Abstract
Background
Maintenance and reliever therapy (MART) with budesonide/formoterol (BUD/FORM) may offer asthma control with a single inhaler. This 6-month exploratory study monitored asthma symptoms, reliever use, lung function, airway inflammation and exacerbation events to determine treatment effectiveness in patients receiving BUD/FORM MART or BUD/FORM maintenance therapy plus short-acting β2-agonist (SABA).
Methods
In the open-label STIFLE study (NCT03924635), patients were randomised to BUD/FORM MART (100 μg/6 μg or 200 μg/6 μg per inhalation, pro re nata (PRN)) or the same dose of BUD/FORM BID as maintenance therapy plus SABA (salbutamol) reliever PRN (100 μg per inhalation). Data were captured at home each day using devices connected to a smartphone via the STIFLE application. Occurrence of pre-defined exacerbation events required patients to attend hospital for assessment.
Results
42 patients were randomised. Adherence to daily measurements exceeded 80% in both treatment groups. The proportion of patients experiencing an exacerbation was 27.8% in the BUD/FORM MART versus 70.8% in the BUD/FORM maintenance plus SABA group. A similar trend was observed in patients who experienced ≥1 day with ≥6 reliever uses (3 (16.7%) versus 9 (37.5%) patients, respectively). Patients treated with BUD/FORM MART showed less variation in airway inflammation, asthma symptom scores, lung function parameters and reliever use, versus BUD/FORM maintenance therapy plus SABA. No unexpected safety findings were observed.
Conclusions
Patients with moderate asthma treated with BUD/FORM MART recorded less variation in asthma outcomes and lower rates of exacerbation events than those treated with BUD/FORM maintenance therapy plus SABA, suggesting improved asthma control.
Shareable abstract
Patients with moderate asthma receiving budesonide/formoterol (BUD/FORM) maintenance and reliever therapy had less variation in asthma outcomes and lower exacerbation rates versus those receiving BUD/FORM maintenance therapy plus short-acting β2-agonist. https://bit.ly/48bZ2ty
Introduction
Asthma is a chronic inflammatory disease of the airways that affects over 260 million people worldwide [1, 2]. Despite marked decline in global prevalence rates over the past 30 years, asthma is still associated with significant rates of mortality [2, 3].
Increased airway inflammation is associated with worsening of asthma symptoms and higher rates of asthma exacerbations [4]. While short-acting β2-agonist (SABA)-only inhalers can provide symptomatic relief, they do not address the underlying inflammatory cause of asthma and, as a result, do not protect against exacerbations [5–7]. Over-reliance on SABA inhalers can be associated with increased exacerbations and mortality risk, and SABA over-use is recognised as a marker of poor asthma control [8, 9]. Nearly 40% of people using SABAs at the time of their asthma-related death had been prescribed more than 12 SABAs in the year before they died [9]. In the UK, it is estimated that 38% of people with asthma over-use their SABA-only inhalers [5].
Combinations of inhaled corticosteroid/long-acting β2-agonists (ICS/LABAs), such as budesonide/formoterol (BUD/FORM), treat asthma symptoms as well as address underlying inflammation, thereby reducing the risk of exacerbations [10]. Maintenance and reliever therapy (MART) with BUD/FORM offers the possibility of controlling asthma with a single inhaler [11]. Compared with separate ICS/LABA and SABA regimens, use of BUD/FORM MART has been shown to reduce the number of pro re nata (PRN) inhalations for symptom relief while reducing severe exacerbations [11, 12].
This exploratory study examined airway inflammation (measured as fractional exhaled nitric oxide (FENO)) [13], asthma symptoms, lung function and reliever use, assessed daily over a period of 6 months, and surrounding exacerbation events, in adults with asthma receiving BUD/FORM MART or BUD/FORM maintenance therapy plus SABA. The primary objective was to descriptively characterise the relationship between inflammation, asthma symptoms, lung function and reliever use measured daily over 24 weeks of treatment in each treatment arm. The secondary objective was to similarly profile symptoms and characteristics surrounding any recorded exacerbation event.
