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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
Many patients remain symptomatic despite receiving ICS monotherapy. The recent update in GINA 2019 recommends the addition of long-acting β2-agonist (LABA) to ICS monotherapy as the preferred controller and maintenance therapy in patients with inadequately controlled asthma.
•What does this article add to our knowledge?
To our knowledge, this is the first study to compare a low-dose ICS/LABA FDC o.d. to low-dose ICS monotherapy in adult and adolescent patients with inadequately controlled asthma.
•How does this study impact current management guidelines?
Once-daily, low-dose IND/MF can be a potential option for treatment of adult and adolescent patients with asthma who remain inadequately controlled on ICS (with/without LABA). Data from this study add to the existing evidence supporting, the efficacy of ICS/LABA over ICS alone and the efficacy of a once-daily combination of low-dose IND/MF 150/80 μg o.d., in patients with inadequately controlled asthma.
Abstract
Background
Global initiative for asthma (GINA) 2019 recommends adding a long-acting β2-agonist (LABA) to an inhaled corticosteroid (ICS) as a maintenance controller therapy in patients with inadequately controlled asthma. Indacaterol acetate (IND, a LABA) in combination with mometasone furoate (MF, an ICS) is under development for the treatment of these patients.
Objective
This phase III QUARTZ was a multicentre, randomised, double-blind, double-dummy and parallel-group study to assess the efficacy and safety of low-dose IND/MF 150/80 μg once daily (o.d.) versus MF 200 μg o.d. in adult and adolescent patients with inadequately controlled asthma.
Methods
Eligible patients (n = 802) were randomised (1:1) to receive either low-dose IND/MF 150/80 μg o.d. via Breezhaler® or MF 200 μg o.d. via Twisthaler® for 12 weeks. Primary endpoint was trough forced expiratory volume in 1 s (FEV1) and key secondary endpoint was Asthma Control Questionnaire (ACQ-7) treatment difference after 12-week treatment. Other secondary endpoints included ACQ-7 responder analysis, morning and evening peak expiratory flow, Asthma Quality of Life Questionnaire total score, rescue medication use, daily symptom score, nighttime awakenings and rate of exacerbations, evaluated over 12-week treatment. Safety was also assessed including serious asthma outcomes.
Results
Low-dose IND/MF significantly improved trough FEV1 (least squares mean treatment difference [LSMTD]: 0.182 L; p < 0.001) and ACQ-7 (LSMTD: −0.218; p < 0.001) versus MF at Week 12. Improvements in all other secondary endpoints favoured low-dose IND/MF. Safety was comparable.
Conclusion
These results support the use of low-dose IND/MF 150/80 μg o.d. as a potential therapy for adult and adolescent patients with inadequately controlled asthma.
Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.
]. Global Initiative for Asthma (GINA) recommends short-acting β2-agonists (SABAs) as the preferred initial reliever option and low-dose inhaled corticosteroids (ICS) as the preferred initial controller option in patients with persistent asthma [
Effect of once-daily indacaterol maleate/mometasone furoate on exacerbation risk in adolescent and adult asthma: a double-blind randomised controlled trial.
