- Email: [email protected]
formoterol pressurised metered-dose inhaler – Results from a non-interventional study
Accepted Manuscript Real-life effectiveness of asthma treatment with a fixed-dose fluticasone/formoterol pressurised metered-dose inhaler – Results from a non-interventional study O. Schmidt, W. Petro, G. Hoheisel, F. Kanniess, P. Oepen, B. Langer-Brauburger PII:
S0954-6111(17)30287-1
DOI:
10.1016/j.rmed.2017.08.017
Reference:
YRMED 5238
To appear in:
Respiratory Medicine
Received Date: 26 January 2017 Revised Date:
17 August 2017
Accepted Date: 17 August 2017
Please cite this article as: Schmidt O, Petro W, Hoheisel G, Kanniess F, Oepen P, Langer-Brauburger B, Real-life effectiveness of asthma treatment with a fixed-dose fluticasone/formoterol pressurised metered-dose inhaler – Results from a non-interventional study, Respiratory Medicine (2017), doi: 10.1016/j.rmed.2017.08.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Real-life effectiveness of asthma treatment with a fixed-dose fluticasone/formoterol pressurised metered-dose inhaler – results from a non-interventional study
O. Schmidt1, W. Petro2, G. Hoheisel3, F. Kanniess4, P. Oepen5, B. Langer-Brauburger5* 1
2
RI PT
Pneumologische Gemeinschaftspraxis, Emil-Schüller-Str. 29, Koblenz, Germany Medizinisches Versorgungszentrum (MVZ) Bad Reichenhall im Gesundheitszentrum Salus,
Rinckstr. 7-9, Bad Reichenhall, Germany 3
Praxis für Pneumologie und Allergologie, August-Bebel-Str. 69, Leipzig, Germany
4
SC
Gemeinschaftspraxis Reinfeld, Praxis für Allgemeinmedizin und Allergologie,
Bahnhofstrasse 5a, Reinfeld, Germany
Mundipharma GmbH, Mundipharmastraße 2, Limburg (Lahn), Germany
M AN U
5
*Corresponding author
Mundipharma GmbH, Mundipharmastraße 2, 65549 Limburg (Lahn), Germany
TE D
Tel: +49 6431 701423
AC C
EP
Email: [email protected]
1
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Abstract Objective Prospective, non-interventional study of fixed-dose inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA) combination therapy with fluticasone propionate/formoterol fumarate
RI PT
(FP/FORM) across a spectrum of community-based patients with asthma in a real-life setting. Methods
In FP/FORM-treated patients aged ≥12 years, asthma control (Asthma Control Test™
SC
[ACT]), incidence of severe exacerbations, lung function, quality of life (asthma quality of life questionnaire [AQLQ]) and adverse events (AEs) were assessed over one year.
M AN U
Results
Almost 40% (n=555) of the full analysis population (N=1,410) were receiving ICS/LABA therapy prior to enrolment; 69.8% completed the study. Asthma control (mean ACT ± standard deviation) improved from 16.3 ± 5.0 at baseline to 19.8 ± 4.5 at study end.
TE D
ACT scores were significantly (p<0.0001) higher than baseline at all observation timepoints, including the first assessment at 4–6 weeks. The percentage of patients with asthma control increased (baseline: 30.9%; study end: 62.4%), and the percentage of patients with ≥1
EP
severe asthma exacerbation decreased (12 months before: 35.8%; during study: 5.9%). Lung function (forced expiratory volume in one second, peak expiratory flow) improved from
AC C
baseline to each observation timepoint (p<0.0001 for all). Improvement in asthma status was accompanied by ameliorated quality of life: AQLQ scores improved significantly from baseline to all observation timepoints (p<0.0001 for all). AEs accorded with the summary of product characteristics. After study completion, 70% of patients continued FP/FORM treatment. Conclusion In this one-year study, FP/FORM treatment was associated with clinically relevant improvements in asthma status in a diverse population of patients under real-life conditions.
2
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Keywords: asthma control; quality of life; fluticasone; formoterol; fixed combination; non-
AC C
EP
TE D
M AN U
SC
RI PT
interventional
3
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Introduction Asthma is one of the most common chronic diseases [1]. The main goals of asthma therapy are to achieve good symptomatic control, improve lung function, reduce the risk of exacerbations and minimise side effects of treatment [2]. Current Global Initiative for Asthma
RI PT
(GINA) and national guidelines recommend a stepwise approach to the management of chronic asthma based on disease severity or level of control [2-4]. Treatment is typically initiated using inhaled corticosteroid (ICS). For asthma that is not controlled with low to
treatment option in the majority of patients [2-4].
SC
medium-dose ICS alone, addition of a long-acting beta2-agonist (LABA) is the preferred
A number of studies have shown that addition of a LABA to ICS provides better symptom
M AN U
control, greater improvement in lung function and a greater reduction of severe exacerbations than increasing the dose of ICS [5-9]. LABA and ICS can be administered via separate inhalers or combined in one inhaler. Advantages of fixed-dose ICS/LABA inhalers include greater patient convenience, an increase in patient adherence as a result of
TE D
simplification of the regime [10, 11] and elimination of the possibility of LABA monotherapy and its attendant risks [12].
Treatment with a fixed combination of the ICS, fluticasone propionate, and the LABA,
EP
formoterol fumarate (fluticasone propionate/formoterol fumarate [FP/FORM]), as an aerosol suspension in a hydrofluoroalkane (HFA)-based pressurised metered-dose inhaler (pMDI) is
AC C
associated with greater efficacy than treatment with each its components (fluticasone or formoterol) administered as monotherapy [13-16]. Efficacy of FP/FORM has been proven in randomised controlled trials for all asthma severities for adolescents and adults [15-19] and for long-term treatment over both 6 and 12 months [20]. FP/FORM is comparable in efficacy to budesonide/formoterol [21] and fluticasone/salmeterol [18], but patients receiving FP/FORM experience a consistently faster onset of bronchodilation than patients receiving fluticasone/salmeterol [18]. Although data from randomised clinical trials provide important safety and efficacy data, they may not accurately reflect the situation in clinical practice, in which many patients fail to 4
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
achieve adequate control of their asthma [22, 23]. Data from prospective, non-interventional studies complement the results of clinical trials [24, 25] by providing data on the effectiveness and safety of interventions in a diverse and clinically relevant population of patients, to which few exclusion criteria have been applied.
RI PT
The current non-interventional study was designed to evaluate the safety and effectiveness of FP/FORM across a diverse spectrum of community-based patients with asthma in a reallife setting for one year.
SC
Patients and methods Study design
M AN U
This multicentre, prospective, non-interventional post-authorisation safety study, conducted in Germany, started in November 2012 and was completed in July 2015. The study incorporated a series of 6 visits over a one-year observational period for each patient. Visits
Patients
TE D
2 through 6 occurred 4–6 weeks, and 3, 6, 9 and 12 months after the baseline visit (visit 1).
Male and female outpatients aged ≥12 years with a diagnosis of asthma were enrolled. The
EP
decision to initiate treatment with FP/FORM was at the discretion of the prescribing physician. It always preceded and was independent of the decision to enrol the patient into
AC C
the study. There were no restrictions regarding asthma type or severity, duration of disease, bronchodilator reversibility, smoking history, co-morbidity, concomitant asthma or other medication or correct inhaler technique. Contraindications to enrolment and FP/FORM treatment were as mandated in the FP/FORM summary of product characteristics (SmPC) [26].
Informed consent and registration Written informed consent was signed by the patient or, for patients <18 years, signed according to local requirements by one or both of the patient’s parent(s) or legal 5
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
representative(s) and an assent form was signed by the patient. The study was conducted in accordance with AMG (German Medicines Act) chapter 67, section 6. It was approved by the responsible ethics committees and registered with the German Federal Institute for Drugs and Medical Devices (BfArM; study code FLT9501). The study was also registered in the
RI PT
European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP; study code ENCePP/SDPP/3702).
Study treatment
SC
All patients received treatment with a fixed combination of FP/FORM in a pMDI (Flutiform®, Mundipharma GmbH, Limburg, Germany) at one of the following dose strengths (FP/FORM):
M AN U
50/5 µg; 125/5 µg; 250/10 µg (the latter indicated only for patients aged ≥18 years). The recommended dose is two inhalations twice daily. Patients were to be treated in compliance with the FP/FORM marketing authorisation. Initial dose and adjustments were performed at
TE D
the discretion of each patient’s physician.
Data collection and outcome measures
Primary effectiveness parameters were asthma control, assessed by the change in Asthma
EP
Control Test™ (ACT) total score between baseline and study end, and frequency of severe asthma exacerbations. The primary safety parameter was the recording of adverse events.
AC C
Data collected at the baseline visit included medical history, demographic and asthmarelated data prior to treatment. Additional data collected at this and all post-baseline visits included asthma control, asthma-related quality of life, lung function (forced expiratory volume in one second [FEV1; absolute and % predicted values] and peak expiratory flow [PEF: absolute and % predicted values]), severe asthma exacerbations (worsening of asthma requiring medical intervention with administration of systemic corticosteroids), patient satisfaction with treatment and the number of ‘disability days’. At all post-baseline visits the investigators additionally documented the patients’ FP/FORM dosage, any history of adverse events (AEs) or unscheduled and emergency asthma-related medical care and, if 6
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
the patient had discontinued treatment, the reason for discontinuation. The last observation carried forward (LOCF) method was used for all ‘end of study’ analyses. Asthma control was assessed using the 5-item ACT [27]. The total summed score ranges from 5 to 25. The extent of asthma control was defined as follows: controlled (ACT total
RI PT
score ≥20), somewhat controlled (16–19), poorly controlled (≤15). Asthma-related quality of life was assessed using the Asthma Quality of Life Questionnaire (AQLQ) for 12 years and older (AQLQ(S)+12) [28]. Results are expressed as the mean of each of the 4 domain scores (symptoms, activities limitation, emotional function and
SC
environmental stimuli) and as the mean of the overall summed score.