Materials and methods
Study design
STIFLE (NCT03924635) was a phase 4, randomised, exploratory, open-label study. All patients received BUD/FORM maintenance therapy (100 μg/6 μg or 200 μg/6 μg per inhalation, twice daily based on their ICS dose at study entry) and SABA reliever (100 μg per inhalation, PRN) during the 2-week period before randomisation. Patients were then randomised 1:1, with randomisation stratified according to their ongoing ICS dose at study entry (low or medium), to BUD/FORM MART (100 μg/6 μg or 200 μg/6 μg per inhalation based on ICS dose, twice daily for maintenance and PRN for relief) or the same dose of BUD/FORM BID as maintenance therapy plus salbutamol (SABA) reliever (100 μg per inhalation, PRN) for 24 weeks (figure 1a).
FIGURE 1.
a) Study design and b) patient disposition. #: Patients experiencing an exacerbation event of interest were instructed to attend a hospital visit at the earliest possible date and were required to attend three further visits at approximately 4-day intervals. ¶: Based on inhaled corticosteroid dose at study entry. +: All randomised patients were included in the analyses. BUD: budesonide; FENO: fractional exhaled nitric oxide; FEV1: forced expiratory volume in 1 s; FORM: formoterol; MART: maintenance and reliever therapy; PEF: peak expiratory flow; PRN: pro re nata; R: randomisation; SABA: short-acting β2-agonist.
Throughout the study, patients were required to capture data at home each day using four devices connected to a smartphone via the STIFLE application (figure 1a). FENO was measured in the morning using the Vivatmo Me (Bosch) device. Peak expiratory flow (PEF) and forced expiratory volume in 1 s (FEV1) were captured in the morning and evening with the Spirobank Smart (MIR) device. For the measurement of reliever use, the Turbu+ (SmartTurbo) and the Hailie (Adherium) devices recorded use of BUD/FORM and salbutamol, respectively. Patients recorded asthma symptom score and reliever use twice daily (morning and evening) in an asthma symptom diary within the STIFLE application. Patients were asked to record reliever use because device-measured reliever use may have been overestimated since SABA inhalers must be primed when new or if they have not been used for some time. Asthma symptoms were scored twice daily on a scale of 0–3 (morning and evening scores combined), with 0 representing no asthma symptoms and 3 representing an inability to perform normal activities or sleep due to asthma symptoms. All measurements were made before taking study medications.
Three pre-defined exacerbation events of interest required patients to attend a hospital visit at the earliest possible date, as follows: 1) severe exacerbations (SevEx) (events treated with at least 3 days of oral corticosteroids, an emergency room visit (or other urgent care visit) resulting in the administration of systemic corticosteroids or an inpatient hospitalisation for asthma), 2) a composite end-point for exacerbations in asthma event (CompEx) (a SevEx or diary-based event, identified using an established algorithm as described in the study protocol, involving worsening PEF, increased reliever use or worsening symptoms) [14], and 3) single days (24 h) with at least six reliever uses.
Serious adverse events (SAEs) and adverse events (AEs) leading to treatment discontinuation were reported by the patient at study visits.
Study participants
Patients (at least 18 years of age) were recruited from six sites within the UK. All patients had been diagnosed with moderate asthma for at least 6 months, were receiving step 3 or step 4 (ICS/LABA, low- or medium-dose for asthma, in accordance with Global Initiative for Asthma (GINA) 2018 guidelines [15]) treatment for at least 3 months and had experienced at least one episode of symptom worsening requiring reliever over-use (defined as more than the standard for the individual patient) in the last 30 days. Patients had to be able to perform at home FENO and spirometry assessments and to complete an asthma symptom diary on a daily basis.