]. However, many patients remain symptomatic despite receiving ICS monotherapy. Recent update in GINA 2019 recommends the addition of long-acting β2-agonist (LABA) to ICS monotherapy as the preferred controller and maintenance therapy in patients with inadequately controlled asthma [
]. Several twice-daily LABA/ICS combinations are currently available along with one once-daily combination (fluticasone furoate/vilanterol) for GINA Step 3 to 5 treatment of asthma [
The LABA indacaterol acetate (IND) is approved for chronic obstructive pulmonary disease (COPD) at a dosing regimen of 150 μg and 300 μg once daily (o.d.) in the EU and 75 μg o.d. in the US [
]. IND demonstrated sustained 24-h bronchodilator efficacy, with a rapid onset of action in patients with moderate-to-severe asthma when administered o.d. via a dry powder inhaler [
]. Mometasone furoate (MF) is an ICS approved as a once-daily dosing regimen for the treatment of asthma in patients aged ≥12 years (220 μg–440 μg) and for children aged 4–11 years (110 μg) in the US, which is administered as a dry powder via Twisthaler® in the evening [
IND/MF 150/80 μg o.d. delivered via Breezhaler®, a single-dose dry powder inhaler, is a fixed-dose combination (FDC) of IND and MF, and is under development for treatment of symptomatic adult and adolescent patients with inadequately controlled asthma. IND/MF is being developed for the treatment of asthma at three doses; high dose 150/320 μg; medium dose 150/160 μg and low dose 150/80 μg o.d. as a lactose-blended inhalation powder, hard capsule, delivered via the Breezhaler® device. Previous studies demonstrated that 80, 160 and 320 μg doses of MF administered via the Breezhaler® device were comparable to the 200, 400 and 2 × 400 μg doses of MF administered via the Twisthaler® device, respectively, based on the pharmacokinetic data, in vitro fine particle mass adjustments and subsequent pharmacodynamic confirmation in an efficacy and safety study in asthma patients [
The Phase III QUARTZ study was conducted to evaluate efficacy and safety of low-dose IND/MF 150/80 μg o.d. delivered via Breezhaler® compared with MF 200 μg o.d. delivered via Twisthaler® in terms of lung function (trough forced expiratory volume in 1 s [FEV1]) and asthma control (Asthma Control Questionnaire [ACQ-7] score) in patients with inadequately controlled asthma.
2. Methods
2.1 Study design
The QUARTZ study was a Phase III, multicentre, randomised, double-blind, double-dummy and parallel-group study that included a 12-week treatment period (Clinical trials identifier: NCT02892344). A 2-week screening period was followed by a 3-week run-in period, during which all patients were administered open-label fluticasone propionate 100 μg twice daily delivered via Accuhaler®. After the run-in period, the patients were randomised (1:1) to receive either IND/MF 150/80 μg o.d. via Breezhaler® or MF 200 μg o.d. via Twisthaler® for 12 weeks; study medication was administered to the patients as evening doses between 5 and 8 pm at approximately the same time each evening; patients entered a follow-up period for 30 days after completion of the treatment period (Fig. 1).
The study was approved by institutional review boards or ethics committees at participating centres, and was conducted in accordance with ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with local regulations applied, and the Declaration of Helsinki. All patients provided written informed consent to participate in the study.
2.2 Patients
The study population consisted of men and women aged ≥12 and ≤ 75 years with a documented diagnosis of asthma for a period of at least 3 months prior to screening, who were taking low-dose ICS (with or without controller, e.g., LABA) for at least 1 month prior to screening visit. Patients had FEV1 <90% predicted and were symptomatic (as measured by ACQ-7 ≥1.5) prior to randomisation as per GINA 2016 [
]. Further information on inclusion and exclusion data is available in the online Supplementary Appendix.
2.3 Study objectives
The primary objective of the study was to demonstrate superiority of IND/MF 150/80 μg o.d. to MF 200 μg o.d. in terms of trough FEV1 after 12 weeks of treatment in adults and adolescents with inadequately controlled asthma. The key secondary objective was to demonstrate superiority of IND/MF 150/80 μg o.d. over MF 200 μg o.d. in terms of improvements in asthma control (ACQ-7 score) after 12 weeks of treatment.
Other secondary objectives included the assessment of IND/MF versus MF with respect to – ACQ-7 responder analysis (a responder was defined as a patient achieving an improvement of at least 0.5 units in ACQ-7 score also known as minimal clinically important difference [MCID]) [
] after 12 weeks of treatment, morning and evening peak expiratory flow (PEF) over 4 and 12 weeks of treatment, Asthma Quality of Life Questionnaire (AQLQ) total score, mean total daily symptom score, nighttime awakenings, rescue medication use and rescue medication free days (collected via electronic diary [eDiary]) over 12 weeks of treatment. Rate of exacerbations was evaluated in terms of exacerbation categories: all (mild, moderate, severe), and the combination of moderate or severe for the 12-week treatment period.
In our study, mild exacerbation was defined as the occurrence of deterioration of asthma symptoms, lung function and increased use of “rescue” inhaled bronchodilators. Moderate exacerbation was defined as progressive increase of asthma symptoms, deterioration of lung function and increased use of “rescue” inhaled bronchodilators. Severe exacerbation was defined as an aggravation of asthma symptoms (like shortness of breath, cough, wheezing, or chest tightness) that requires systemic corticosteroids for ≥3 consecutive days and/or a need for an emergency hospitalisation due to asthma or death due to asthma.
