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. 2022 Dec 6;12(12):CD013799.
doi: 10.1002/14651858.CD013799.pub2.

Effectiveness and tolerability of dual and triple combination inhaler therapies compared with each other and varying doses of inhaled corticosteroids in adolescents and adults with asthma: a systematic review and network meta-analysis

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

Effectiveness and tolerability of dual and triple combination inhaler therapies compared with each other and varying doses of inhaled corticosteroids in adolescents and adults with asthma: a systematic review and network meta-analysis

Yuji Oba et al. Cochrane Database Syst Rev. .

Abstract

Background: Current guidelines recommend a higher-dose inhaled corticosteroids (ICS) or adding a long-acting muscarinic antagonist (LAMA) when asthma is not controlled with medium-dose (MD) ICS/long-acting beta2-agonist (LABA) combination therapy.

Objectives: To assess the effectiveness and safety of dual (ICS/LABA) and triple therapies (ICS/LABA/LAMA) compared with each other and with varying doses of ICS in adolescents and adults with uncontrolled asthma.

Search methods: We searched multiple databases for pre-registered randomised controlled trials (RCTs) of at least 12 weeks of study duration from 2008 to 18 February 2022.

Selection criteria: We searched studies, including adolescents and adults with uncontrolled asthma who had been treated with, or were eligible for, MD-ICS/LABA, comparing dual and triple therapies. We excluded cluster- and cross-over RCTs.

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

Main results: We included 17,161 patients with uncontrolled asthma from 17 studies (median duration 26 weeks; mean age 49.1 years; male 40%; white 81%; mean forced expiratory volume in 1 second (MEF 1)1.9 litres and 61% predicted). The quality of included studies was generally good except for some outcomes in a few studies due to high attrition rates. Medium-dose (MD) and high-dose (HD) triple therapies reduce steroid-requiring asthma exacerbations (hazard ratio (HR) 0.84 [95% credible interval (CrI) 0.71 to 0.99] and 0.69 [0.58 to 0.82], respectively) (high-certainty evidence), but not asthma-related hospitalisations, compared to MD-ICS/LABA. High-dose triple therapy likely reduces steroid-requiring asthma exacerbations compared to MD triple therapy (HR 0.83 [95% CrI 0.69 to 0.996], [moderate certainty]). Subgroup analyses suggest the reduction in steroid-requiring exacerbations associated with triple therapies may be only for those with a history of asthma exacerbations in the previous year but not for those without. High-dose triple therapy, but not MD triple, results in a reduction in all-cause adverse events (AEs) and likely reduces dropouts due to AEs compared to MD-ICS/LABA (odds ratio (OR) 0.79 [95% CrI 0.69 to 0.90], [high certainty] and 0.50 [95% CrI 0.30 to 0.84], [moderate certainty], respectively). Triple therapy results in little to no difference in all-cause or asthma-related serious adverse events (SAEs) compared to dual therapy (high certainty). The evidence suggests triple therapy results in little or no clinically important difference in symptoms or quality of life compared to dual therapy considering the minimal clinically important differences (MCIDs) and HD-ICS/LABA is unlikely to result in any significant benefit or harm compared to MD-ICS/LABA.

Authors' conclusions: Medium-dose and HD triple therapies reduce steroid-requiring asthma exacerbations, but not asthma-related hospitalisations, compared to MD-ICS/LABA especially in those with a history of asthma exacerbations in the previous year. High-dose triple therapy is likely superior to MD triple therapy in reducing steroid-requiring asthma exacerbations. Triple therapy is unlikely to result in clinically meaningful improvement in symptoms or quality of life compared to dual therapy considering the MCIDs. High-dose triple therapy, but not MD triple, results in a reduction in all-cause AEs and likely reduces dropouts due to AEs compared to MD-ICS/LABA. Triple therapy results in little to no difference in all-cause or asthma-related SAEs compared to dual therapy. HD-ICS/LABA is unlikely to result in any significant benefit or harm compared to MD-ICS/LABA, although long-term safety of higher rather than MD- ICS remains to be demonstrated given the median duration of included studies was six months. The above findings may assist deciding on a treatment option when asthma is not controlled with MD-ICS/LABA.