Current smokers, or people with any significant disease or a drug/substance abuse disorder that could interfere with the conduct of the study, were excluded from participation. Additional exclusion criteria included any asthma worsening requiring a change in asthma treatment and acute upper or lower respiratory tract infections requiring treatment within 30 days before the first study visit. People with a history of life-threatening asthma requiring intubation, a medical condition that could influence FENO, concurrent respiratory disease or a severe asthma exacerbation within 30 days of screening were also not eligible to participate.
The study was performed in accordance with the Declaration of Helsinki and with the International Council for Harmonisation/Good Clinical Practice guidelines, as well as in compliance with applicable regulatory requirements. An Independent Ethics Committee (Health and Social Care Research Ethics Committee, Lisburn, Northern Ireland, UK) reviewed and approved the study protocol. All participants provided written informed consent before study participation.
Statistical analyses
This study was exploratory in nature with no formal hypotheses and was not designed or powered to test for significant differences between treatment arms. All analyses were descriptive and conducted using SAS Version 9.3. Analyses were based on the full analysis set, which comprised all randomised patients with at least one post-baseline measurement, irrespective of protocol adherence and continued study participation. Outcomes were assessed between treatment arms and at the individual patient-level. Safety outcomes were assessed in the safety analysis set, which included all patients who received at least one dose of study medication.
Mean overall adherence by patients to daily measures during the treatment period was calculated as:
The study planned to randomise 60–80 patients, with the goal of having at least 54 patients completing the study, which was considered feasible to allow for individual patient plots to be generated and reviewed as per the primary objective of the study. Recruitment was put on hold during the COVID-19 pandemic (March–November 2020). Afterwards, three additional sites were included to aid recruitment. However, the study was stopped early due to continuing recruitment issues attributed to a reduction in exacerbation events observed in clinical practice, resulting in a smaller sample size than originally planned.
Results
Patient characteristics
A total of 42 patients (64.3% female, mean±sd age 49.2±15.8 years) were randomised to receive treatment with BUD/FORM MART (n=18) or BUD/FORM as maintenance therapy plus SABA reliever (n=24) (figure 1b) (the first participant was enrolled on 1 August 2019 and the last participant visit was on 16 December 2022). Mean follow-up time was 159.9 days for those receiving BUD/FORM MART and 156.2 days for those receiving BUD/FORM as maintenance therapy plus SABA. Additionally, two and four patients in the respective treatment arms withdrew from the study early (figure 1b).
Baseline demographic and clinical characteristics were generally comparable between the treatment arms (table 1), although there were a few notable differences. Patients treated with BUD/FORM MART were older (mean age: 54.1 versus 45.5 years), included more former smokers (five versus two) and had a lower average morning and evening PEF (morning mean: 374.1 versus 426.0 L·min−1; evening mean: 392.0 versus 440.6 L·min−1) compared with those receiving BUD/FORM as maintenance therapy plus SABA.
TABLE 1.
