol versus twice-daily fluticasone propionate/salmeterol in patients with asthma well controlled on ICS/LABA. Journal of Asthma 2018;55(9):984-93. [DOI: 10.1080/02770903.2017.1386214] [PMID: ] - DOI - PubMed
Bodzenta‐Lukaszyk 2011 {published data only}FLT3501
    1. Bodzenta-Lukaszyk A, Dymek A, McAulay K, Mansikka H. Fluticasone/formoterol combination therapy is as effective as fluticasone/salmeterol in the treatment of asthma, but has a more rapid onset of action: an open-label, randomized study. BMC Pulmonary Medicine 2011;11:28. [DOI: 10.1186/1471-2466-11-28] [PMID: ] - DOI - PMC - PubMed
Bodzenta‐Lukaszyk 2013 {published data only}FLT3505
    1. Bodzenta-Lukaszyk A, Noord J, Schröder-Babo W, McAulay K, McIver T. Efficacy and safety profile of fluticasone/formoterol combination therapy compared to its individual components administered concurrently in asthma: a randomised controlled trial. Current Medical Research and Opinion 2013;29(5):579-88. [DOI: 10.1185/03007995.2013.772506] [PMID: ] - DOI - PubMed
Boyd 1995 {published data only}
    1. Boyd G. Salmeterol xinafoate in asthmatic patients under consideration for maintenance oral corticosteroid therapy. European Respiratory Journal 1995;8(9):1494-8. [PMID: ] - PubMed
Busse 2013 {published data only}
    1. Busse WW, O'Byrne PM, Bleecker ER, Lötvall J, Woodcock A, Andersen L, et al. Safety and tolerability of the novel inhaled corticosteroid fluticasone furoate in combination with the β2 agonist vilanterol administered once daily for 52 weeks in patients >=12 years old with asthma: a randomised trial. Thorax 2013;68(6):513-20. [DOI: ] [PMID: ] - PMC - PubMed
Busse 2018 {published data only}
    1. Busse WW, Bateman ED, Caplan AL, Kelly HW, O'Byrne PM, Rabe KF, et al. Combined analysis of asthma safety trials of long-acting β2-agonists. New England Journal of Medicine 2018;378(26):2497-505. [DOI: 10.1056/NEJMoa1716868] [PMID: ] - DOI - PubMed
Corradi 2016 {published data only}
    1. Corradi M, Spinola M, Petruzzelli S, Kuna P. High-dose beclometasone dipropionate/formoterol fumarate in fixed-dose combination for the treatment of asthma. Therapeutic Advances in Respiratory Disease 2016;10(5):492-502. [DOI: 10.1177/1753465816654442] [PMID: ] - DOI - PMC - PubMed
Devillier 2018 {published data only}
    1. Devillier P, Humbert M, Boye A, Zachgo W, Jacques L, Nunn C, et al. Efficacy and safety of once-daily fluticasone furoate/vilanterol (FF/VI) versus twice-daily inhaled corticosteroids/long-acting β2-agonists (ICS/LABA) in patients with uncontrolled asthma: an open-label, randomized, controlled trial. Respiratory Medicine 2018;141:111-20. [DOI: 10.1016/j.rmed.2018.06.009] [PMID: ] - DOI - PubMed
Hamelmann 2017 {published data only}
    1. Hamelmann E, Bernstein JA, Vandewalker M, Moroni-Zentgraf P, Verri D, Unseld A, et al. A randomised controlled trial of tiotropium in adolescents with severe symptomatic asthma. European Respiratory Journal 2017;49(1):1601100. [DOI: 10.1183/13993003.01100-2016] [PMID: ] - DOI - PMC - PubMed
Hoshino 2016 {published data only}
    1. Hoshino M, Ohtawa J, Akitsu K. Effects of the addition of tiotropium on airway dimensions in symptomatic asthma. Allergy & Asthma Proceedings 2016;37(6):147-53. [DOI: 10.2500/aap.2016.37.3991] [PMID: ] - DOI - PubMed
Kerwin 2009 {published data only}
    1. Kerwin EM, Oppenheimer JJ, LaForce C, Parasuraman B, Miller CJ, O'Dowd L, et al. Efficacy and tolerability of once-daily budesonide/formoterol pressurized metered-dose inhaler in adults and adolescents with asthma previously stable with twice-daily budesonide/formoterol dosing. Annals of Allergy, Asthma & Immunology 2009;103(1):62-72. [DOI: 10.1016/S1081-1206(10)60145-7] [PMID: ] - DOI - PubMed
Kerwin 2017 {published data only}
    1. Kerwin EM, Gillespie M, Song S, Steinfeld J. Randomized, dose-ranging study of a fluticasone propionate multidose dry powder inhaler in adolescents and adults with uncontrolled asthma not previously treated with inhaled corticosteroids. Journal of Asthma 2017;54(1):89-98. [DOI: 10.1080/02770903.2016.1193870] [PMID: ] - DOI - PubMed
Koenig 2008 {published data only}
    1. Koenig SM, Murray JJ, Wolfe J, Andersen L, Yancey S, Prillaman B, et al. Does measuring BHR add to guideline derived clinical measures in determining treatment for patients with persistent asthma? Respiratory Medicine 2008;102(5):665-73. [DOI: 10.1016/j.rmed.2007.12.023] [PMID: ] - DOI - PubMed