Additional secondary endpoints for which the data are not reported in this publication can be found at ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02892344). The safety and tolerability of low-dose IND/MF and MF were also evaluated in terms of adverse events, deaths, other serious or clinically significant AEs and serious asthma outcomes (defined as asthma-related hospitalisation, or asthma-related intubation, or asthma-related death).
2.4 Statistical analysis
All efficacy analyses were performed in the full analysis set (FAS), which consisted of all patients in the randomised set who received at least one dose of study medication. All safety evaluations were performed in the safety set, which consisted of all patients who received at least one dose of study medication including non-randomised patients who received study medication in error. All safety evaluations were based on the safety set. The primary endpoint: trough FEV1 and key secondary endpoint: ACQ-7 treatment differences were analysed using a Mixed Model for Repeated Measure (MMRM). For multiplicity adjustment, a hierarchical testing procedure was applied to control the type-I error rate for the primary and the key secondary endpoint. ACQ-7 responder analysis was analysed using a logistic regression model. Percentage of nights with no nighttime awakenings was analysed using linear mixed model. AQLQ total score, mean morning/evening PEF, mean total daily symptom score and mean rescue medication use over a 12-week treatment period were analysed using an ANCOVA model. In addition, mean morning/evening PEF over 4 weekly intervals were analysed using a similar MMRM as for the primary analysis. The rate of all and the combination of moderate or severe exacerbations was analysed using a generalised linear model assuming the negative binomial distribution.
3. Results
3.1 Study population
Of the 802 randomised patients, 768 (95.8%) completed the study treatment (IND/MF, 386; MF, 382) (Fig. 2).
Overall, baseline demographic characteristics were balanced between the two treatment groups (Table 1). The mean age was 45.6 years with 13.5% of randomised patients aged ≥65 years. This study also included 64 (8.0%) adolescent patients (aged ≥12 to <18 years). The majority of randomised patients were Caucasian (65.7%) and there were more women (60.8%) than men (39.2%). The mean duration of asthma in all patients was 14.0 years with >50% patients having asthma for >10 years.
Table 1Baseline demographics and clinical characteristics of the patients (randomised set).
Characteristic
IND/MF 150/80 μg o.d. (N = 398)
MF 200 μg o.d. (N = 404)
Total (N = 802)
Age, years
46.1 ± 16.26
45.1 ± 16.27
45.6 ± 16.26
Men, n (%)
151 (37.9)
163 (40.3)
314 (39.2)
BMI, kg/m2
26.3 ± 5.81
26.7 ± 6.00
26.5 ± 5.91
Duration of asthma, years
14.4 ± 13.18
13.6 ± 12.48
14.0 ± 12.83
Number of asthma exacerbations in the previous year, n (%)
0
324 (81.4)
319 (79.0)
643 (80.2)
1
70 (17.6)
74 (18.3)
144 (18.0)
>1
3 (0.8)
10 (2.5)
13 (1.6)
Missing
1 (0.3)
1 (0.2)
2 (0.2)
Baseline ACQ-7 score
2.24 ± 0.40
2.30 ± 0.39
2.27 ± 0.39
Prior asthma treatment, n (%)
Low-dose ICS
177 (44.5)
167 (41.3)
344 (42.9)
Medium- to high-dose ICS
1 (0.3)
0
1 (0.1)
Low-dose ICS/LABA
217 (54.5)
232 (57.4)
449 (56.0)
Medium- to high-dose ICS/LABA
3 (0.8)
0
3 (0.4)
Missing
0
5 (1.2)
5 (0.6)
FEV1 pre-bronchodilator (L)
2.23 ± 0.64
2.22 ± 0.58
2.23 ± 0.61
FEV1 pre-bronchodilator (% predicted)
73.3 ± 7.57
72.2 ± 7.63
72.7 ± 7.61
FEV1 reversibility (% increase)
20.6 ± 11.66
20.7 ± 11.94
20.7 ± 11.79
Data are presented as mean ± SD unless otherwise specified.