Baseline demographic and clinical characteristics of patients receiving budesonide (BUD)/formoterol (FORM) maintenance and reliever therapy (MART) or BUD/FORM maintenance therapy plus short-acting β2-agonist (SABA) (full analysis set)
| Parameter | BUD/FORM MART (n=18) |
BUD/FORM maintenance+SABA (n=24) |
Total (n=42) |
|---|---|---|---|
| Age, years | 54.1±14.6 | 45.5±16.0 | 49.2±15.8 |
| Sex, female | 12 (66.7) | 15 (62.5) | 27 (64.3) |
| Race | |||
| White | 17 (94.4) | 22 (91.7) | 39 (92.9) |
| Asian | 0 | 1 (4.2) | 1 (2.4) |
| Other | 1 (5.6) | 1 (4.2) | 2 (4.8) |
| BMI, kg·m−2 | 33.3±8.5 | 31.7±9.0 | 32.4±8.7 |
| Smoking status | |||
| Non-smoker | 13 (72.2) | 22 (91.7) | 35 (83.3) |
| Former smoker | 5 (27.8) | 2 (8.3) | 7 (16.7) |
| Time since smoking cessation, years | 24.0±15.7 | 38.5±9.2 | 28.1±15.1 |
| Smoking consumption, pack-years | 7.0±4.1 | 2.5±2.1 | 5.7±4.1 |
| Asthma duration, years | 21.4±14.1 | 25.9±13.6 | 24.0±13.8 |
| Prior use of ICS # | |||
| Low dose | 3 (16.7) | 7 (29.2) | 10 (23.8) |
| Medium dose | 12 (66.7) | 17 (70.8) | 29 (69.0) |
| Missing | 3 (16.7) | 0 | 3 (7.1) |
| Number of exacerbations treated with systemic CS in the last 12 months | 1.3±1.1 | 1.3±1.2 | 1.3±1.2 |
| Number of exacerbations leading to ER visit and treatment with systemic CS experienced in last 12 months | 0.4±0.8 | 0.2±0.4 | 0.3±0.6 |
| Number of exacerbations leading to hospitalisation and treatment with systemic CS experienced in last 12 months | 0.2±0.5 | 0.3±0.6 | 0.2±0.6 |
| Time since most recent exacerbation, days | 200.5±115.1 | 178.8±97.5 | 187.7±104.0 |
| Baseline defined as mean values over last 10 days of run-in period prior to randomisation, mean±sd (median (Q1, Q3)) | |||
| Average total asthma symptom score | 1.5±0.8 (1.7 (0.8, 2.0)) |
1.5±0.7 (1.5 (0.9, 2.0)) |
1.5±0.8 (1.5 (0.9, 2.0)) |
| Average total reliever medication use, number of occasions | 0.8±0.7 (0.6 (0.3, 1.2)) |
1.0±1.0 (0.7 (0.4, 1.2)) |
0.9±0.9 (0.7 (0.3, 1.2)) |
| Night-time awakening days | 18.0±19.9 (10.6 (0.0, 30.0)) |
14.7±27.0 (10.0 (0.0, 10.6)) |
16.1±24.0 (10.0 (0.0, 20.0)) |
| Asthma control days | 22.2±28.8 (5.0 (0.0, 40.0)) |
19.6±21.6 (15.0 (0.0, 30.0)) |
20.7±24.6 (10.0 (0.0, 30.0)) |
| Reliever-free days | 55.0±19.8 (50.0 (40.0, 70.0)) |
49.6±17.6 (50.0 (45.0, 60.0)) |
51.9±18.5 (50.0 (40.0, 60.0)) |
| Symptom-free days | 22.2±28.8 (5.0 (0.0, 40.0)) |
19.6±21.6 (15.0 (0.0, 30.0)) |
20.7±24.6 (10.0 (0.0, 30.0)) |
| Average FENO, ppb | 29.6±29.0 (17.8 (10.5, 32.6)) |
21.9±13.1 (17.9 (12.1, 26.7)) |
25.2±21.5 (17.9 (11.4, 30.7)) |
| Average morning PEF, L·min−1 | 374.1±99.0 (356.5 (301.4, 423.5)) |
426.0±116.6 (396.7 (350.1, 511.5)) |
403.8±111.2 (378.6 (332.5, 448.1)) |
| Average evening PEF, L·min−1 | 392.0±94.6 (379.1 (324.5, 424.9)) |
440.6±107.4 (418.8 (369.4, 508.2)) |
419.8±103.8 (398.4 (355.8, 461.7)) |
| Average morning FEV1, L | 2.1±0.7 (1.9 (1.6, 2.9)) |
2.5±0.8 (2.3 (1.9, 2.9)) |
2.3±0.7 (2.2 (1.8, 2.9)) |
| Average evening FEV1, L | 2.2±0.6 (2.0 (1.6, 2.7)) |
2.5±0.7 (2.3 (2.0, 2.9)) |
2.3±0.7 (2.2 (1.8, 2.8)) |
Data are mean±sd or n (%), unless otherwise stated. Total asthma symptoms score was the sum of non-missing morning and evening scores; higher scores represent more severe symptoms. Total reliever medication use was the sum of non-missing morning and evening reliever medication use. BMI: body mass index; CS: corticosteroid; ER: emergency room; FENO: fractional exhaled nitric oxide; FEV1: forced expiratory volume in 1 s; ICS: inhaled corticosteroid; PEF: peak expiratory flow; Q1: first quartile; Q3: third quartile. #: Based on [15].