Patient satisfaction was assessed by asking patients to rate both the efficacy and tolerability
M AN U
of their therapy on a 5-item scale (1=very good; 2=good; 3=moderate; 4=poor; 5=very poor). The ‘disability days’ were defined as the number of days for which asthma had caused the patient to be absent from work or education or unable to perform everyday activities. They were assessed in the previous 30 days and at each study visit for the period since the
TE D
previous visit. The data were normalised based on the number of days between visits. Unscheduled and emergency asthma-related medical care, which occurred from the 4–6 week visit onwards, were documented, and the data were expressed as annualised rates.
EP
AEs that were categorised as being possibly related to treatment (any AE that was considered by the investigator as ‘unlikely to be’, ‘possibly’, ‘probably’ or ‘definitely’ related to
AC C
FP/FORM treatment, including those events where the assessed relationship to FP/FORM was missing) were also reported.
Statistical analyses
The safety population comprised all patients who received at least one dose of observed medication. Effectiveness analyses were conducted using data from the full analysis population (all patients who received at least one dose of observed medication and had at least one post-baseline primary effectiveness endpoint).
7
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
The ACT and AQLQ total and item/domain scores, and the changes from baseline at each post-baseline timepoint and end of study (LOCF) were treated as continuous data. A LOCF imputation approach was used for missing data (last non-missing post-baseline value observed during the treatment period imputed).
RI PT
For the ACT, AQLQ and lung function data, summary statistics and 2-sided 95% confidence intervals (CIs) were used to estimate the change from baseline to each post-baseline
timepoint based on a one sample t-test (lung function: change from baseline to end of
study). To control for multiple testing, a repeated-measures ANOVA was additionally applied
SC
for ACT and AQLQ data. Summary measures are shown as proportions or mean ± standard deviation (SD). The unscheduled and emergency asthma-related medical care data are
M AN U
shown as an annualised rate. The reported analyses are descriptive and exploratory.
Results Patients
TE D
A total of 1,563 patients were enrolled in 168 pulmonology practices and 23 general medical practices and received at least one dose of FP/FORM (safety population). Of these, 153 were excluded from the full analysis population (N=1,410). Reasons for exclusion were
EP
absence of any post-baseline effectiveness assessments (n=117), retrospectively collected data (n=35) or both of the before mentioned reasons (n=1). In total, 1,087 patients (77.1%)
AC C
of the full analysis population completed the first follow-up at 4–6 weeks post-baseline, and 984 patients (69.8%) completed the last follow-up at 12 months post-baseline. The most frequent reasons for study discontinuation were loss to follow-up (184 patients [13.0%]) and patient choice (97 [6.9%]). A total of 86 patients (6.1%) discontinued due to AEs and 30 (2.1%) due to insufficient efficacy. After study completion, 991 patients (70.3%) continued FP/FORM treatment. Baseline characteristics of the full analysis population (Table 1) show that the majority of the population (96.3%) were ≥18 years of age with a mean age of 49.0 ± 17.6 years and an age range of 12–89 years. More patients were female (n=847; 60.1%). Almost 40% of patients 8
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
(n=555, 39.4%) were treated with ICS plus LABA prior to study enrolment. Of these, 462 patients received a fixed combination of either beclomethasone dipropionate/formoterol fumarate (n=195, 13.8%), fluticasone propionate/salmeterol xinafoate (n=147, 10.4%), budesonide/formoterol fumarate (n=120, 8.5%) or FP/FORM (n=112, 7.9%). Asthma was not
RI PT
fully controlled at baseline in more than half of the population (ACT total score ≤19, n=956 [67.8%]). FEV1 was ≤80% predicted in 47.2% of patients (n=665). Fifteen percent of patients (n=220) smoked at study start and did not stop smoking during the study. During the
SC
observational period, 1% (n=14) stopped smoking and 1.3% (n=10 ex-smoker, n=8 non-
M AN U
smoker) started smoking.
Treatment
Analysis of data from the full analysis population shows that the daily dosages most commonly prescribed at both baseline and end of study were FP/FORM 500/20 µg (prescribed to 643 patients [45.6%] at baseline), 250/10 µg (476 patients [33.8%] at
TE D
baseline) and 1,000/40 µg (152 patients [10.8%] at baseline). The percentage of patients receiving each FP/FORM dose showed little change from baseline to the end of the study. The daily dose remained stable throughout the study in 1,109 patients (78.7%). Dosage
EP
increased in 163 patients (11.6%), decreased in 165 patients (11.7%) and was interrupted in 33 patients (2.3%). Multiple dosage adjustments (increases or decreases) were made in 52
AC C
patients (3.7%).
Effectiveness
Asthma Control Test™ scores In the overall population, the mean ACT total score at baseline was 16.3 ± 5.0 (possible range, 5–25). This increased significantly during the study (mean value at 12 months, 20.1 ± 4.3, change from baseline to month 12, 3.5 ± 5.3). The corresponding change from baseline to end of study (LOCF) was 3.4 ± 5.4 (mean value at end of study, 19.8 ± 4.5) (Figure 1).
9
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
The mean total score was significantly higher than baseline at all study observation timepoints. The data demonstrate that there was substantial improvement in total score from baseline to the second observation (4–6 weeks after baseline) and that this degree of improvement was maintained throughout the observation period. A similar pattern of
RI PT
improvement was evident for all ACT single item scores. The improvement from baseline was significant for all items at all study observation timepoints and at the end of the study (Supplementary Table 1). In the subgroup of patients with ICS plus LABA pretreatment (fixed or open combination), the mean ACT total score at baseline was 16.5 ± 5.2. This also
SC
increased significantly during the study (mean value at 12 months, 19.6 ± 4.7, change from baseline to month 12, 2.7 ± 5.3). The corresponding change from baseline to end of study
M AN U
(LOCF) was 2.5 ± 5.4 (mean value at end of study, 19.1 ± 5.0). The mean total score was significantly higher than baseline at all study observation timepoints (p=0.004 ANOVA). Similar to the overall population, there was substantial improvement from baseline to the second observation, which was maintained throughout the observation period.
TE D
The percentage of patients whose ACT total score indicated control of disease (score ≥20) increased from 30.9% at baseline to 62.4% at the end of the study (Figure 2). The percentage of patients whose disease was ‘somewhat controlled’ (total score 16–19)
EP
decreased slightly from baseline to end of study (25.9% vs. 21.0%); the percentage of patients whose disease was poorly controlled (total score ≤15) decreased substantially
AC C
(43.1% vs. 16.7%).
Severe exacerbations
The numbers of patients without and with severe asthma exacerbations (worsening of asthma requiring medical intervention with administration of systemic corticosteroids) during the 12 months prior to enrolment and under treatment with FP/FORM are shown in Table 2. The percentage of patients with ≥1 asthma exacerbation was 35.8% within the last 12 months prior to enrolment and 5.9% during the observation period. This led to a decrease in the mean number of severe asthma exacerbations from 0.7 ± 1.9 per patient to 0.07 ± 0.3 10
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
per patient. The annualised rate of severe asthma exacerbations per patients with FP/FORM treatment was 0.11 ± 0.6.
Asthma Quality of Life Questionnaire scores
RI PT
The AQLQ total and domain scores improved significantly from baseline to the end of the study and at all observations (Figure 3; Supplementary Table 2). As for the ACT scores, there was substantial improvement in total score and in all domain scores, from baseline to
SC
the second observation, after which time the scores remained fairly stable.
Lung function
M AN U
In the overall population, absolute values of FEV1, FEV1 percentage predicted, PEF and PEF percentage predicted all increased significantly from baseline to end of study, and from baseline to each study observation timepoint (p<0.0001 for all; Table 3). Both FEV1 and PEF increased in all lung function subgroups (FEV1 40–60% predicted; FEV1 60–80% predicted;
TE D
FEV1 >80% predicted): FEV1 increases of 0.41 L, 0.23 L, and 0.02 L, respectively (Supplementary Figure 1); PEF increases of 0.93 L/s, 0.70 L/s, and 0.31 L/s, respectively. The improvements in PEF were more pronounced than the improvements in FEV1. With one
EP
exception, the changes from baseline to end of study in the PEF- and FEV1-based endpoints were statistically significant (p<0.0001) for the overall population and all lung function
AC C
subgroups; the exception was the change from baseline in FEV1-based endpoints in the subgroup with FEV1 >80% predicted, in which the improvements failed to achieve statistical significance. For both FEV1 and PEF, the improvement was greatest in the patients with the most severe impairment of lung function. In all subgroups, the majority of the improvement in both parameters occurred prior to the 4–6 week visit, lung function then remaining stable for the remaining duration of the observation period.
Patient satisfaction
11
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
At baseline, 506 patients (35.9%) rated the efficacy of their existing asthma treatment as ‘good’ or ‘very good’; 1,214 patients (86.1%) gave their treatment these ratings at the end of the study. Patient satisfaction with the tolerability of their asthma treatment also increased during the study (‘good’ or ‘very good’ rating at baseline, 898 patients [63.7%]; end of study,
RI PT
1,276 patients [90.5%]).
Degree to which asthma interfered with patients’ lives – ‘disability days’
In the 30 days prior to the baseline visit, the mean (SD) normalised number of days for which
SC
asthma had caused patients to be absent from work or education or unable to perform
everyday activities (‘disability days’) was 1.6 (4.5). The mean number of disability days
M AN U
decreased to 0.5 (2.7) after 4-6 weeks and to 0.2 (1.1) at month 6. By the end of the study, the average number of days between study visits lost to asthma was 0.3 (1.8).