ACQ-7, Asthma Control Questionnaire; BMI, body mass index; FEV1, forced expiratory volume in 1 s; ICS, inhaled corticosteroid; IND/MF, indacaterol acetate/mometasone furoate; LABA, long-acting β2-agonist; MF, mometasone furoate; o.d., once-daily.
Low-dose IND/MF 150/80 μg o.d. showed statistically significant improvements in trough FEV1 from baseline (0.234 L) compared with MF 200 μg o.d. (0.051 L) after 12 weeks of treatment in symptomatic adult and adolescent patients with inadequately controlled asthma with a least squares mean (LSM) treatment difference of 0.182 L (95% CI: 0.148 to 0.217; p < 0.001) (Fig. 3, Table 2).
Fig. 3Treatment difference with IND/MF 150/80 μg o.d. versus MF 200 μg o.d. for trough FEV1after 12 weeks of treatment (full analysis set).
In sub-group analysis by age group, the LSM treatment difference for trough FEV1 after 12 weeks of treatment was 0.251 L (95% CI: 0.130 to 0.371) for adolescent patients and 0.176 L (95% CI: 0.141 to 0.212) for patients ≥18 years. With IND/MF treatment, the improvements in FEV1 were evident on Day 2 and treatment differences were maintained throughout the study in favour of low-dose IND/MF (Fig. 4).
Fig. 4Least squares means and associated 95% CI of trough and pre-dose trough FEV1(L) over post-baseline visits (full analysis set).
3.3 ACQ-7 treatment difference and proportion of patients achieving MCID after 12 weeks of treatment
At Week 12, low-dose IND/MF 150/80 μg o.d. demonstrated statistically significant decrease in ACQ-7 score from baseline compared with MF 200 μg o.d. with a LSM treatment difference of −0.218 (95% CI: −0.293 to −0.143; p < 0.001) (Table 2).
A decrease in ACQ-7 score represents an improvement in asthma control. A higher proportion of patients in the low-dose IND/MF 150/80 μg o.d. group compared with the MF 200 μg o.d. group achieved clinically meaningful improvement of at least 0.5 units from baseline in the ACQ-7 score [
Over Weeks 1–4, LSM treatment difference between low-dose IND/MF 150/80 μg o.d. and MF 200 μg o.d. for both morning PEF 27.7 L/min (95% CI: 22.7 to 32.8) and evening PEF 26.4 L/min (95% CI: 21.4 to 31.3) was in favour of IND/MF 150/80 μg o.d.
Over Weeks 1–12, LSM treatment difference between low-dose IND/MF 150/80 μg o.d. and MF 200 μg o.d. for both morning PEF 27.2 L/min (95% CI: 22.1 to 32.4) and evening PEF 26.1 L/min (95% CI: 21.0 to 31.2) was in favour of IND/MF 150/80 μg o.d (Table 2).
The improvements in mean morning and evening PEF were evident from Week 1–4, after start of the treatment in favour of low-dose IND/MF and were maintained throughout the study (Fig. 6A, Fig. 6BA and B ).
Fig. 6AChange from baseline in mean morning PEF (L/min) at 4-weekly intervals (full analysis set).
A greater reduction in the mean daily number of puffs of rescue medication was observed in those patients treated with low-dose IND/MF 150/80 μg o.d. compared with MF 200 μg o.d. with LSM treatment difference of −0.26 (95% CI: −0.37 to −0.14) that favoured IND/MF (Table 2).
The percentage of rescue medication free days were greater with low-dose IND/MF 150/80 μg o.d. compared with MF 200 μg o.d. with treatment difference of 8.1% (95% CI: 4.3 to 11.8) (Table 2).
3.6 Quality of life (AQLQ total score) over 12 weeks
Patients treated with low-dose IND/MF 150/80 μg o.d. showed greater improvements in AQLQ overall score compared with the MF 200 μg o.d., with an LSM treatment difference from baseline of 0.149 (95% CI: 0.064 to 0.234) (Table 2).