Trial registration: ClinicalTrials.gov NCT00424008 NCT01686633 NCT01099722 NCT00646594 NCT03158311 NCT00772538 NCT00776984 NCT02571777 NCT02924688 NCT02175771 NCT00394368 NCT00651768 NCT01475721 NCT02554786 NCT02676076 NCT02676089 NCT00381485 NCT01147848 NCT01202084 NCT00901368 NCT00350207 NCT02301975 NCT01018186 NCT01257230 NCT01277523 NCT03358147 NCT00379288 NCT01570478 NCT02892344 NCT03376932 NCT01244984 NCT01340209 NCT01316380 NCT00565266 NCT02139644 NCT03063086 NCT01290874 NCT01471340 NCT03387241 NCT04191434 NCT04191447 NCT04609878 NCT04609904.

PubMed Disclaimer

Conflict of interest statement

Y. Oba: has provided consultation and received honoraria from Genentech unrelated to the current review.

T Patel: none known.

S Anwer: none known.

T Maduke: none known.

S Dias: none known.

Figures

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Network diagram for severe exacerbations for grouped interventions. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for moderate to severe exacerbations for grouped interventions. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for change from baseline ACQ score at 3 months for grouped interventions. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for change from baseline ACQ score at 6 months for grouped interventions. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for change from baseline ACQ score at 12 months for grouped interventions. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for change from baseline AQLQ scores at 6 months for grouped interventions. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for change from baseline AQLQ scores at 12 months for grouped interventions. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for ACQ Responders at 6 months for grouped interventions. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for ACQ responders at 12 months for grouped interventions. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for all‐cause SAEs for grouped interventions. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for asthma‐related SAEs for grouped interventions The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for all‐cause AEs for grouped interventions. Node colors denote the treatment group. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for drop‐outs due to AEs for grouped interventions. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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PRISMA flow diagram
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Summary of risk of bias assessment using Cochrane 'Risk of bias 2' tool. ACQ: Asthma Control Questionnaire; AE: adverse event; AQLQ: Asthma Quality of Life Questionnaire; CFB: change from baseline; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose; SAE: serious adverse event.
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Forest plot of hazard ratios for severe exacerbations for grouped treatments. Hazard ratios less than one favors the first named treatment. CrI: Credible Interval; HD: high dose; HR: hazard ratio; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Rank plots for grouped treatments for severe exacerbations (fixed effect model). HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for severe exacerbations for high‐risk individuals. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Forest plot of hazard ratios for severe exacerbations for high‐risk individuals. Hazard ratio less than one favours the first named treatment. Crl: credible interval, HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Rank plots for severe exacerbations for high‐risk individuals. (fixed effect model). HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for severe exacerbations for low‐risk individuals. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Forest plot of hazard ratios for severe exacerbations for low‐risk individuals. Hazard ratio less than one favours the first named treatment. Crl: credible interval, HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Rank plots for severe exacerbations for low‐risk individuals. (fixed effect model). HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Forest plot for threshold analysis for grouped treatments for severe exacerbations (fixed effect model) Treatment Codes: 1=MD‐ICS/LABA, 2= HD‐ICS/LABA, 3=MD Triple, 4= HD Triple. The optimum treatment for this analysis was MD‐ICS/LABA. HD: high dose; HR: hazard ratio; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; LD: low dose; MD: medium dose; NT: no threshold (no amount of change in this direction would change the recommendation).
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Network diagram for severe exacerbations for individual interventions. Node colors denote the treatment group. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. BUD:budesonide, CrI:Credible Interval, FF:fluticasone furoate, FM:formoterol, FP:fluticasone propionate, GLY: glycopyrronium, IND:indacaterol, MF:mometasone furoate, SAL:salmeterol, Tio: tiotropium, UMEC: umeclidinium, VI:vilanterol.