Unscheduled and emergency medical care
TE D
During the study, the mean (SD) annualised rates of asthma-related unscheduled physician visits, emergency visits, hospital admissions and days spent in hospital were 0.46 (2.23),
Safety
EP
0.01 (0.10), 0.02 (0.19) and 0.12 (1.56), respectively.
AC C
One third of patients (n=519, 33.2%) experienced 1,072 AEs during the observation period (most of them of mild or moderate severity), and 62 (4.0%) experienced 80 serious AEs. No deaths occurred. AEs caused 102 patients (6.5%) to discontinue the study. A total of 160 patients (10.2%) had 254 AEs possibly related to FP/FORM. Treatment-related AEs that occurred at a frequency ≥0.3% were dysphonia (n=44; 2.8%), tremor (n=11; 0.7%), cough (n=10; 0.6%), oral candidiasis (n=8; 0.5%), asthma (n=7; 0.4%), dizziness (n=7; 0.4%), dry mouth (n=6; 0.4%), headache (n=6; 0.4%), oropharyngeal pain (n=6; 0.4%), sleep disorder (n=6; 0.4%) and tachycardia (n=5; 0.3%). All AEs were in line with the SmPC.
12
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Discussion This is the first large real-life study with patients receiving FP/FORM treatment. In the prospective, non-interventional study, 1,563 patients with asthma (safety population) receiving treatment with FP/FORM were observed over one year. Using data from the full
RI PT
analysis population (N=1,410), on-study outcomes (ACT scores, control rate, AQLQ scores, lung function parameters) were compared with baseline. Furthermore, the severe
exacerbation rate was documented in the 12 months prior to and during the study, and AEs were recorded at each study visit. A diverse spectrum of community-based patients with
SC
asthma were enrolled: the population included male and female adolescents ≥12 years and adults with differing degrees of disease control, a range of FEV1 and PEF values, and
M AN U
various smoking habits prior to study enrolment. Approximately 40% of patients were already receiving combination ICS/LABA treatment prior to study enrolment. Although excluded by the protocol, 7.9% were being treated with FP/FORM at baseline (patients included in full analysis population).
TE D
The data at baseline relating to ACT scores (mean total score, 16.3), control rate (disease poorly controlled in 42.3% of patients), AQLQ scores (mean total score, 4.73), lung function (FEV1, 2.45 L; FEV1 % predicted, 80.2%) and severe exacerbation rate (21.2% of patients
EP
affected in 12 months prior to enrolment) reveal that treatment was not optimal at baseline in many of the patients enrolled. The results show significant improvements in all effectiveness
AC C
outcomes that were subject to statistical analysis (ACT total and domain scores, AQLQ total and domain scores, FEV1 and PEF values). In addition, an increase by 100% of the percentage of patients with asthma control from baseline and a lower rate of severe exacerbations compared to the 12 months prior to start of the observation period was observed. In the overall population, the mean change in ACT total score from baseline to the end of the study (3.4 points) exceeded the change of 3 points, which is defined as the minimal clinically important difference for this instrument [29]. In the subgroup of patients with ICS plus LABA pretreatment, ACT total score also significantly increased from baseline to the end of the 13
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
study (mean change 2.5 points); however the minimal clinical important difference was not reached [29]. The mean change in AQLQ total score from baseline to the end of the study (0.85) and the mean changes in each domain (0.63–1.02) all exceeded the minimum change of 0.5, which is defined as the minimal clinically important difference for this instrument [30].
RI PT
The increase in the number of patients with asthma control from 30.9% at baseline to 62.4% at the end of the study was comparable to that observed in a recent non-interventional study including 5789 asthma patients receiving three different ICS/LABA combinations over six months [31]. These data suggest that initiation of FP/FORM therapy was associated with
SC
clinically relevant improvements in disease status and in patients’ quality of life.
These improvements may at least partly relate to the intensification of the treatment
M AN U
regimen, e.g., in patients who received monotherapy with an ICS before study enrolment. However, especially the improvement of asthma control in patients with ICS plus LABA pretreatment may be explained by a number of factors including provision of FP/FORM in a fixed combination rather than as concurrent treatments [32], use of a pMDI rather than a dry
TE D
powder inhaler [33], the high and consistent fine particle fraction of FP/FORM [34], and the rapid onset of action of formoterol [18] (which is likely to promote adherence [35]). However, the possible improvement of the patients’ treatment adherence upon study inclusion cannot
EP
be ruled out. It was notable that, for almost all effectiveness outcomes, the improvement associated with FP/FORM therapy was already evident one month after treatment initiation
AC C
and that this degree of benefit was then sustained for the duration of the study. These data demonstrate that the FP/FORM therapy results in rapid benefit, which is sustained during long-term treatment. Certainly, patient satisfaction with both the efficacy and tolerability of their asthma treatment increased from baseline to the end of the study. These data are supported by the fact that 70% of patients intended to continue using FP/FORM therapy after the observational period. The decrease in the incidence of severe asthma exacerbations in this study (a 10-fold reduction) was particularly marked. Predictors of future exacerbations include a history of exacerbations, poor asthma control, activity limitation and low FEV1 values [36], many of 14
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
which were prevalent in the study population at baseline (Tables 1–3, Supplementary Table 2). The effectiveness of FP/FORM in management of exacerbation risk was recently highlighted by Papi et al. [36], who found that the incidence of corticosteroid-requiring exacerbations in patients receiving long-term FP/FORM therapy (2.1%) was considerably
RI PT
lower than the incidence in patients receiving other ICS/LABA combinations (9.5–16.7%). Although trial duration varied in the studies reviewed by Papi et al., the studies involving FP/FORM therapy were generally of similar or longer duration than many of the studies
involving other ICS/LABA combinations with which they were compared [36]. Papi et al.
SC
could find no study-related explanations for the difference in exacerbation incidence between FP/FORM and other ICS/LABA combinations. They thus suggested that the relatively low
M AN U
exacerbation rate in FP/FORM-treated patients may be related to the favourable pharmacological and mechanistic characteristics of fluticasone propionate and formoterol. Although half of the patients enrolled in this study had relatively good lung function at baseline, both FEV1 and PEF improved during the 12 months of treatment in the overall
TE D
population (Table 3). The improvement in PEF (0.55 L/s [9.6%] increase), which was more pronounced than the improvement in FEV1 (0.15 L [6.1%] increase), exceeded the average minimal patient perceivable improvement of 0.31 L/s [37]. The increase in PEF over the
EP
course of the study also matched or exceeded the minimal perceivable improvement in all the lung function subgroups (FEV1, 40–60%: 0.93 L/s; FEV1, 60–80%: 0.70 L/s; FEV1, >80%:
AC C
0.31 L/s). The increase in FEV1 exceeded the minimal perceivable improvement of 0.23 L in all but the patients with FEV1 >80% at baseline (FEV1, 40–60%: 0.41 L; FEV1, 60–80%: 0.23 L). For both FEV1 and PEF, the magnitude of the improvement was inversely related to the severity of the pulmonary impairment at baseline. In all subgroups, the majority of the improvement in lung function occurred prior to the 4–6 week visit, lung function then remaining stable for the duration of the observation period, reflecting the changes seen for asthma control and quality of life. This confirms the results of an open-label study with FP/FORM over 12 months, in which the lung function improvements were seen within the first two months and were sustained throughout the whole study [20]. 15
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
The clinical improvements associated with initiation of FP/FORM therapy were accompanied by a substantial reduction in the number of days on which asthma caused patients to be absent from work or education or unable to perform everyday activities. When compared with the results of other studies, the annualised rates of asthma-related unscheduled
RI PT
physician visits, emergency visits, hospital admissions and days spent in hospital appeared to be low. For example, data from the German Statutory Health Insurance database showed annual rates of asthma-related hospital admissions and days of hospitalisation in 2010 of 0.08 and 0.56, respectively [38]. In our study, the mean numbers of asthma-related hospital
SC
admissions and days spent in hospital were 0.02 and 0.12 per year, respectively.
M AN U
The prevalence of AEs in this study (33.2% of patients with ≥1 AE) is similar to that reported in an open-label study in which 413 patients received FP/FORM 100/10 µg or 250/10 µg for up to 12 months (AEs in 36.9% of patients) [20]. However, the percentages of patients reporting serious AEs and who discontinued therapy as a result of AEs were higher in the current study than in the open-label study (4.0% vs. 2.1% and 6.5% vs. 3.0%, respectively).
TE D
The reasons for these differences may relate to the strict patient selection criteria or study environment in clinical trials [24, 39]. The current study did not reveal any new safety signals in patients treated with FP/FORM. The most frequently reported treatment-related AE was
EP
dysphonia, which is common in patients with asthma who have been treated with ICS [40]. One of the strengths of this study lies in its prospective, non-interventional design. Due to
AC C
restrictive inclusion/exclusion criteria of randomised clinical trials they may not accurately reflect the situation in clinical practice [22, 23]. For example, it has been estimated that only approximately 5% of the asthma patients seen in clinical practice would have been eligible for many of the major asthma randomised clinical trials [39, 41]. Another difference between real-life and controlled trials relates to the level of patient monitoring, which tends to lead to better adherence in clinical trials than in real-life studies [24, 25, 42, 43]. Data from prospective, non-interventional studies such as this one complement the results of clinical trials [24, 25] by providing data from patients in routine clinical practice.