3.7 Daily symptom score during weeks 1–12
Improvements from baseline in all asthma symptoms were collected via eDiary. A greater reduction in total daily symptom scores were achieved in patients treated with low-dose IND/MF 150/80 μg o.d. compared with MF 200 μg o.d. [treatment difference: −0.15 (95% CI: −0.26 to −0.05)] (Table 2).
The percentage of nights with no nighttime awakenings were greater with low-dose IND/MF 150/80 μg o.d. compared with MF 200 μg o.d. with treatment difference 4.8% (95% CI: 1.8 to 7.7) (Table 2).
3.8 Rate of exacerbations over 12 weeks of treatment
Lower rates of moderate-to-severe [rate ratio (RR) 0.25, 95% CI: 0.12 to 0.52] and all exacerbations (RR: 0.30, 95% CI: 0.18 to 0.50) were observed in patients treated with low-dose IND/MF 150/80 μg o.d. versus MF 200 μg o.d (Fig. A1A and A1B; Table 2).
3.9 Safety assessments
The overall incidence of AEs was lower in patients treated with low-dose IND/MF compared with MF (32.3% vs 38.3%, respectively). The majority of AEs (>90% AEs) in both treatment groups were mild-to-moderate in severity, and were comparable between the treatment groups. One serious asthma outcome (asthma-related hospitalisation) was reported in the MF group and none in the IND/MF group. No death was reported in any treatment group throughout the study. Overall, the incidence of serious AEs (SAEs) was comparable between the treatment groups (1.3% in the low-dose IND/MF group and 1.8% in the MF group).
4. Discussion
This QUARTZ study demonstrates that treatment with low-dose IND/MF 150/80 μg o.d. in symptomatic adult and adolescent patients with inadequately controlled asthma significantly improves lung function and asthma control after 12 weeks of treatment compared to MF alone. Overall, the study met its primary endpoint, trough FEV1 at 12 weeks, with low-dose IND/MF treatment demonstrating statistically significant superiority compared to MF alone [LSM treatment difference 0.182 L, p < 0.001 (Fig. 3)]. Subgroup analyses of trough FEV1 in adolescents were generally consistent with results from overall population in this study and other published studies [
]. Lung function benefits were supported by PEF, which demonstrated improvements in both the morning and evening PEF (Fig. 6A, Fig. 6BA and B). Although PEF was not part of statistical hierarchy, it provides important supportive evidence of lung function benefit, which was measured on a daily basis by patients using an eDiary. The magnitude of improvement in PEF is in the range considered perceivable by patients [
Treatment with low-dose IND/MF showed statistically significant improvements in asthma control (p < 0.001) measured by ACQ-7 as compared to MF. This was supported by responder analysis, which demonstrated that a greater proportion of patients achieved MCID (≥0.5 points improvement from baseline) in ACQ-7 overall score (Fig. 5). Of note, the MF arm also demonstrated a 64.9% responder rate. This finding is consistent with meta-analyses of asthma clinical studies, which demonstrated that use of ICS is associated with ‘placebo’ effect in comparator arms. This is likely attributable to improved adherence in a clinical trial setting [
Magnitude of effect of asthma treatments on asthma quality of life questionnaire and asthma control questionnaire scores: systematic review and network meta-analysis.
]. Despite this and the limited duration of treatment (12 weeks), the results of the responder analysis demonstrated that low-dose IND/MF provided greater benefits in asthma control as compared to MF.
All other secondary efficacy variables such as rescue medication use, rescue medication free days, nighttime awakenings and daily symptom score collected via eDiary as well as AQLQ total score also showed improvement in favour of low-dose IND/MF 150/80 μg o.d.
The results from this study are consistent with previous studies that compared ICS/LABA combination therapies over ICS monotherapy in terms of improvements in lung function and asthma control in patients with asthma [
Effect of once-daily indacaterol maleate/mometasone furoate on exacerbation risk in adolescent and adult asthma: a double-blind randomised controlled trial.
Superiority of fluticasone propionate/formoterol fumarate versus fluticasone propionate alone in patients with moderate-to-severe asthma: a randomised controlled trial.