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Forest plot of hazard ratios relative to FP/SAL 250 for severe exacerbations for individual treatments. Hazard ratio less than one favors the first named treatment. BUD:budesonide, CrI:Credible Interval, FF:fluticasone furoate, FM:formoterol, FP:fluticasone propionate, GLY: glycopyrronium, HR: hazard ratio; IND:indacaterol, MF:mometasone furoate, SAL:salmeterol, UMEC: umeclidinium, VI:vilanterol
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Rank plots for individual treatments for severe exacerbations (fixed effect model). Line colors denote the treatment group. BUD:budesonide, FF:fluticasone furoate, FM:formoterol, FP:fluticasone propionate, GLY: glycopyrronium, IND:indacaterol, MF:mometasone furoate, SAL:salmeterol, Tio:tiotropium, UMEC: umeclidinium, VI:vilanterol.
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Forest plot of hazard ratios relative for moderate to severe exacerbations for grouped treatments. Hazard ratio less than one favors the first named treatment. CrI: Credible Interval; HD: high dose; HR: hazard ratio; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Rank plots for grouped treatments for moderate to severe exacerbations (fixed effect model). HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for moderate to severe exacerbations for high‐risk individuals. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Forest plot of hazard ratios for moderate to severe exacerbations for high‐risk individuals. Hazard ratio less than one favours the first named treatment. Crl: credible interval, HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Rank plots for modearate to severe exacerbations for high‐risk individuals. (fixed effect model). HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for moderate to severe exacerbations for low‐risk individuals. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Forest plot of hazard ratios for moderate to severe exacerbations for low‐risk individuals. Hazard ratio less than one favours the first named treatment. Crl: credible interval, HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Rank plots for modearate to severe exacerbations for low‐risk individuals. (fixed effect model). HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Forest plot for threshold analysis for moderate to severe exacerbations for grouped treatments (fixed effect model). Treatment Codes: 1=MD‐ICS/LABA, 2= HD‐ICS/LABA, 3=MD Triple, 4= HD Triple. The optimum treatment for this analysis was HD Triple. HD: high dose; HR: hazard ratio; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose; NT: no threshold (no amount of change in this direction would change the recommendation).
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Network diagram for moderate to severe exacerbations for individual interventions. Node colors denote the treatment group. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. BDP: beclomethasone dipropionate, BUD:budesonide, FF:fluticasone furoate, FM:formoterol, FP:fluticasone propionate, GLY: glycopyrronium, IND:indacaterol, MF:mometasone furoate, SAL:salmeterol, UMEC: umeclidinium, VI:vilanterol
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Forest plot of hazard ratios relative to FP/SAL 250 for moderate to severe exacerbations for individual treatments. Hazard Ratios greater than one favor the comparator treatment over FP/SAL 250. BUD:budesonide, CrI:Credible Interval; FF:fluticasone furoate, FM:formoterol, FP:fluticasone propionate, GLY: glycopyrronium, HR: hazard ratio; IND:indacaterol, MF:mometasone furoate, SAL:salmeterol, Tio:tiotropium, UMEC: umeclidinium, VI:vilanterol.
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Rank plots for individual treatments for moderate to severe exacerbations (fixed effect model) Line colors denote the treatment group. BUD:budesonide, FF:fluticasone furoate, FM:formoterol, FP:fluticasone propionate, GLY: glycopyrronium, IND:indacaterol, MF:mometasone furoate, SAL:salmeterol, Tio:tiotropium, UMEC: umeclidinium, VI:vilanterol.
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Forest plot of relative effects for the change from baseline ACQ score at 3 months using the fixed effect model. Mean differences less than zero favor the first named treatment. CrI:Credible Interval; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: mean difference; MD: medium dose.
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Rank plots for grouped treatments for change from baseline in ACQ scores at 3 months (fixed effect model). HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose
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Forest plot of relative effects for the change from baseline in ACQ score at 6 months using fixed‐ and random‐effects models. Mean differences less than zero favor the first named treatment. CrI:Credible Interval; FE: fixed effect; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: mean difference; MD: medium dose; RE: random effects.
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Rank plots for grouped treatments for change from baseline in ACQ scores at 6 months for the fixed effect (A) and random effects (B) models. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Forest plot of mean differences for change from baseline in ACQ scores at 12 months using the fixed effect model. Mean differences less than zero favor the first named treatment. CrI: Credible Interval; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: mean difference; MD: medium dose.
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Rank plots for grouped treatments for change from baseline in ACQ scores at 12 months (fixed effect model) HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Forest plot of mean differences for change from baseline in AQLQ scores at 6 months using the fixed effect model. Mean differences less than zero favor the first named treatment. CrI: Credible Interval; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: mean difference; MD: medium dose.
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Rank plots for grouped treatments for change from baseline in AQLQ scores at 6 months (fixed effect model) HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Forest plot of mean differences for change from baseline in AQLQ scores at 12 months using the fixed effect model. Mean differences less than zero favor the first named treatment. CrI: Credible Interval; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: mean difference; MD: medium dose.
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Rank plots for grouped treatments for change from baseline in AQLQ scores at 12 months (fixed effect model) HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Forest plot of odds ratios relative for ACQ responders at 6 months for grouped treatments. Odds ratio greater than one favors the first named treatment. CrI: Credible Interval; HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Rank plots for grouped treatments for ACQ responders at 6 months (fixed effect model) HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for ACQ responders at 6 months for individual interventions. Node colors denote the treatment group. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. FP:fluticasone propionate, GLY: glycopyrronium, IND:indacaterol, MF:mometasone furoate, SAL:salmeterol, Tio:tiotropium.
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Forest plot of odds ratios relative to MF/IND160 for ACQ responders at 6 months for individual treatments. Odds ratio greater than one favors the comparator treatment over MF/IND 160. CrI: credible interval, FP:fluticasone propionate, GLY: glycopyrronium, IND:indacaterol, MF:mometasone furoate, SAL:salmeterol, Tio:tiotropium.
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Rank plots for individual treatments for ACQ responders at 6 months (fixed effect model) Line colors denote the treatment group. FP:fluticasone propionate, GLY: glycopyrronium, IND:indacaterol, MF:mometasone furoate, SAL:salmeterol, Tio:tiotropium.
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Forest plot of odds ratios relative to MD‐ICS/LABA for ACQ responders at 12 months for grouped treatments (fixed‐ and random‐effectsmodel). Odds ratio greater than one favors the comparator treatment over MD‐ICS/LABA. CrI: credible interval, HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Density plot for the between‐study standard deviation (SD) for the random effects model for ACQ Responders at 12 months for grouped interventions
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Rank plots for grouped treatments for ACQ responders at 12 months for the fixed effect (A) and random effects (B) model. HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for ACQ responders at 12 months for individual interventions. Node colors denote the treatment group. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. FP:fluticasone propionate, GLY: glycopyrronium, IND:indacaterol, MF:mometasone furoate, SAL:salmeterol.
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Forest plot of odds ratios relative to MF/IND160 for ACQ responders at 12 months for individual treatments (fixed effect model) Odds Ratio greater than one favors the comparator treatment over MF/IND 160.CrI: credible interval, FP:fluticasone propionate, GLY: glycopyrronium, IND:indacaterol, MF:mometasone furoate, SAL:salmeterol.
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Rank plots for individual treatments for ACQ responders at 12 months (fixed effect model) Line colors denote the treatment group. FP:fluticasone propionate, GLY: glycopyrronium, IND:indacaterol, MF:mometasone furoate, SAL:salmeterol.