16
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
This study did have a number of limitations, mainly based on its non-interventional character. These include the absence of a control arm in which patients’ medication remained unchanged from baseline, so the potentially beneficial effect on patients of involvement in the study could not be assessed. Additionally, it cannot be ruled out that the physicians may
RI PT
have influenced the patients’ perception of the drug’s effectiveness and that this led to an improved treatment adherence. A further feature was the emphasis on having few exclusion criteria, which may have allowed unmeasured confounding factors to influence the outcome in some patients. The dropout rate of 30.2% during the study is only a bit higher than in two
SC
other non-interventional asthma studies over 12 months (18.0%, 26.7%) [45, 46] and lies within the range reported in 12-month non-interventional omalizumab studies [44]. The
M AN U
dropout rate should be taken into account when interpreting the data, as patients with less treatment benefit and more adverse events are often more likely to drop out than patients with improvement of disease control. In addition, patients with seasonal asthma tend to use their medication only in the period in which they have asthma symptoms. These patients
TE D
may also have dropped out before study end. The study population showed diversity in age, gender and asthma severity, but not in ethnic origin. It is hoped that future studies will allow exploration of any ethnicity-based differences in treatment response, because differences in
EP
the response to treatment among asthmatic patients of different ethnic backgrounds and
AC C
genotypes have been reported [47, 48].
We can nevertheless conclude from this study that initiation of FP/FORM, or substitution of FP/FORM for participants’ usual therapy was associated with substantial and clinically important improvements in asthma status in a diverse population of patients in routine clinical practice.
Acknowledgments and conflict of interest We are indebted to the physicians who documented the patients in this study and thank the patients who participated. The study was sponsored by Mundipharma GmbH, who provided 17
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
funding for data analysis and medical writing support. We thank the Contract Research Organization Scope International AG for the operational conduct of the study and data analyses and Physicians World Europe GmbH for medical writing assistance. OS received payments for lectures and consultancy from Astellas, AstraZeneca, Berlin-
RI PT
Chemie, Boehringer Ingelheim, Chiesi, GSK, Mundipharma, and Roche. WP declares receiving payments for lectures from Boehringer Ingelheim, MEDA, AstraZeneca and Mundipharma. GH received educational grants and payments for lectures from Allergopharma, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Mundipharma, Novartis,
SC
and Teva. FK received payments for consultancy and lectures from Chiesi, Mundipharma,
M AN U
Novartis, and Teva. PO and BLB are employees of Mundipharma.
AC C
EP
TE D
® FLUTIFORM is a registered trade mark of Jagotec AG and is used under licence.
18
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
References
[1] M. Masoli, D. Fabian, S. Holt, R. Beasley, P. Global Initiative for Asthma, The global burden of asthma: executive summary of the GINA Dissemination Committee report, Allergy 59(5) (2004) 469-78.
RI PT
[2] GINA, Global Strategy for Asthma Management and Prevention.
M AN U
SC
[4] K.B.K. Bundesärztekammer (BÄK), Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF),, Nationale VersorgungsLeitlinie Asthma – Long version, 2nd edition. version 5. 2013 (http://www.leitlinien.de/mdb/downloads/nvl/asthma/asthma-2aufl-vers5-lang.pdf, accessed Sep 2016). [5] J.A. van Noord, A.J. Schreurs, S.J. Mol, P.G. Mulder, Addition of salmeterol versus doubling the dose of fluticasone propionate in patients with mild to moderate asthma, Thorax 54(3) (1999) 207-12.
TE D
[6] P.M. O'Byrne, P.J. Barnes, R. Rodriguez-Roisin, E. Runnerstrom, T. Sandstrom, K. Svensson, A. Tattersfield, Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial, Am. J. Respir. Crit. Care Med. 164(8 Pt 1) (2001) 1392-7.
EP
[7] R.A. Pauwels, C.G. Lofdahl, D.S. Postma, A.E. Tattersfield, P. O'Byrne, P.J. Barnes, A. Ullman, Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group, N. Engl. J. Med. 337(20) (1997) 1405-11.
AC C
[8] A. Woolcock, B. Lundback, N. Ringdal, L.A. Jacques, Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids, Am. J. Respir. Crit. Care Med. 153(5) (1996) 1481-8. [9] A.P. Greening, P.W. Ind, M. Northfield, G. Shaw, Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & Hanburys Limited UK Study Group, Lancet 344(8917) (1994) 219-24. [10] T.E. Delea, M. Hagiwara, R.H. Stanford, D.A. Stempel, Effects of fluticasone propionate/salmeterol combination on asthma-related health care resource utilization and costs and adherence in children and adults with asthma, Clin. Ther. 30(3) (2008) 560-71. [11] S.W. Stoloff, D.A. Stempel, J. Meyer, R.H. Stanford, J.R. Carranza Rosenzweig, Improved refill persistence with fluticasone propionate and salmeterol in a single inhaler compared with other controller therapies, J. Allergy Clin. Immunol. 113(2) (2004) 245-51.
19
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
[12] C.J. Cates, L.S. Wieland, M. Oleszczuk, K.M. Kew, Safety of regular formoterol or salmeterol in adults with asthma: an overview of Cochrane reviews, Cochrane Database Syst Rev 2 (2014) Cd010314. [13] D.S. Pearlman, C.F. LaForce, K. Kaiser, Fluticasone/Formoterol combination therapy compared with monotherapy in adolescent and adult patients with mild to moderate asthma, Clin. Ther. 35(7) (2013) 950-66.
RI PT
[14] T. Pertseva, S. Dissanayake, K. Kaiser, Superiority of fluticasone propionate/formoterol fumarate versus fluticasone propionate alone in patients with moderate-to-severe asthma: a randomised controlled trial, Curr. Med. Res. Opin. 29(10) (2013) 1357-69.
SC
[15] J. Corren, L.E. Mansfield, T. Pertseva, V. Blahzko, K. Kaiser, Efficacy and safety of fluticasone/formoterol combination therapy in patients with moderate-to-severe asthma, Respir. Med. 107(2) (2013) 180-95.
M AN U
[16] R.A. Nathan, A. D'Urzo, V. Blazhko, K. Kaiser, Safety and efficacy of fluticasone/formoterol combination therapy in adolescent and adult patients with mild-tomoderate asthma: a randomised controlled trial, BMC Pulm. Med. 12 (2012) 67. [17] A. Bodzenta-Lukaszyk, G. Pulka, A. Dymek, D. Bumbacea, T. McIver, B. Schwab, H. Mansikka, Efficacy and safety of fluticasone and formoterol in a single pressurized metered dose inhaler, Respir. Med. 105(5) (2011) 674-82.
TE D
[18] A. Bodzenta-Lukaszyk, A. Dymek, K. McAulay, H. Mansikka, Fluticasone/formoterol combination therapy is as effective as fluticasone/salmeterol in the treatment of asthma, but has a more rapid onset of action: an open-label, randomized study, BMC Pulm. Med. 11 (2011) 28.
EP
[19] A. Bodzenta-Lukaszyk, J. Van Noord, W. Schröder-Babo, Kombinationstherapie mit Fluticason/Formoterol in einem Dosieraerosol hat vergleichbare Wirksamkeit wie die freie Konbination Fluticason und Formoterol, Pneumologie 66(3) (2012) 29.
AC C
[20] A.H. Mansur, K. Kaiser, Long-term safety and efficacy of fluticasone/formoterol combination therapy in asthma, J. Aerosol Med. Pulm. Drug Deliv. 26(4) (2013) 190-9. [21] A. Bodzenta-Lukaszyk, R. Buhl, B. Balint, M. Lomax, K. Spooner, S. Dissanayake, Fluticasone/formoterol combination therapy versus budesonide/formoterol for the treatment of asthma: a randomized, controlled, non-inferiority trial of efficacy and safety, J. Asthma 49(10) (2012) 1060-70. [22] L. Cazzoletti, A. Marcon, C. Janson, A. Corsico, D. Jarvis, I. Pin, S. Accordini, E. Almar, M. Bugiani, A. Carolei, I. Cerveri, E. Duran-Tauleria, D. Gislason, A. Gulsvik, R. Jogi, A. Marinoni, J. Martinez-Moratalla, P. Vermeire, R. de Marco, Asthma control in Europe: a realworld evaluation based on an international population-based study, J. Allergy Clin. Immunol. 120(6) (2007) 1360-7. [23] P. Demoly, B. Gueron, K. Annunziata, L. Adamek, R.D. Walters, Update on asthma control in five European countries: results of a 2008 survey, Eur. Respir. Rev. 19(116) (2010) 150-7. 20
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
[24] S. Saturni, F. Bellini, F. Braido, P. Paggiaro, A. Sanduzzi, N. Scichilone, P.A. Santus, L. Morandi, A. Papi, Randomized Controlled Trials and real life studies. Approaches and methodologies: a clinical point of view, Pulm. Pharmacol. Ther. 27(2) (2014) 129-38. [25] D. Price, G. Brusselle, N. Roche, D. Freeman, A. Chisholm, Real-world research and its importance in respiratory medicine, Breathe (Sheff) 11(1) (2015) 26-38.
RI PT
[26] flutiform® summary of product characteristics (http://www.medicines.ie; accessed March 2016). [27] R.A. Nathan, C.A. Sorkness, M. Kosinski, M. Schatz, J.T. Li, P. Marcus, J.J. Murray, T.B. Pendergraft, Development of the asthma control test: a survey for assessing asthma control, J. Allergy Clin. Immunol. 113(1) (2004) 59-65.
M AN U
SC
[28] E.F. Juniper, K. Svensson, A.C. Mork, E. Stahl, Modification of the asthma quality of life questionnaire (standardised) for patients 12 years and older, Health Qual Life Outcomes 3 (2005) 58. [29] M. Schatz, M. Kosinski, A.S. Yarlas, J. Hanlon, M.E. Watson, P. Jhingran, The minimally important difference of the Asthma Control Test, J. Allergy Clin. Immunol. 124(4) (2009) 71923.e1. [30] E.F. Juniper, G.H. Guyatt, A. Willan, L.E. Griffith, Determining a minimal important change in a disease-specific Quality of Life Questionnaire, J. Clin. Epidemiol. 47(1) (1994) 81-7.