Kornmann 2020 {published data only}
    1. Kornmann O, Mucsi J, Kolosa N, Bandelli L, Sen B, Satlin LC, et al. Efficacy and safety of inhaled once-daily low-dose indacaterol acetate/mometasone furoate in patients with inadequately controlled asthma: phase III randomised QUARTZ study findings. Respiratory Medicine 2020;161:105809. [DOI: 10.1016/j.rmed.2019.105809] [PMID: ] - DOI - PubMed
Lenney 2013 {published data only}
    1. Lenney W, McKay AJ, Tudur Smith C, Williamson PR, James M, Price D. Management of Asthma in School age Children On Therapy (MASCOT): a randomised, double-blind, placebo-controlled, parallel study of efficacy and safety. Health Technology Assessment 2013;17(4):1-218. [DOI: 10.3310/hta17040] [PMID: ] - DOI - PMC - PubMed
Lötvall 2014 {published data only}
    1. Lötvall J, Bateman ED, Busse WW, O'Byrne PM, Woodcock A, Toler WT, et al. Comparison of vilanterol, a novel long-acting beta2 agonist, with placebo and a salmeterol reference arm in asthma uncontrolled by inhaled corticosteroids. Journal of Negative Results in Biomedicine 2014;13(1):9. [DOI: 10.1186/1477-5751-13-9] [PMID: ] - DOI - PMC - PubMed
Maspero 2010 {published data only}
    1. Maspero JF, Nolte H, Chérrez-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. [DOI: 10.3109/02770903.2010.514634] [PMID: ] - DOI - PMC - PubMed
Murphy 2012 {published data only}
    1. Murphy KR, Uryniak T, Martin UJ, Zangrilli J. The effect of budesonide/formoterol pressurized metered-dose inhaler on predefined criteria for worsening asthma in four different patient populations with asthma. Drugs in R&D 2012;12(1):9-14. [DOI: 10.2165/11630600-000000000-00000] [SPRUCE] [PMID: ] - DOI - PMC - PubMed
Murphy 2015x {published data only}
    1. Murphy KR, Uryniak T, Martin UJ, Zangrilli J. The effect of budesonide/formoterol pressurized metered-dose inhaler on predefined criteria for worsening asthma in four different patient populations with asthma. Drugs in R&D 2012;12(1):15. [DOI: 10.2165/11630600-000000000-00000] [PMID: ] - DOI - PMC - PubMed
Nathan 2012 {published data only}
    1. Nathan RA, D'Urzo A, Blazhko V, Kaiser K. Safety and efficacy of fluticasone/formoterol combination therapy in adolescent and adult patients with mild-to-moderate asthma: a randomised controlled trial. BMC Pulmonary Medicine 2012;12:67. [DOI: 10.1186/1471-2466-12-67] [PMID: ] - DOI - PMC - PubMed
NCT00529529 {unpublished data only}
    1. Novartis. Safety of indacaterol in patients (≥ 12 years) with moderate to severe persistent asthma. https://clinicaltrials.gov/ct2/show/NCT00529529 (accessed 29 August 2011). [STUDY ID: CQAB149B2338]
NCT01001364 {unpublished data only}
    1. Eurofarma Laboratorios. A Comparative Study Between Foraseq And Formoterol/Budesonide Inhalation Capsules in Patients With Asthma (CAINAS). https://clinicaltrials.gov/ct2/show/NCT01001364 (accessed 28 June 2011). [STUDY ID: EF-091]
NCT01202084 {unpublished data only}
    1. Eurofarma Laboratorios. A study comparative of formoterol/fluticasone Foraseq® and fluticasone in asthma patients. https://www.clinicaltrials.gov/ct2/show/NCT01202084 (accessed 18 June 2015). [STUDY ID: EF 065]
NCT01609478 {unpublished data only}
    1. Novartis. Efficacy, safety and pharmacokinetics of indacaterol acetate in patients with persistent asthma. https://clinicaltrials.gov/ct2/show/NCT01609478 (accessed 27 January 2015). [STUDY ID: CQMF149E2203]
NCT01720069 {unpublished data only}
    1. Vectura Limited. Clinical study to evaluate the efficacy and safety of VR506 using a new inhaler for the treatment of asthma. https://clinicaltrials.gov/ct2/show/NCT01720069 (accessed 21 April 2020). [STUDY ID: VR506/2/004]
NCT01845025 {unpublished data only}
    1. Novartis. Study of safety of foradil in patients with persistent asthma. https://clinicaltrials.gov/ct2/show/NCT01845025 (accessed March 2017). [STUDY ID: CFOR258D2416]
NCT02094937 {unpublished data only}
    1. GlaxoSmithKline. A study to compare the efficacy and safety of fluticasone furoate (FF) 100 mcg once daily with fluticasone propionate (FP) 250 mcg twice daily (BD) and FP 100 mcg BD in well-controlled asthmatic Japanese subjects. https://www.clinicaltrials.gov/ct2/show/NCT02094937 (accessed 25 May 2017). [GSK STUDY ID: 201135]