Exacerbation events
Overall, the number of patients with any exacerbation event of interest was 5 (27.8%) in the BUD/FORM MART group and 17 (70.8%) in the BUD/FORM maintenance plus SABA group. Fewer patients in the BUD/FORM MART arm than the BUD/FORM maintenance plus SABA arm experienced ≥1 SevEx or CompEx event (2 (11.1%) versus 7 (29.2%) and 4 (22.2%) versus 12 patients (50.0%), respectively). Similarly, fewer patients in the BUD/FORM MART arm experienced ≥1 day with ≥6 reliever uses (3 (16.7%) versus 9 patients (37.5%)). Of the total CompEx events reported, there was a similar trend in the proportion of SevEx events within each arm (2/8 events (25.0%) versus 8/15 events (53.3%), respectively).
Asthma-related outcomes captured with the STIFLE application
Median overall adherence by patients to daily measurements post-randomisation for the BUD/FORM MART treatment arm ranged from 84.8% (evening FEV1) to 92.3% (FENO). Adherence rates were broadly similar for the BUD/FORM maintenance therapy plus SABA arm, ranging from 86.4% (evening PEF) to 90.0% (morning asthma symptom diary). Across treatment arms, individual patient adherence to daily measurements post-randomisation ranged from a minimum of 22.6% to a maximum of 99.4%.
Over 24 weeks, patient-recorded FENO, total asthma symptom score, PEF and FEV1 outcomes, and total reliever medication use was variable in both treatment arms, with a trend towards less variation in the BUD/FORM MART arm (figure 2 and supplementary figure S1). Across outcomes, the median of individual patient standard deviations trended lower, and interquartile ranges as an indicator of inter-group variability were generally narrower in the BUD/FORM MART treatment arm compared with the BUD/FORM maintenance plus SABA arm (figure 2 and supplementary figure S1). Importantly, patient-level data showed pronounced variability for all parameters, both between patients and within individual patients (figure 3 and supplementary figure S2). Notably, patients with exacerbations did not necessarily have poorer asthma outcomes; for instance, some patients had low FENO values on average whereas others had high FENO values on average (figures 2a and 3a).
FIGURE 2.
Variation in a) fractional exhaled nitric oxide (FENO), b) total asthma symptom score, c) morning peak expiratory flow (PEF), d) morning forced expiratory volume in 1 s (FEV1) and e) total reliever medication use in patients receiving budesonide (BUD)/formoterol (FORM) maintenance and reliever therapy (MART) or BUD/FORM maintenance therapy plus short-acting β2-agonist (SABA) during the 24-week treatment period (full analysis set#). Dots show sd values for a given parameter during the 24-week treatment period for individual patients; pink dots represent patients who experienced a clinical event (≥1 severe exacerbation (SevEx) and/or composite surrogate end-point for severe exacerbations of asthma (CompEx)) and purple dots represent patients without a clinical event (without ≥1 SevEx and/or CompEx). Box shows the interquartile range (IQR), spanning from the first to third quartile, representing the middle 50% of the data. The horizontal line inside the box represents the median. Whiskers extending from the box represent the minimum and maximum nonoutlier values (smallest and largest values within 1.5×IQR from the quartiles). Individual points plotted outside of the whiskers are “outliers” (values that are more than 1.5×IQR from the quartiles). The diamond inside the box represents the mean. #: All randomised patients with ≥1 post-baseline measurement. Summary statistics are based on individual patient-level sd to summarise variation over the observational period by treatment arm.