TE D
[31] B. Rogala, P. Majak, J. Gluck, T. Debowski, Asthma control in adult patients treated with a combination of inhaled corticosteroids and longacting beta2agonists: a prospective observational study, Pol Arch Intern Med 127(2) (2017) 100-106.
EP
[32] C. Marceau, C. Lemiere, D. Berbiche, S. Perreault, L. Blais, Persistence, adherence, and effectiveness of combination therapy among adult patients with asthma, J. Allergy Clin. Immunol. 118(3) (2006) 574-81.
AC C
[33] D. Price, N. Roche, J. Christian Virchow, A. Burden, M. Ali, A. Chisholm, A.J. Lee, E.V. Hillyer, J. von Ziegenweidt, Device type and real-world effectiveness of asthma combination therapy: an observational study, Respir. Med. 105(10) (2011) 1457-66. [34] B. Johal, M. Howald, M. Fischer, J. Marshall, G. Venthoye, Fine Particle Profile of Fluticasone Propionate/Formoterol Fumarate Versus Other Combination Products: the DIFFUSE Study, Comb Prod Ther 3 (2013) 39-51. [35] B.G. Bender, Overcoming barriers to nonadherence in asthma treatment, J. Allergy Clin. Immunol. 109(6 Suppl) (2002) S554-9. [36] A. Papi, A.H. Mansur, T. Pertseva, K. Kaiser, T. McIver, B. Grothe, S. Dissanayake, Long-Term Fluticasone Propionate/Formoterol Fumarate Combination Therapy Is Associated with a Low Incidence of Severe Asthma Exacerbations, J. Aerosol Med. Pulm. Drug Deliv. 29(4) (2016) 346-61.
21
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
[37] N.C. Santanello, J. Zhang, B. Seidenberg, T.F. Reiss, B.L. Barber, What are minimal important changes for asthma measures in a clinical trial?, Eur. Respir. J. 14(1) (1999) 23-7. [38] C. Jacob, B. Bechtel, S. Engel, P. Kardos, R. Linder, S. Braun, W. Greiner, Healthcare costs and resource utilization of asthma in Germany: a claims data analysis, Eur J Health Econ 17(2) (2016) 195-201.
RI PT
[39] J. Travers, S. Marsh, M. Williams, M. Weatherall, B. Caldwell, P. Shirtcliffe, S. Aldington, R. Beasley, External validity of randomised controlled trials in asthma: to whom do the results of the trials apply?, Thorax 62(3) (2007) 219-23. [40] H.E. Hassen, A.M. Abo Hasseba, Voice evaluation in asthma patients using inhaled corticosteroids, Kulak Burun Bogaz Ihtis Derg 26(2) (2016) 101-8.
M AN U
SC
[41] K. Herland, J.-P. Akselsen, O.H. Skjønsberg, L. Bjermer, How representative are clinical study patients with asthma or COPD for a larger “real life” population of patients with obstructive lung disease?, Respir. Med. 99(1) (2005) 11-19. [42] A. Kondla, T. Glaab, R. Pedersini, M. Lommatzsch, Asthma control in patients treated with inhaled corticosteroids and long-acting beta agonists: A population-based analysis in Germany, Respir. Med. 118 (2016) 58-64. [43] D. Price, M. Fletcher, T. van der Molen, Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey, NPJ Prim Care Respir Med 24 (2014) 14009.
TE D
[44] M. Caminati, G. Senna, G. Stefanizzi, R. Bellamoli, S. Longhi, F. Chieco-Bianchi, G. Guarnieri, S. Tognella, M. Olivieri, C. Micheletto, G. Festi, E. Bertocco, M. Mazza, A. Rossi, A. Vianello, g. North East Omalizumab Network study, Drop-out rate among patients treated with omalizumab for severe asthma: Literature review and real-life experience, BMC Pulm. Med. 16(1) (2016) 128.
AC C
EP
[45] B. Stallberg, I. Naya, J. Ekelund, G. Eckerwall, Real-life use of budesonide/formoterol in clinical practice: a 12-month follow-up assessment in a multi-national study of asthma patients established on single-inhaler maintenance and reliever therapy, Int. J. Clin. Pharmacol. Ther. 53(6) (2015) 447-55. [46] C. Terzano, G. Cremonesi, G. Girbino, E. Ingrassia, S. Marsico, G. Nicolini, L. Allegra, 1-year prospective real life monitoring of asthma control and quality of life in Italy, Respir. Res. 13 (2012) 112. [47] M.E. Wechsler, M. Castro, E. Lehman, V.M. Chinchilli, E.R. Sutherland, L. Denlinger, S.C. Lazarus, S.P. Peters, E. Israel, N.A.C.R. Network, Impact of race on asthma treatment failures in the asthma clinical research network, Am. J. Respir. Crit. Care Med. 184(11) (2011) 1247-53. [48] M.E. Wechsler, S.J. Kunselman, V.M. Chinchilli, E. Bleecker, H.A. Boushey, W.J. Calhoun, B.T. Ameredes, M. Castro, T.J. Craig, L. Denlinger, J.V. Fahy, N. Jarjour, S. Kazani, S. Kim, M. Kraft, S.C. Lazarus, R.F. Lemanske, A. Markezich, R.J. Martin, P. Permaul, S.P. Peters, J. Ramsdell, C.A. Sorkness, E.R. Sutherland, S.J. Szefler, M.J. 22
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Walter, S.I. Wasserman, E. Israel, Effect of β2-adrenergic receptor polymorphism on response to longacting β2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial, The Lancet 374(9703) (2009) 1754-1764.
23
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Tables Table 1. Baseline characteristics Characteristic
Full analysis population N=1,410
Age, years
49.0 ± 17.6
RI PT
Gender, n (%) Male
557 (39.5)
Female
847 (60.1)
Missing
6 (0.4)
Ethnic origin, n (%) BMI, kg/m
1,377 (97.7)
SC
Caucasian 2
27.68 ± 5.64 10.9 ± 12.7
Treatment prior to Visit 1, n (%) ICS without LABA ICS plus LABA Free combination Fixed combination Other
M AN U
Asthma duration, years
191 (13.5) 555 (39.4) 93 (6.6) 462 (32.8) 664 (47.1)
Controlled (≥ 20)
TE D
ACT-Score at Visit 1, n (%)
428 (30.4) 359 (25.5)
Poorly controlled (≤ 15)
597 (42.3)
Unclassified
EP
Somewhat controlled (16-19)
26 (1.8)
FEV1 at Visit 1, n (% predicted)
AC C
40–60%
216 (15.3)
>60–80%
449 (31.8)
>80%
708 (50.2)
Unclassified
37 (2.6)
Smoking habit during study, n (%) Non-smoker1
857 (60.8)
Ex-smoker2
252 (17.9)
Smoker
3
220 (15.6)
Values shown are for mean ± standard deviation unless stated otherwise ACT, Asthma Control Test™; BMI, body mass index; FEV1; forced expiratory volume in one second; ICS, inhaled corticosteroid; LABA, long-acting beta2-agonist 24
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Never smoked before entering study and did not start smoking during study; 2Stopped smoking at least one year before entering study and did not start smoking during study; 3 Smoked when entering study and did not stop smoking during study.
AC C
EP
TE D
M AN U
SC
RI PT
1
25
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Table 2. Severe asthma exacerbations Full analysis population N=1,410 Within the 12 months prior to enrolment
Treatment-emergent
835 (59.2)
1, n (%)
299 (21.2)
2, n (%)
116 (8.2)
3, n (%)
49 (3.5)
≥4, n (%)
41 (2.9)
Mean (SD) severe asthma exacerbations per patient
70 (5.0) 0.72 (1.91)
67 (4.8)
10 (0.7) 6 (0.4) 0
0
0.07 (0.33)
M AN U
Missing assessments, n (%)
1,327 (94.1)
SC
0, n (%)
RI PT
Number of severe exacerbations
AC C
EP
TE D
n, number of patients; SD, standard deviation
26
ACCEPTED MANUSCRIPT
Schmidt et al.