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Forest plots of odds ratios for all‐cause SAEs for grouped treatments (fixed effect model). Odds ratio less than one favors the first named treatment. CrI: credible interval, HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Rank plots for grouped treatments for all‐cause SAEs (fixed effect model) HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for all‐cause SAEs for individual interventions. Node colors denote the treatment group. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. FF:fluticasone furoate, FM:formoterol, FP:fluticasone propionate, GLY: glycopyrronium, IND:indacaterol, MF:mometasone furoate, SAL:salmeterol, Tio:tiotropium, UMEC: umeclidinium, VI:vilanterol.
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Forest plot of odds ratios relative to FP/SAL 250 for all‐cause SAEs for individual treatments. Odds ratio less than one favors the comparator treatment over FP/SAL 250. Crl:credible interval, FF:fluticasone furoate, FM:formoterol, FP:fluticasone propionate, GLY: glycopyrronium, IND:indacaterol, MF:mometasone furoate, SAL:salmeterol, Tio:tiotropium, UMEC: umeclidinium, VI:vilanterol.
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Rank plots for individual treatments for all‐cause SAEs (fixed effect model). Line colors denote the treatment group. FF:fluticasone furoate, FM:formoterol, FP:fluticasone propionate, GLY: glycopyrronium, IND:indacaterol, MF:mometasone furoate, SAL:salmeterol, Tio:tiotropium, UMEC: umeclidinium, VI:vilanterol.
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Forest plots of odds ratios relative for asthma‐related SAEs for grouped treatments (fixed effect model). Odds ratio (OR) less than one favors the first named treatment. Crl: credible interval, HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Rank plots for grouped treatments for asthma‐related SAEs (fixed effect model) HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for asthma‐related SAEs for individual interventions. Node colors denote the treatment group. The size of the nodes and the thickness of edges depend on the number of people randomised and the number of trials conducted. FF:fluticasone furoate, FM:formoterol, FP:fluticasone propionate, GLY: glycopyrronium, IND:indacaterol, MF:mometasone furoate, SAL:salmeterol, Tio:tiotropium, UMEC: umeclidinium, VI:vilanterol.
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Forest plot of odds ratios for asthma‐related SAEs relative to FP/SAL 250 for individual treatments. Odds ratio less than one favors the comparator treatment over FP/SAL 250. FF:fluticasone furoate, FM:formoterol, FP:fluticasone propionate, GLY: glycopyrronium, IND:indacaterol, MF:mometasone furoate, SAL:salmeterol, Tio:tiotropium, UMEC: umeclidinium, VI:vilanterol.
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Rank plots for individual treatments for asthma‐related SAEs (fixed effect model) Line colors denote the treatment group. FF:fluticasone furoate, FM:formoterol, FP:fluticasone propionate, GLY: glycopyrronium, IND:indacaterol, MF:mometasone furoate, SAL:salmeterol, Tio:tiotropium, UMEC: umeclidinium, VI:vilanterol.
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Forest plots of odds ratios for all‐cause AEs for grouped treatments (fixed effect model). Odds ratio less than one favors the first named treatment. Crl: credible interval, HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Rank plots for grouped treatments for all‐cause AEs (fixed effect model) HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for all‐cause AEs for individual interventions. Node colors denote the treatment group. BUD: budesonide, FF: fluticasone furoate, FM: formoterol, FP: fluticasone propionate, GLY: glycopyrronium, IND: indacaterol, MF: mometasone furoate, SAL: salmeterol, Tio: tiotropium, UMEC: umeclidinium, VI: vilanterol.
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Forest plot of odds ratios relative to FP/SAL 250 for all‐cause AEs for individual treatments. Odds ratio less than one favors the comparator treatment. BUD: budesonide, Crl: credible interval, FF: fluticasone furoate, FM: formoterol, FP: fluticasone propionate, GLY: glycopyrronium, IND: indacaterol, MF: mometasone furoate, OR: odds ratio, SAL: salmeterol, Tio: tiotropium, UMEC: umeclidinium, VI: vilanterol.
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Rank plots for individual treatments for all‐cause AEs (fixed‐effect model). Line colors denote the treatment group. BUD: budesonide, FF: fluticasone furoate, FM: formoterol, FP: fluticasone propionate, GLY: glycopyrronium, IND: indacaterol, MF: mometasone furoate, SAL: salmeterol, Tio: tiotropium, UMEC: umeclidinium, VI: vilanterol.