]. For instance, the 28-week Phase III SMART study demonstrated the efficacy of ICS/LABA combination inhalers when compared to the individual mono-components ICS and LABAs [
Furthermore, previous studies reported that ICS/LABA combinations are safe, effective, well tolerated and not associated with increased risk of death or cardiac-related SAEs or discontinuations due to adverse events (DAEs), and asthma-related SAEs and DAEs [
Effect of once-daily indacaterol maleate/mometasone furoate on exacerbation risk in adolescent and adult asthma: a double-blind randomised controlled trial.
All currently approved ICS/LABA combinations are twice-daily dosing regimens except for fluticasone/vilanterol, which is a once-daily dosing regimen; hence, there is a need to evaluate once-daily dosing regimens for effective asthma treatment, which may provide adherence benefits. It has been well established that once-daily regimens lead to better compliance when compared with twice-daily regimens in asthma patients [
]. This study also provides evidence of the benefit of adding LABA to a lower dose ICS as per GINA guidelines and provides an important treatment option prior to advancing to combination therapies that include higher ICS dose.
To our knowledge, this is the first study to compare a low-dose ICS/LABA FDC o.d. to low-dose ICS monotherapy in adult and adolescent patients with inadequately controlled asthma. Overall, this study was conducted in a clinically appropriate cohort of asthma patients for the IND/MF dose studied and was of adequate length to make clinically meaningful conclusions from the efficacy data. A strength of this study is the use of eDiary, which provided daily electronic recording and transmission of PEF, symptoms and rescue medication data. In addition, spirometry was assessed in a standardised manner using centralised spirometry through an external vendor. Taken together, these helped ensure a high level of rigour in the assessment of these endpoints [
]. A potential limitation of the study is that the 12-week duration does not allow for longer-term safety data to be evaluated. In addition, limited conclusions can be drawn from the exacerbation results due to the short duration of the study.
5. Conclusions
The QUARTZ study showed that IND/MF 150/80 μg o.d. delivered via Breezhaler® significantly improved trough FEV1 and asthma control versus MF 200 μg o.d. and provided benefits across a range of lung function and symptomatic endpoints including morning and evening PEF, rescue medication use, nighttime awakenings, AQLQ total score, mean daily symptom scores and exacerbation rates. Once-daily, low-dose IND/MF can be a potential option for treatment of adult and adolescent patients with asthma who remain inadequately controlled on ICS (with/without LABA). IND/MF 150/80 μg o.d. was well tolerated. Data from this study add to the existing evidence supporting, the efficacy of ICS/LABA over ICS alone and the efficacy of a once-daily combination of low-dose IND/MF 150/80 μg o.d., in patients with inadequately controlled asthma.
Support statement
This study was supported by Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Author contributions
All the authors contributed in the conception and design of the study, facilitated the writing and reviewed the manuscript. All the authors contributed to the development of the manuscript and approved the final version.
Declaration of competing interest
OK's institution received fees for conducting the study as participating site; OK reports personal fees from Sanofi, Boehringer Ingelheim, Novartis, AstraZeneca and GlaxoSmithKline outside the submitted work. JM declares financial support from Novartis during the conduct of the study; from AstraZeneca, Chiesi, Sanofi-Aventis, GlaxoSmithKline, Boehringer-Ingelheim, MSD, TEVA, and ACTELION outside the submitted work. NK has nothing to disclose. LCS, BS, LB and PDA are Novartis employees.
Acknowledgements
The authors would like to thank the investigators and patients at the investigative sites for their support of this study. We acknowledge Abhijit Pethe, Kiran Bapatla and Sheikh Vikarunnessa from Novartis. We acknowledge Juergen Lilienthal, Anna-Marie Hamann and their team for support from DATAMAP. Hasitha Shilpa Anantaraju, Ph.D., and Rahul Lad, Ph.D., professional medical writers at Novartis (Hyderabad, India) provided editorial and technical support in the preparation of the manuscript.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.
Effect of once-daily indacaterol maleate/mometasone furoate on exacerbation risk in adolescent and adult asthma: a double-blind randomised controlled trial.
Magnitude of effect of asthma treatments on asthma quality of life questionnaire and asthma control questionnaire scores: systematic review and network meta-analysis.
Superiority of fluticasone propionate/formoterol fumarate versus fluticasone propionate alone in patients with moderate-to-severe asthma: a randomised controlled trial.
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