Real-life effectiveness FP/FORM
Table 3. Lung function parameters in the overall population and stratified by lung function at baseline Baseline
4–6 weeks
Month 3
Month 6
Month 9
FEV1 (L)
2.45 (0.90)
2.63 (0.91)
2.61 (0.90)
2.61 (0.92)
2.58 (0.90)
FEV1 predicted (%)
80.2 (24.2)
85.6 (20.2)
85.3 (19.6)
85.6 (19.5)
PEF rate (L/s)
5.72 (2.09)
6.26 (2.19)
6.30 (2.20)
PEF rate predicted (%)
77.5 (23.1)
84.6 (23.4)
FEV1 (L)
1.57 (0.41)
1.92 (0.73)
FEV1 predicted (%)
52.6 (5.6)
65.0 (18.0)
PEF rate (L/s)
3.98 (1.49)
4.77 (1.99)
PEF rate predicted (%)
53.7 (16.4)
65.4 (23.7)
FEV1 (L)
2.23 (0.61)
2.49 (0.78)
FEV1 predicted (%)
71.3 (5.7)
PEF rate (L/s)
5.33 (1.66)
PEF rate predicted (%)
70.6 (16.9)
Month 12
End of study (LOCF)
Change from baseline to end of study (LOCF)
2.59 (0.89)
2.60 (0.90)
0.16 (0.56)*
84.8 (20.4)
85.2 (19.7)
85.2 (19.8)
4.9 (20.4)*
6.21 (2.23)
6.30 (2.29)
6.30 (2.25)
6.27 (2.26)
0.57 (1.43)*
85.1 (23.3)
84.5 (23.8)
85.2 (24.5)
85.5 (23.9)
84.9 (24.0)
7.5 (18.9)*
1.99 (0.75)
1.93 (0.72)
1.93 (0.76)
1.92 (0.76)
1.98 (0.79)
0.43 (0.57)*
66.5 (17.8)
65.5 (17.3)
65.8 (19.9)
65.2 (18.5)
66.2 (18.9)
13.7 (17.9)*
4.96 (1.96)
4.76 (1.85)
4.93 (2.16)
4.80 (2.05)
4.91 (2.09)
1.02 (1.72)*
67.3 (22.5)
65.5 (21.7)
67.8 (25.0)
66.0 (23.2)
66.7 (23.6)
13.9 (22.1)*
2.49 (0.81)
2.47 (0.82)
2.47 (0.81)
2.46 (0.79)
2.46 (0.81)
0.23 (0.46)*
78.5 (12.3)
78.4 (13.1)
7901 (12.3)
77.7 (13.3)
78.3 (13.4)
78.1 (13.8)
6.9 (13.8)*
6.01 (1.81)
6.12 (1.93)
5.93 (2.05)
6.19 (2.14)
6.14 (2.00)
6.03 (2.11)
0.69 (1.49)*
79.1 (18.0)
79.7 (18.4)
78.8 (20.5)
80.5 (20.6)
81.0 (19.7)
79.5 (20.7)
8.6 (19.5)*
2.98 (0.86)
2.94 (0.85)
2.94 (0.86)
2.92 (0.83)
2.92 (0.83)
2.93 (0.84)
0.02 (0.56)
RI PT
Full analysis population
M AN U
Overall population (N=1,410)
AC C
EP
TE D
FEV1 40–60% predicted (n=216)
FEV1 >60–80% predicted (n=449)
SC
Lung function parameter
FEV1 >80% predicted (n=708) FEV1 (L)
2.91 (0.88)
27
ACCEPTED MANUSCRIPT
Schmidt et al.
Real-life effectiveness FP/FORM 96.2 (22.5)
97.8 (14.8)
97.3 (14.8)
97.1 (14.5)
97.3 (14.7)
97.3 (14.1)
96.6 (14.7)
0.5 (23.1)
PEF rate (L/s)
6.61 (1.99)
6.97 (2.16)
6.95 (2.18)
6.91 (2.15)
6.93 (2.16)
6.95 (2.18)
6.92 (2.14)
0.34 (1.25)*
PEF rate predicted (%)
90.6 (18.5)
95.1 (20.0)
95.6 (20.6)
95.1 (19.9)
95.6 (20.8)
95.7 (20.5)
95.0 (20.4)
4.6 (16.8)*
RI PT
FEV1 predicted (%)
All values represent mean (standard deviation) * p<0.0001 vs. baseline (one sample t-test)
AC C
EP
TE D
M AN U
SC
FEV1, forced expiratory volume in 1 second; LOCF, last observation carried forward; PEF, peak expiratory flow
28
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Figure legends
Figure 1. Asthma Control Test™ (ACT) total score (full analysis population). *p<0.0001 vs. baseline (one-sample t-test), difference to baseline for all visits: p<0.0001
LOCF, last observation carried forward; SD, standard deviation.
RI PT
(repeated measures ANOVA).
LOCF, last observation carried forward.
SC
Figure 2. Asthma Control Test™ (ACT) total score classification (full analysis population).
M AN U
Figure 3. Asthma Quality of Life Questionnaire (AQLQ) total score and domain scores (full analysis population). The range of patient numbers with results is given for each visit. *
p<0.0001 vs. baseline (one-sample t-test), difference to baseline for all visits: p<0.0001
(repeated measures ANOVA).
AC C
EP
TE D
LOCF, last observation carried forward; SD, standard deviation.
29
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
*
*
*
*
*
*
Baseline
4-6 weeks
Month 3
Month 6
Month 9
Month 12
End of study (LOCF)
1,384
1,074
1,010
1,042
ACT total score (mean ± SD)
25
20
15
10
n
966
977
1,363
100 80
30.9
AC C
% patients with asthma control
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
54.5 60
67.1
65.3
62.4
20.1
19.3
21.0
15.7
12.8
15.4
16.7
Month 6
Month 9
Month 12
End of study (LOCF)
61.8
61.4
24.7
22.8
18.2
13.6
4-6 weeks
Month 3
25.9
40 27.3 20
43.1
0 Baseline
Poorly controlled (ACT ≤ 15) n
1,384
1,074
Somewhat controlled (ACT 16-19) 1,010
1,042
Controlled (ACT ≥ 20) 966
977
1,363
AQLQ scores (mean ± SD)
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
* * ** *
7
* * ** *
* * * * *
5.60 5.56 5.58 5.73 5.59
5.69 5.63 5.69 5.83 5.69
5.72 5.59 5.58 5.52 5.58
* * * * *
6 5.39 5.31 5.40 5.51 5.44
5 4.73
4
4.50
4.84 4.87 4.97
3 2 1
n
Baseline
4–6 week
Month 3
Month 12
Total score
Symptoms
Activities limitation
Emotional function
Environmental stimuli
991–998
953–968
1,356–1,366
1,350–1,371
1,068–1,082
End of study (LOCF)
Schmidt et al.
Highlights
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Real-life effectiveness of asthma treatment with a fixed-dose fluticasone/formoterol pressurised metered-dose inhaler – results from a non-interventional study
Highlights Prospective, non-interventional study in 1,563 community-based patients with
RI PT
•
asthma
First real-life data set with fluticasone propionate/formoterol fumarate (FP/FORM)
•
Clinically important improvement in asthma control and quality of life with FP/FORM
•
Decreased incidence of severe asthma exacerbations with FP/FORM
•
Improvements were evident 1 month after treatment start and sustained for 12
M AN U
SC
•
AC C
EP
TE D
months
S0954-6111(17)30287-1
DOI:
10.1016/j.rmed.2017.08.017
Reference:
YRMED 5238
To appear in:
Respiratory Medicine
Received Date: 26 January 2017 Revised Date:
17 August 2017
Accepted Date: 17 August 2017
Please cite this article as: Schmidt O, Petro W, Hoheisel G, Kanniess F, Oepen P, Langer-Brauburger B, Real-life effectiveness of asthma treatment with a fixed-dose fluticasone/formoterol pressurised metered-dose inhaler – Results from a non-interventional study, Respiratory Medicine (2017), doi: 10.1016/j.rmed.2017.08.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Real-life effectiveness of asthma treatment with a fixed-dose fluticasone/formoterol pressurised metered-dose inhaler – results from a non-interventional study
O. Schmidt1, W. Petro2, G. Hoheisel3, F. Kanniess4, P. Oepen5, B. Langer-Brauburger5* 1
2
RI PT
Pneumologische Gemeinschaftspraxis, Emil-Schüller-Str. 29, Koblenz, Germany Medizinisches Versorgungszentrum (MVZ) Bad Reichenhall im Gesundheitszentrum Salus,
Rinckstr. 7-9, Bad Reichenhall, Germany 3
Praxis für Pneumologie und Allergologie, August-Bebel-Str. 69, Leipzig, Germany
4
SC
Gemeinschaftspraxis Reinfeld, Praxis für Allgemeinmedizin und Allergologie,
Bahnhofstrasse 5a, Reinfeld, Germany
Mundipharma GmbH, Mundipharmastraße 2, Limburg (Lahn), Germany
M AN U
5
*Corresponding author
Mundipharma GmbH, Mundipharmastraße 2, 65549 Limburg (Lahn), Germany
TE D
Tel: +49 6431 701423
AC C
EP
Email: [email protected]
1
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Abstract Objective Prospective, non-interventional study of fixed-dose inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA) combination therapy with fluticasone propionate/formoterol fumarate
RI PT
(FP/FORM) across a spectrum of community-based patients with asthma in a real-life setting. Methods
In FP/FORM-treated patients aged ≥12 years, asthma control (Asthma Control Test™
SC
[ACT]), incidence of severe exacerbations, lung function, quality of life (asthma quality of life questionnaire [AQLQ]) and adverse events (AEs) were assessed over one year.
M AN U
Results
Almost 40% (n=555) of the full analysis population (N=1,410) were receiving ICS/LABA therapy prior to enrolment; 69.8% completed the study. Asthma control (mean ACT ± standard deviation) improved from 16.3 ± 5.0 at baseline to 19.8 ± 4.5 at study end.
TE D
ACT scores were significantly (p<0.0001) higher than baseline at all observation timepoints, including the first assessment at 4–6 weeks. The percentage of patients with asthma control increased (baseline: 30.9%; study end: 62.4%), and the percentage of patients with ≥1
EP
severe asthma exacerbation decreased (12 months before: 35.8%; during study: 5.9%). Lung function (forced expiratory volume in one second, peak expiratory flow) improved from
AC C
baseline to each observation timepoint (p<0.0001 for all). Improvement in asthma status was accompanied by ameliorated quality of life: AQLQ scores improved significantly from baseline to all observation timepoints (p<0.0001 for all). AEs accorded with the summary of product characteristics. After study completion, 70% of patients continued FP/FORM treatment. Conclusion In this one-year study, FP/FORM treatment was associated with clinically relevant improvements in asthma status in a diverse population of patients under real-life conditions.