FIGURE 3.
Patient-level variation in a) fractional exhaled nitric oxide (FENO), b) morning peak expiratory flow (PEF), c) morning forced expiratory volume in 1 s (FEV1), score d) total asthma symptom score and e) total reliever medication use in adults with asthma receiving budesonide (BUD)/formoterol (FORM) maintenance and reliever therapy (MART) or BUD/FORM maintenance therapy plus short-acting β2-agonist (SABA) during the 24-week treatment period (full analysis set). Each line represents an individual patient; pink denotes those with a clinical event (≥1 severe exacerbation (SevEx) and/or composite surrogate end-point for severe exacerbations of asthma (CompEx)); purple denotes those without a clinical event (without ≥1 SevEx and/or CompEx). Box shows the interquartile range (IQR), spanning from the first to third quartile, representing the middle 50% of the data. The horizontal line inside the box that marks the median. Whiskers extending from the box represent the minimum and maximum nonoutlier values (smallest and largest values within 1.5×IQR from the quartiles). Individual points plotted outside of the whiskers are “outliers” (values that are more than 1.5×IQR from the quartiles). The diamond inside the box represents the mean.
Safety outcomes
No new or unexpected safety findings were observed (table 2). No AEs were reported in the BUD/FORM MART arm. One SAE of central nervous system infection was reported in one patient in the BUD/FORM maintenance plus SABA arm. No AEs with an outcome of death or AEs leading to treatment discontinuation were reported.
TABLE 2.
Number and duration of exacerbation events of interest in patients receiving budesonide (BUD)/formoterol (FORM) maintenance and reliever therapy (MART) or BUD/FORM maintenance therapy plus short-acting β2-agonist (SABA) during the 24-week treatment period (full analysis set)
| Event | BUD/FORM MART (n=18) |
BUD/FORM maintenance+SABA (n=24) |
|---|---|---|
| All exacerbation events of interest | ||
| Patients with ≥1 event, n (%) | 5 (27.8) | 17 (70.8) |
| Total number of events | 13 | 41 |
| SevEx events | ||
| Patients with ≥1 exacerbation, n (%) | 2 (11.1) | 7 (29.2) |
| Total number of exacerbations | 2 | 8 |
| Duration, days (mean±sd) | 7.5±0.7 | 11.6±6.9 |
| CompEx events | ||
| Patients with ≥1 exacerbation, n (%) | 4 (22.2) | 12 (50.0) |
| Total number of exacerbations | 8 | 15 |
| Duration, days (mean±sd) | 4.0±2.4 | 7.9±6.8 |
| Single day with ≥6 reliever uses | ||
| Patients with ≥1 event, n (%) | 3 (16.7) | 9 (37.5) |
| Total number of events | 3 | 18 |
| Duration, days (mean±sd) | 1.0±0.0 | 3.7±4.0 |
CompEx: composite surrogate end-point for severe exacerbations of asthma; SevEx: severe exacerbation.
Discussion
The aim of this exploratory study was to generate real-world insights on asthma control and exacerbation risk, using daily digital home monitoring, in adults with moderate asthma treated with either BUD/FORM MART or BUD/FORM maintenance therapy plus SABA reliever [10]. Over 24-weeks of self-monitoring, patients in the BUD/FORM MART treatment arm experienced fewer exacerbation events of interest and single days with ≥6 reliever uses relative to those in the BUD/FORM maintenance therapy plus SABA arm. Our finding of fewer SevEx events in the BUD/FORM MART group versus the BUD/FORM maintenance plus SABA group is consistent with that of a previous study [12]. The observation that patients receiving BUD/FORM MART reported fewer CompEx events with SevEx events, compared with those receiving BUD/FORM as maintenance therapy with SABA, could be due to the delivery of additional ICS at the point of symptom worsening [10].