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Forest plots of odds ratios for drop‐outs due to AEs for grouped treatments (fixed‐effect model). Odds ratio less than one favors the first named treatment. Crl: credible interval, HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Rank plots for grouped treatments for dropouts due to AEs (fixed‐effect model) HD: high dose; ICS: inhaled corticosteroids; LABA: long‐acting beta‐2 agonist; MD: medium dose.
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Network diagram for dropouts due to AEs for individual interventions. Node colors denote the treatment group. BUD: budesonide, FF: fluticasone furoate, FM: formoterol, FP: fluticasone propionate, GLY: glycopyrronium, IND: indacaterol, MF: mometasone furoate, SAL: salmeterol, Tio: tiotropium, UMEC: umeclidinium, VI: vilanterol.
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Forest plot of odds ratios for dropouts due to AEs relative to FP/SAL 250 for dropouts due to AEs for individual treatments. Odds ratio less than one favors the comparator treatment. BUD: budesonide, Crl: credible interval, FF: fluticasone furoate, FM: formoterol, FP: fluticasone propionate, GLY: glycopyrronium, IND: indacaterol, MF: mometasone furoate,OR: odds ratio, SAL: salmeterol, Tio: tiotropium, UMEC: umeclidinium, VI: vilanterol.
80
80
Rank plots for individual treatments for dropouts due to AEs (fixed‐effect model). Line colors denote the treatment group. BUD: budesonide, FF: fluticasone furoate, FM: formoterol, FP: fluticasone propionate, GLY: glycopyrronium, IND: indacaterol, MF: mometasone furoate, SAL: salmeterol, Tio: tiotropium, UMEC: umeclidinium, VI: vilanterol.
1.1
1.1. Analysis
Comparison 1: Asthma exacerbations, Outcome 1: Severe exacerbations
1.2
1.2. Analysis
Comparison 1: Asthma exacerbations, Outcome 2: Moderate to severe exacerbations
2.1
2.1. Analysis
Comparison 2: Asthma Control Questionnaire: change from baseline, Outcome 1: CFB in ACQ at 3 months
2.2
2.2. Analysis
Comparison 2: Asthma Control Questionnaire: change from baseline, Outcome 2: CFB in ACQ at 6 months
2.3
2.3. Analysis
Comparison 2: Asthma Control Questionnaire: change from baseline, Outcome 3: CFB in ACQ at 12 months
3.1
3.1. Analysis
Comparison 3: Asthma Quality of Life Questionnaire: change from baseline, Outcome 1: CFB in AQLQ at 6 months
3.2
3.2. Analysis
Comparison 3: Asthma Quality of Life Questionnaire: change from baseline, Outcome 2: CFB in AQLQ at 12 months
4.1
4.1. Analysis
Comparison 4: Asthma Control Questionnaire responders, Outcome 1: ACQ responders at 6 months
4.2
4.2. Analysis
Comparison 4: Asthma Control Questionnaire responders, Outcome 2: ACQ responders at 12 months
5.1
5.1. Analysis
Comparison 5: Serious adverse events, adverse events, and dropouts due to adverse event, Outcome 1: All cause SAEs
5.2
5.2. Analysis
Comparison 5: Serious adverse events, adverse events, and dropouts due to adverse event, Outcome 2: Asthma‐related SAEs
5.3
5.3. Analysis
Comparison 5: Serious adverse events, adverse events, and dropouts due to adverse event, Outcome 3: All cause AEs
5.4
5.4. Analysis
Comparison 5: Serious adverse events, adverse events, and dropouts due to adverse event, Outcome 4: Dropouts due to adverse event
6.1
6.1. Analysis
Comparison 6: Severe exacerbations (high and low risk subgroups), Outcome 1: HD‐ICS/LABA vs MD‐ICS/LABA
6.2
6.2. Analysis
Comparison 6: Severe exacerbations (high and low risk subgroups), Outcome 2: MD TRIPLE vs MD‐ICS/LABA
6.3
6.3. Analysis
Comparison 6: Severe exacerbations (high and low risk subgroups), Outcome 3: HD TRIPLE vs MD‐ICS/LABA
6.4
6.4. Analysis
Comparison 6: Severe exacerbations (high and low risk subgroups), Outcome 4: MD TRIPLE vs HD‐ICS/LABA
6.5
6.5. Analysis
Comparison 6: Severe exacerbations (high and low risk subgroups), Outcome 5: HD TRIPLE vs HD‐ICS/LABA
6.6
6.6. Analysis
Comparison 6: Severe exacerbations (high and low risk subgroups), Outcome 6: HD TRIPLE vs MD TRIPLE
6.7
6.7. Analysis
Comparison 6: Severe exacerbations (high and low risk subgroups), Outcome 7: TRIPLE vs DUAL
7.1
7.1. Analysis
Comparison 7: Moderate to severe exacerbations (high and low risk subgroups), Outcome 1: HD‐ICS/LABA vs MD‐ICS/LABA
7.2
7.2. Analysis
Comparison 7: Moderate to severe exacerbations (high and low risk subgroups), Outcome 2: MD TRIPLE vs MD‐ICS/LABA
7.3
7.3. Analysis
Comparison 7: Moderate to severe exacerbations (high and low risk subgroups), Outcome 3: HD TRIPLE vs MD‐ICS/LABA
7.4
7.4. Analysis
Comparison 7: Moderate to severe exacerbations (high and low risk subgroups), Outcome 4: MD TRIPLE vs HD‐ICS/LABA
7.5
7.5. Analysis
Comparison 7: Moderate to severe exacerbations (high and low risk subgroups), Outcome 5: HD TRIPLE vs HD‐ICS/LABA
7.6
7.6. Analysis
Comparison 7: Moderate to severe exacerbations (high and low risk subgroups), Outcome 6: HD TRIPLE vs MD TRIPLE
7.7
7.7. Analysis
Comparison 7: Moderate to severe exacerbations (high and low risk subgroups), Outcome 7: TRIPLE vs DUAL
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References