2
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Keywords: asthma control; quality of life; fluticasone; formoterol; fixed combination; non-
AC C
EP
TE D
M AN U
SC
RI PT
interventional
3
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Introduction Asthma is one of the most common chronic diseases [1]. The main goals of asthma therapy are to achieve good symptomatic control, improve lung function, reduce the risk of exacerbations and minimise side effects of treatment [2]. Current Global Initiative for Asthma
RI PT
(GINA) and national guidelines recommend a stepwise approach to the management of chronic asthma based on disease severity or level of control [2-4]. Treatment is typically initiated using inhaled corticosteroid (ICS). For asthma that is not controlled with low to
treatment option in the majority of patients [2-4].
SC
medium-dose ICS alone, addition of a long-acting beta2-agonist (LABA) is the preferred
A number of studies have shown that addition of a LABA to ICS provides better symptom
M AN U
control, greater improvement in lung function and a greater reduction of severe exacerbations than increasing the dose of ICS [5-9]. LABA and ICS can be administered via separate inhalers or combined in one inhaler. Advantages of fixed-dose ICS/LABA inhalers include greater patient convenience, an increase in patient adherence as a result of
TE D
simplification of the regime [10, 11] and elimination of the possibility of LABA monotherapy and its attendant risks [12].
Treatment with a fixed combination of the ICS, fluticasone propionate, and the LABA,
EP
formoterol fumarate (fluticasone propionate/formoterol fumarate [FP/FORM]), as an aerosol suspension in a hydrofluoroalkane (HFA)-based pressurised metered-dose inhaler (pMDI) is
AC C
associated with greater efficacy than treatment with each its components (fluticasone or formoterol) administered as monotherapy [13-16]. Efficacy of FP/FORM has been proven in randomised controlled trials for all asthma severities for adolescents and adults [15-19] and for long-term treatment over both 6 and 12 months [20]. FP/FORM is comparable in efficacy to budesonide/formoterol [21] and fluticasone/salmeterol [18], but patients receiving FP/FORM experience a consistently faster onset of bronchodilation than patients receiving fluticasone/salmeterol [18]. Although data from randomised clinical trials provide important safety and efficacy data, they may not accurately reflect the situation in clinical practice, in which many patients fail to 4
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
achieve adequate control of their asthma [22, 23]. Data from prospective, non-interventional studies complement the results of clinical trials [24, 25] by providing data on the effectiveness and safety of interventions in a diverse and clinically relevant population of patients, to which few exclusion criteria have been applied.
RI PT
The current non-interventional study was designed to evaluate the safety and effectiveness of FP/FORM across a diverse spectrum of community-based patients with asthma in a reallife setting for one year.
SC
Patients and methods Study design
M AN U
This multicentre, prospective, non-interventional post-authorisation safety study, conducted in Germany, started in November 2012 and was completed in July 2015. The study incorporated a series of 6 visits over a one-year observational period for each patient. Visits
Patients
TE D
2 through 6 occurred 4–6 weeks, and 3, 6, 9 and 12 months after the baseline visit (visit 1).
Male and female outpatients aged ≥12 years with a diagnosis of asthma were enrolled. The
EP
decision to initiate treatment with FP/FORM was at the discretion of the prescribing physician. It always preceded and was independent of the decision to enrol the patient into
AC C
the study. There were no restrictions regarding asthma type or severity, duration of disease, bronchodilator reversibility, smoking history, co-morbidity, concomitant asthma or other medication or correct inhaler technique. Contraindications to enrolment and FP/FORM treatment were as mandated in the FP/FORM summary of product characteristics (SmPC) [26].
Informed consent and registration Written informed consent was signed by the patient or, for patients <18 years, signed according to local requirements by one or both of the patient’s parent(s) or legal 5
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
representative(s) and an assent form was signed by the patient. The study was conducted in accordance with AMG (German Medicines Act) chapter 67, section 6. It was approved by the responsible ethics committees and registered with the German Federal Institute for Drugs and Medical Devices (BfArM; study code FLT9501). The study was also registered in the
RI PT
European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP; study code ENCePP/SDPP/3702).
Study treatment
SC
All patients received treatment with a fixed combination of FP/FORM in a pMDI (Flutiform®, Mundipharma GmbH, Limburg, Germany) at one of the following dose strengths (FP/FORM):
M AN U
50/5 µg; 125/5 µg; 250/10 µg (the latter indicated only for patients aged ≥18 years). The recommended dose is two inhalations twice daily. Patients were to be treated in compliance with the FP/FORM marketing authorisation. Initial dose and adjustments were performed at
TE D
the discretion of each patient’s physician.
Data collection and outcome measures
Primary effectiveness parameters were asthma control, assessed by the change in Asthma
EP
Control Test™ (ACT) total score between baseline and study end, and frequency of severe asthma exacerbations. The primary safety parameter was the recording of adverse events.
AC C
Data collected at the baseline visit included medical history, demographic and asthmarelated data prior to treatment. Additional data collected at this and all post-baseline visits included asthma control, asthma-related quality of life, lung function (forced expiratory volume in one second [FEV1; absolute and % predicted values] and peak expiratory flow [PEF: absolute and % predicted values]), severe asthma exacerbations (worsening of asthma requiring medical intervention with administration of systemic corticosteroids), patient satisfaction with treatment and the number of ‘disability days’. At all post-baseline visits the investigators additionally documented the patients’ FP/FORM dosage, any history of adverse events (AEs) or unscheduled and emergency asthma-related medical care and, if 6
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
the patient had discontinued treatment, the reason for discontinuation. The last observation carried forward (LOCF) method was used for all ‘end of study’ analyses. Asthma control was assessed using the 5-item ACT [27]. The total summed score ranges from 5 to 25. The extent of asthma control was defined as follows: controlled (ACT total
RI PT
score ≥20), somewhat controlled (16–19), poorly controlled (≤15). Asthma-related quality of life was assessed using the Asthma Quality of Life Questionnaire (AQLQ) for 12 years and older (AQLQ(S)+12) [28]. Results are expressed as the mean of each of the 4 domain scores (symptoms, activities limitation, emotional function and
SC
environmental stimuli) and as the mean of the overall summed score.
Patient satisfaction was assessed by asking patients to rate both the efficacy and tolerability
M AN U
of their therapy on a 5-item scale (1=very good; 2=good; 3=moderate; 4=poor; 5=very poor). The ‘disability days’ were defined as the number of days for which asthma had caused the patient to be absent from work or education or unable to perform everyday activities. They were assessed in the previous 30 days and at each study visit for the period since the
TE D
previous visit. The data were normalised based on the number of days between visits. Unscheduled and emergency asthma-related medical care, which occurred from the 4–6 week visit onwards, were documented, and the data were expressed as annualised rates.
EP
AEs that were categorised as being possibly related to treatment (any AE that was considered by the investigator as ‘unlikely to be’, ‘possibly’, ‘probably’ or ‘definitely’ related to
AC C
FP/FORM treatment, including those events where the assessed relationship to FP/FORM was missing) were also reported.
Statistical analyses
The safety population comprised all patients who received at least one dose of observed medication. Effectiveness analyses were conducted using data from the full analysis population (all patients who received at least one dose of observed medication and had at least one post-baseline primary effectiveness endpoint).
7
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
The ACT and AQLQ total and item/domain scores, and the changes from baseline at each post-baseline timepoint and end of study (LOCF) were treated as continuous data. A LOCF imputation approach was used for missing data (last non-missing post-baseline value observed during the treatment period imputed).
RI PT
For the ACT, AQLQ and lung function data, summary statistics and 2-sided 95% confidence intervals (CIs) were used to estimate the change from baseline to each post-baseline
timepoint based on a one sample t-test (lung function: change from baseline to end of
study). To control for multiple testing, a repeated-measures ANOVA was additionally applied
SC
for ACT and AQLQ data. Summary measures are shown as proportions or mean ± standard deviation (SD). The unscheduled and emergency asthma-related medical care data are
M AN U
shown as an annualised rate. The reported analyses are descriptive and exploratory.
Results Patients
TE D
A total of 1,563 patients were enrolled in 168 pulmonology practices and 23 general medical practices and received at least one dose of FP/FORM (safety population). Of these, 153 were excluded from the full analysis population (N=1,410). Reasons for exclusion were
EP
absence of any post-baseline effectiveness assessments (n=117), retrospectively collected data (n=35) or both of the before mentioned reasons (n=1). In total, 1,087 patients (77.1%)
AC C
of the full analysis population completed the first follow-up at 4–6 weeks post-baseline, and 984 patients (69.8%) completed the last follow-up at 12 months post-baseline. The most frequent reasons for study discontinuation were loss to follow-up (184 patients [13.0%]) and patient choice (97 [6.9%]). A total of 86 patients (6.1%) discontinued due to AEs and 30 (2.1%) due to insufficient efficacy. After study completion, 991 patients (70.3%) continued FP/FORM treatment. Baseline characteristics of the full analysis population (Table 1) show that the majority of the population (96.3%) were ≥18 years of age with a mean age of 49.0 ± 17.6 years and an age range of 12–89 years. More patients were female (n=847; 60.1%). Almost 40% of patients 8
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
(n=555, 39.4%) were treated with ICS plus LABA prior to study enrolment. Of these, 462 patients received a fixed combination of either beclomethasone dipropionate/formoterol fumarate (n=195, 13.8%), fluticasone propionate/salmeterol xinafoate (n=147, 10.4%), budesonide/formoterol fumarate (n=120, 8.5%) or FP/FORM (n=112, 7.9%). Asthma was not
RI PT
fully controlled at baseline in more than half of the population (ACT total score ≤19, n=956 [67.8%]). FEV1 was ≤80% predicted in 47.2% of patients (n=665). Fifteen percent of patients (n=220) smoked at study start and did not stop smoking during the study. During the
SC
observational period, 1% (n=14) stopped smoking and 1.3% (n=10 ex-smoker, n=8 non-
M AN U
smoker) started smoking.