NCT04677959 {unpublished data only}
    1. Teva Branded Pharmaceutical. A 24-week treatment study to compare standard of care versus the eMDPI DS in patients 13 years or older with asthma (CONNECT2). https://clinicaltrials.gov/ct2/show/NCT04677959 (accessed 18 July 2022). [STUDY ID: FSS-AS-40139]
Ohta 2015 {published data only}
    1. Ohta K, Ichinose M, Tohda Y, Engel M, Moroni-Zentgraf P, Kunimitsu S, et al. Long-term once-daily tiotropium Respimat® is well tolerated and maintains efficacy over 52 weeks in patients with symptomatic asthma in Japan: a randomised, placebo-controlled study. PLoS One 2015;10(4):e0124109. [DOI: 10.1371/journal.pone.0124109] [PMID: ] - DOI - PMC - PubMed
Paggiaro 2016a {published data only}
    1. Paggiaro P, Halpin DM, Buhl R, Engel M, Zubek VB, Blahova Z, et al. The effect of tiotropium in symptomatic asthma despite low- to medium-dose inhaled corticosteroids: a randomized controlled trial. Journal of Allergy and Clinical Immunology 2016;4(1):104-13. [DOI: 10.1016/j.jaip.2015.08.017] [PMID: ] - DOI - PubMed
Peters 2010 {published data only}
    1. Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. New England Journal of Medicine 2010;363(18):1715-26. [DOI: 10.1056/NEJMoa1008770] [TALC] [PMID: ] - DOI - PMC - PubMed
Renzi 2010 {published data only}
    1. Renzi PM, Howard LA, Ortega HG, Ahmad FF, Chapman KR. Low-dose fluticasone propionate with and without salmeterol in steroid-naïve patients with mild, uncontrolled asthma. Respiratory Medicine 2010;104(4):510-7. [DOI: 10.1016/j.rmed.2009.10.025] [PMID: ] - DOI - PubMed
Tashkin 2016 {published data only}
    1. Tashkin DP, Moore GE, Trudo F, DePietro M, Chipps BE. Assessment of consistency of fixed airflow obstruction status during budesonide/formoterol treatment and its effects on treatment outcomes in patients with asthma. Journal of Allergy and Clinical Immunology 2016;4(4):705-12. [DOI: 10.1016/j.jaip.2016.02.014] [PMID: ] - DOI - PubMed
Wechsler 2016 {published data only}
    1. Wechsler ME, Yawn BP, Fuhlbrigge AL, Pace WD, Pencina MJ, Doros G, et al. Anticholinergic vs long-acting β-agonist in combination with Inhaled corticosteroids in Black adults with asthma: the BELT Randomized Clinical Trial. JAMA 2015;314(16):1720-30. [DOI: 10.1001/jama.2015.13277] [PMID: ] - DOI - PubMed
Wechsler 2019 {published data only}
    1. Wechsler ME, Szefler SJ, Ortega VE, Pongracic JA, Chinchilli V, Lima JJ, et al. Step-up therapy in Black children and adults with poorly controlled asthma. New England Journal of Medicine 2019;381(13):1227-39. [DOI: 10.1056/NEJMoa1905560] [PMID: ] - DOI - PMC - PubMed
Weinstein 2019 {published data only}
    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):1395-402. [DOI: 10.1016/j.jaci.2018.10.065] [PMID: ] - DOI - PubMed
Woodcock 2017 {published data only}
    1. Woodcock A, Vestbo J, Bakerly ND, New J, Gibson JM, McCorkindale S, et al. Effectiveness of fluticasone furoate plus vilanterol on asthma control in clinical practice: an open-label, parallel group, randomised controlled trial. Lancet 2017;390(10):32397-8. [DOI: 10.1016/S0140-6736(17)32397-8] [PMID: ] - DOI - PubMed

References to ongoing studies

NCT03248128 {unpublished data only}
    1. GlaxoSmithKline. Safety and efficacy study of fluticasone furoate/vilanterol (FF/VI) fixed dose combination (FDC) compared to FF alone in subjects with asthma. https://clinicaltrials.gov/ct2/show/NCT03248128 (first received 14 August 2017). [GSK STUDY ID: 107116]
NCT03387241 {unpublished data only}
    1. Mundipharma. Efficacy of FLUTIFORM® vs Seretide® in moderate to severe persistent asthma in subjects aged ≥12 years. https://clinicaltrials.gov/ct2/show/NCT03387241 (first received 2 January 2018). [STUDY ID: FLT13-CN-301]
NCT04191434 {unpublished data only}
    1. EMS. Efficacy and safety of flamboyant 125/12 association in the treatment of adults with moderate asthma. https://clinicaltrials.gov/ct2/show/NCT04191434 (first received 9 December 2019). [STUDY ID: EMS0219 - FLAMBOYANT125/12]
NCT04191447 {unpublished data only}
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References to other published versions of this review

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