References to studies included in this review

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Cukier 2013 {published and unpublished data}
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Peters 2008 {published data only}
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Stempel 2016 {published data only}
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van Zyl‐Smit 2020 {published data only}
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Virchow 2019 {published data only}
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Virchow 2019a {published data only}
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Virchow 2019b {published data only}
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Weinstein 2010 {published and unpublished data}
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Woodcock 2013 {published data only}
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References to studies excluded from this review

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D’Urzo 2001 {published data only}
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EUCTR2008‐004833‐70 {unpublished data only}
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Fitzgerald 1999 {published data only}
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Green 2006 {published data only}
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Hamelmann 2016 {published data only}
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Hamelmann 2017 {published data only}
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Hoshino 2016 {published data only}
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Houghton 2007 {published data only}
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Hultquist 2000 {published data only}
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Ind 2003 {published data only}
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Ishiura 2018 {published data only}
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Katial 2011 {published data only}
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Kerstjens 2015 {published data only}
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Kerwin 2009 {published data only}
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Kerwin 2011 {published data only}
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Kerwin 2021 {published data only}
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Koenig 2008 {published data only}
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Kuna 2007 {published data only}
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Langton Hewer 1995 {published data only}
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Lee 2015 {published data only}
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Lenney 2013 {published data only}
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NCT00118690 {unpublished data only}
    1. NCT00118690. A study measuring asthma control in pediatric and adolescent subjects whose asthma is worsened by activity or exercise. clinicaltrials.gov/ct2/show/NCT00118690 (first received 12 July 2005).
NCT00118716 {unpublished data only}
    1. NCT00118716. A study measuring asthma control in pediatric and adolescent subjects whose asthma is worsened by activity or exercise. clinicaltrials.gov/ct2/show/NCT00118716 (first received 12 July 2005).
NCT01192178 {unpublished data only}
    1. NCT01192178. Fall epidemic viral pediatric study. clinicaltrials.gov/ct2/show/NCT01192178 (first received 31 August 2010).
NCT01570478 {unpublished data only}
    1. NCT01570478. A study in patients with asthma (NELSON). clinicaltrials.gov/ct2/show/NCT01570478 (first received 4 April 2012).