Patients receiving BUD/FORM MART had less variation in airway inflammation and lung function and reported less variation in asthma symptoms than those treated with BUD/FORM maintenance therapy plus SABA. Reduced variability in these parameters is consistent with the mechanism of action of BUD/FORM MART, which is designed for the rapid relief of asthma symptoms and the reduction of exacerbation risk [11, 12]. However, as all patients were receiving BUD/FORM as maintenance treatment, this consistency would have controlled inflammation to some degree and may account for the limited variability in FENO observed herein. Additionally, adherence with maintenance treatment is usually better in clinical trials than clinical practice; therefore, reported variability may have been less than is typically seen in everyday clinical practice. The lower variability in total reliever use observed in patients who received BUD/FORM MART may reflect the longer duration of bronchodilation associated with its use as a reliever medication, potentially due to a stabilising effect on airway smooth muscle [10] or due to additional ICS use in response to symptoms.
The STIFLE application is a novel tool that allows for the capture of individual patient-level data in a home-based setting [10]. By gathering patient data on a day-to-day basis, rather than only during periods of symptom deterioration or exacerbation, this analysis provides insight into key parameter changes over a continuous 24-week period. However, several different operational and data synchronisation issues contributed to missing data; and missing data were not imputed. The following three general patterns were identified regarding patients with missing daily measurements: 1) patients performing assessments regularly but not necessarily daily; 2) patients missing daily assessments for multiple consecutive days, typically resulting in large gaps in data availability for all measures; and 3) patients withdrawing consent and not completing the study.
An imbalance in the number of patients between treatment arms was observed despite randomisation being blocked. The smaller number of patients in the BUD/FORM MART treatment arm may have influenced the trending differences observed between treatment arms. The imbalance in randomisation was likely due to recruitment ending early (due to the low number of acute exacerbations observed) and the increased number of study sites, particularly where only small numbers of patients were enrolled. One potential reason for low recruitment is the perception among patients that daily assessments, and the training required from nurses to take these measurements, are burdensome. However, adherence rates were high among randomised patients, ranging from a median of 84.8 to 92.3% across outcomes and treatment arms. Another limitation of the study is the generalisability of the results, which may be affected by the small sample size, the COVID-19 pandemic and the fact that all patients were from the UK. It should also be noted that some patients completed the study early, which may have affected variability estimates for these individuals compared with those who completed the full follow-up period.
Conclusions
Over a 24-week monitoring period, patient and health device recorded measures of airway inflammation, asthma symptoms, lung function and reliever medication use tended to be less variable in patients with moderate asthma taking BUD/FORM MART when compared to those taking BUD/FORM maintenance plus SABA. Lower rates of exacerbation events of interest were observed in the BUD/FORM MART group. These findings suggest improved asthma control in the BUD/FORM MART group and are consistent with the application of BUD/FORM as an anti-inflammatory reliever. These data support the GINA treatment preference for ICS-containing reliever medication over SABA reliever medication in asthma management [16].
Acknowledgements
The authors would like to thank the STIFLE study participants. We would like to acknowledge Malin Fagerås for contributions to the study design and data interpretation. Medical writing support, under the direction of the authors, was provided by Eleanor Finn of CMC Connect, a division of IPG Health Medical Communications, and was funded by AstraZeneca, in accordance with Good Publication Practice 2022 guidelines.
Footnotes
Provenance: Submitted article, peer reviewed.
This clinical trial is prospectively registered with ClinicalTrials.gov as NCT03924635.
Ethics statement: An independent ethics committee (Health and Social Care Research Ethics Committee, Lisburn, UK) reviewed and approved the study protocol. All participants provided written informed consent before study participation.