NCT02127697 {published data only}
    1. NCT02127697. Study of efficacy and safety of NVA237 in patients with poorly controlled asthma. clinicaltrials.gov/ct2/show/NCT02127697 (first received 1 May 2014).
NCT02296411 {published data only}
    1. NCT02296411. Efficacy of LAMA added to ICS in treatment of asthma (ELITRA). www.clinicaltrials.gov/ct2/show/NCT02296411 (first received 20 November 2014).
NCT02433834 {unpublished data only}
    1. NCT02433834. Chronic dosing cross-over study to assess the efficacy and safety of glycopyrronium (PT001) in adult subjects with intermittent asthma or mild to moderate persistent asthma. clinicaltrials.gov/ct2/show/NCT02433834 (first received 5 May 2015).
NCT02892344 {unpublished data only}
    1. NCT02892344. Study of QMF149 (150/80 µg) compared with MF Twisthaler® (200 µg) in patients with asthma. clinicaltrials.gov/ct2/show/NCT02892344 (first received 8 September 2016).
NCT03063086 {published data only}
    1. NCT03063086. Assess bronchodilator effect and safety of two doses of QVM149 compared to a fixed dose combination of salmeterol/fluticasone in patients with asthma. clinicaltrials.gov/ct2/show/NCT03063086 (first received 24 February 2017).
NCT03184987 {unpublished data only}
    1. NCT03184987. A long-term safety study of fixed dose combination therapy fluticasone furoate/umeclidinium bromide/vilanterol trifenatate in Japanese subjects with asthma. clinicaltrials.gov/ct2/show/NCT03184987 (first received 14 June 2017).
NCT03376932 {unpublished data only}
    1. NCT03376932. Effectiveness of fluticasone furoate/ umeclidinium/ vilanterol (FF/UMEC/VI) using the connected inhaler system (CIS) as compared with fluticasone proprionate/ salmeterol (FP/SAL) plus tiotropium (TIO) in inadequately controlled asthma. clinicaltrials.gov/ct2/show/NCT03376932 (first received 19 December 2017).
Norhaya 1999 {published data only}
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References to ongoing studies

NCT03387241 {published data only}
    1. NCT03387241. Efficacy of FLUTIFORM ® vs Seretide® in moderate to severe persistent asthma in subjects aged ≥12 years. clinicaltrials.gov/ct2/show/NCT03387241 (first received 2 January 2018).
NCT04191434 {published data only}
    1. NCT04191434. Efficacy and safety of flamboyant 125/12 association in the treatment of adults with moderate asthma. clinicaltrials.gov/ct2/show/NCT04191434 (first received 9 December 2019).
NCT04191447 {published data only}
    1. NCT04191447. Efficacy and safety of flamboyant 200/12 association in the treatment of adults with severe asthma. clinicaltrials.gov/ct2/show/NCT04191447 (first received 9 December 2019).
NCT04609878 {published data only}
    1. NCT04609878. Study to assess PT010 in adult and adolescent participants with inadequately controlled asthma (KALOS) (KALOS). clinicaltrials.gov/ct2/show/NCT04609878 (first received 30 October 2020).
NCT04609904 {published data only}
    1. NCT04609904. Study to assess PT010 in adult and adolescent participants with inadequately controlled asthma (LOGOS) (LOGOS). clinicaltrials.gov/ct2/show/NCT04609904 (first received 30 October 2020).
NCT04937387 {unpublished data only}
    1. NCT04937387. Efficacy and safety of fluticasone furoate/umeclidinium/vilanterol (ff/umec/vi) in chinese participants with inadequately controlled asthma. clinicaltrials.gov/ct2/show/NCT04937387 (first received 24 June 2021).
NCT05018598 {unpublished data only}
    1. NCT05018598. Step-up to medium strength triple therapy vs high strength ICS/LABA in adult asthmatics uncontrolled on medium strength ICS/LABA (MiSTIC). clinicaltrials.gov/ct2/show/NCT05018598 (first received 24 August 2021).

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