Author contributions: Conceptualisation: I.D. Pavord, L. Belton, P. Gustafson and T. Harrison. Data curation: L. Belton, P. Gustafson and T. Harrison. Formal analysis: M.J. Martin, I.D. Pavord, K.G. Roy, G.W. Clarke, L. Belton, V.R. Gopal and T. Harrison. Funding acquisition: P. Gustafson and T. Harrison. Investigation: J.D. Chalmers, D. Saralaya, M. Patel, P. Gustafson, V.R. Gopal and T. Harrison. Methodology: I.D. Pavord, J.D. Chalmers, G.W. Clarke, L. Belton, P. Gustafson and T. Harrison. Project administration: M. Patel, V.R. Gopal and T. Harrison. Resources: G.W. Clarke, V.R. Gopal and T. Harrison. Software: L. Belton and A. Rutgersson. Supervision: M.J. Martin, I.D. Pavord, K.G. Roy, M. Patel, P. Gustafson, V.R. Gopal and T. Harrison. Validation: M.J. Martin, K.G. Roy, L. Belton, V.R. Gopal and T. Harrison. Visualisation: M. Patel, L. Belton, V.R. Gopal and T. Harrison. Writing (review and editing): M.J. Martin, I.D. Pavord, J.D. Chalmers, D. Saralaya, K.G. Roy, M. Patel, G.W. Clarke, L. Belton, A. Rutgersson, P. Gustafson, V.R. Gopal and T. Harrison. All authors critically reviewed the manuscript for intellectual content and had final responsibility for the decision to submit for publication.
Conflict of interest: M.J. Martin has received support from AstraZeneca and Chiesi for attending scientific meetings and/or travel. I.D. Pavord has received research grants from Chiesi; consulting fees from Aritrea, AstraZeneca, Chiesi, Circassia, Genetech, GlaxoSmithKline, Kymera, Merck, MSD, Novartis, Pfizer, Regeneron Pharmaceuticals Inc., Sanofi, Schering-Plough and Upstream Bio; payment or honoraria from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, Regeneron Pharmaceuticals Inc. and Sanofi; and support for attending meetings from AstraZeneca, Chiesi, GlaxoSmithKline, Regeneron Pharmaceuticals Inc. and Sanofi. J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Grifols, Insmed, Novartis and Trudell; consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell and Zambon; and is an associate editor of this journal. D. Saralaya has received speaker fees for meetings from Sanofi-Aventis and AstraZeneca; and was supported by Sanofi and AstraZeneca to attend the European Respiratory Society Congress. K.G. Roy has received support from AstraZeneca and Chiesi for attending scientific meetings. M. Patel has received speaker's honoraria from AstraZeneca and GlaxoSmithKline at sponsored educational meetings; and support from GlaxoSmithKline for attending scientific meetings. G.W. Clarke is an employee of AstraZeneca and may hold stock and/or stock options in the company. L. Belton is a contractor for AstraZeneca. A. Rutgersson is an employee of Evinova, an AstraZeneca subsidiary, and holds stock and/or stock options in the company. P. Gustafson is an employee of Alexion, an AstraZeneca subsidiary, and holds stock and stock options in the company. V.R. Gopal and T. Harrison are employees of AstraZeneca; they hold stock and/or stock options in the company.
Support statement: The sponsor, AstraZeneca, funded the STIFLE study and all analyses reported in this manuscript. AstraZeneca also funded medical writing support for development of the manuscript. Funding information for this article has been deposited with the Open Funder Registry.
Supplementary material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material
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Figure S1
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Figure S2
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Data availability
Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. The AstraZeneca Vivli member page is also available outlining further details: https://vivli.org/ourmember/astrazeneca/.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material
00116-2026.SUPPLEMENT
Figure S1
00116-2026.SUPPLEMENT1
Figure S2
00116-2026.SUPPLEMENT2
Data Availability Statement
Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. The AstraZeneca Vivli member page is also available outlining further details: https://vivli.org/ourmember/astrazeneca/.