Treatment
Analysis of data from the full analysis population shows that the daily dosages most commonly prescribed at both baseline and end of study were FP/FORM 500/20 µg (prescribed to 643 patients [45.6%] at baseline), 250/10 µg (476 patients [33.8%] at
TE D
baseline) and 1,000/40 µg (152 patients [10.8%] at baseline). The percentage of patients receiving each FP/FORM dose showed little change from baseline to the end of the study. The daily dose remained stable throughout the study in 1,109 patients (78.7%). Dosage
EP
increased in 163 patients (11.6%), decreased in 165 patients (11.7%) and was interrupted in 33 patients (2.3%). Multiple dosage adjustments (increases or decreases) were made in 52
AC C
patients (3.7%).
Effectiveness
Asthma Control Test™ scores In the overall population, the mean ACT total score at baseline was 16.3 ± 5.0 (possible range, 5–25). This increased significantly during the study (mean value at 12 months, 20.1 ± 4.3, change from baseline to month 12, 3.5 ± 5.3). The corresponding change from baseline to end of study (LOCF) was 3.4 ± 5.4 (mean value at end of study, 19.8 ± 4.5) (Figure 1).
9
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
The mean total score was significantly higher than baseline at all study observation timepoints. The data demonstrate that there was substantial improvement in total score from baseline to the second observation (4–6 weeks after baseline) and that this degree of improvement was maintained throughout the observation period. A similar pattern of
RI PT
improvement was evident for all ACT single item scores. The improvement from baseline was significant for all items at all study observation timepoints and at the end of the study (Supplementary Table 1). In the subgroup of patients with ICS plus LABA pretreatment (fixed or open combination), the mean ACT total score at baseline was 16.5 ± 5.2. This also
SC
increased significantly during the study (mean value at 12 months, 19.6 ± 4.7, change from baseline to month 12, 2.7 ± 5.3). The corresponding change from baseline to end of study
M AN U
(LOCF) was 2.5 ± 5.4 (mean value at end of study, 19.1 ± 5.0). The mean total score was significantly higher than baseline at all study observation timepoints (p=0.004 ANOVA). Similar to the overall population, there was substantial improvement from baseline to the second observation, which was maintained throughout the observation period.
TE D
The percentage of patients whose ACT total score indicated control of disease (score ≥20) increased from 30.9% at baseline to 62.4% at the end of the study (Figure 2). The percentage of patients whose disease was ‘somewhat controlled’ (total score 16–19)
EP
decreased slightly from baseline to end of study (25.9% vs. 21.0%); the percentage of patients whose disease was poorly controlled (total score ≤15) decreased substantially
AC C
(43.1% vs. 16.7%).
Severe exacerbations
The numbers of patients without and with severe asthma exacerbations (worsening of asthma requiring medical intervention with administration of systemic corticosteroids) during the 12 months prior to enrolment and under treatment with FP/FORM are shown in Table 2. The percentage of patients with ≥1 asthma exacerbation was 35.8% within the last 12 months prior to enrolment and 5.9% during the observation period. This led to a decrease in the mean number of severe asthma exacerbations from 0.7 ± 1.9 per patient to 0.07 ± 0.3 10
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
per patient. The annualised rate of severe asthma exacerbations per patients with FP/FORM treatment was 0.11 ± 0.6.
Asthma Quality of Life Questionnaire scores
RI PT
The AQLQ total and domain scores improved significantly from baseline to the end of the study and at all observations (Figure 3; Supplementary Table 2). As for the ACT scores, there was substantial improvement in total score and in all domain scores, from baseline to
SC
the second observation, after which time the scores remained fairly stable.
Lung function
M AN U
In the overall population, absolute values of FEV1, FEV1 percentage predicted, PEF and PEF percentage predicted all increased significantly from baseline to end of study, and from baseline to each study observation timepoint (p<0.0001 for all; Table 3). Both FEV1 and PEF increased in all lung function subgroups (FEV1 40–60% predicted; FEV1 60–80% predicted;
TE D
FEV1 >80% predicted): FEV1 increases of 0.41 L, 0.23 L, and 0.02 L, respectively (Supplementary Figure 1); PEF increases of 0.93 L/s, 0.70 L/s, and 0.31 L/s, respectively. The improvements in PEF were more pronounced than the improvements in FEV1. With one
EP
exception, the changes from baseline to end of study in the PEF- and FEV1-based endpoints were statistically significant (p<0.0001) for the overall population and all lung function
AC C
subgroups; the exception was the change from baseline in FEV1-based endpoints in the subgroup with FEV1 >80% predicted, in which the improvements failed to achieve statistical significance. For both FEV1 and PEF, the improvement was greatest in the patients with the most severe impairment of lung function. In all subgroups, the majority of the improvement in both parameters occurred prior to the 4–6 week visit, lung function then remaining stable for the remaining duration of the observation period.
Patient satisfaction
11
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
At baseline, 506 patients (35.9%) rated the efficacy of their existing asthma treatment as ‘good’ or ‘very good’; 1,214 patients (86.1%) gave their treatment these ratings at the end of the study. Patient satisfaction with the tolerability of their asthma treatment also increased during the study (‘good’ or ‘very good’ rating at baseline, 898 patients [63.7%]; end of study,
RI PT
1,276 patients [90.5%]).
Degree to which asthma interfered with patients’ lives – ‘disability days’
In the 30 days prior to the baseline visit, the mean (SD) normalised number of days for which
SC
asthma had caused patients to be absent from work or education or unable to perform
everyday activities (‘disability days’) was 1.6 (4.5). The mean number of disability days
M AN U
decreased to 0.5 (2.7) after 4-6 weeks and to 0.2 (1.1) at month 6. By the end of the study, the average number of days between study visits lost to asthma was 0.3 (1.8).
Unscheduled and emergency medical care
TE D
During the study, the mean (SD) annualised rates of asthma-related unscheduled physician visits, emergency visits, hospital admissions and days spent in hospital were 0.46 (2.23),
Safety
EP
0.01 (0.10), 0.02 (0.19) and 0.12 (1.56), respectively.
AC C
One third of patients (n=519, 33.2%) experienced 1,072 AEs during the observation period (most of them of mild or moderate severity), and 62 (4.0%) experienced 80 serious AEs. No deaths occurred. AEs caused 102 patients (6.5%) to discontinue the study. A total of 160 patients (10.2%) had 254 AEs possibly related to FP/FORM. Treatment-related AEs that occurred at a frequency ≥0.3% were dysphonia (n=44; 2.8%), tremor (n=11; 0.7%), cough (n=10; 0.6%), oral candidiasis (n=8; 0.5%), asthma (n=7; 0.4%), dizziness (n=7; 0.4%), dry mouth (n=6; 0.4%), headache (n=6; 0.4%), oropharyngeal pain (n=6; 0.4%), sleep disorder (n=6; 0.4%) and tachycardia (n=5; 0.3%). All AEs were in line with the SmPC.
12
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Discussion This is the first large real-life study with patients receiving FP/FORM treatment. In the prospective, non-interventional study, 1,563 patients with asthma (safety population) receiving treatment with FP/FORM were observed over one year. Using data from the full
RI PT
analysis population (N=1,410), on-study outcomes (ACT scores, control rate, AQLQ scores, lung function parameters) were compared with baseline. Furthermore, the severe
exacerbation rate was documented in the 12 months prior to and during the study, and AEs were recorded at each study visit. A diverse spectrum of community-based patients with
SC
asthma were enrolled: the population included male and female adolescents ≥12 years and adults with differing degrees of disease control, a range of FEV1 and PEF values, and
M AN U
various smoking habits prior to study enrolment. Approximately 40% of patients were already receiving combination ICS/LABA treatment prior to study enrolment. Although excluded by the protocol, 7.9% were being treated with FP/FORM at baseline (patients included in full analysis population).
TE D
The data at baseline relating to ACT scores (mean total score, 16.3), control rate (disease poorly controlled in 42.3% of patients), AQLQ scores (mean total score, 4.73), lung function (FEV1, 2.45 L; FEV1 % predicted, 80.2%) and severe exacerbation rate (21.2% of patients
EP
affected in 12 months prior to enrolment) reveal that treatment was not optimal at baseline in many of the patients enrolled. The results show significant improvements in all effectiveness
AC C
outcomes that were subject to statistical analysis (ACT total and domain scores, AQLQ total and domain scores, FEV1 and PEF values). In addition, an increase by 100% of the percentage of patients with asthma control from baseline and a lower rate of severe exacerbations compared to the 12 months prior to start of the observation period was observed. In the overall population, the mean change in ACT total score from baseline to the end of the study (3.4 points) exceeded the change of 3 points, which is defined as the minimal clinically important difference for this instrument [29]. In the subgroup of patients with ICS plus LABA pretreatment, ACT total score also significantly increased from baseline to the end of the 13
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
study (mean change 2.5 points); however the minimal clinical important difference was not reached [29]. The mean change in AQLQ total score from baseline to the end of the study (0.85) and the mean changes in each domain (0.63–1.02) all exceeded the minimum change of 0.5, which is defined as the minimal clinically important difference for this instrument [30].
RI PT
The increase in the number of patients with asthma control from 30.9% at baseline to 62.4% at the end of the study was comparable to that observed in a recent non-interventional study including 5789 asthma patients receiving three different ICS/LABA combinations over six months [31]. These data suggest that initiation of FP/FORM therapy was associated with
SC
clinically relevant improvements in disease status and in patients’ quality of life.
These improvements may at least partly relate to the intensification of the treatment
M AN U
regimen, e.g., in patients who received monotherapy with an ICS before study enrolment. However, especially the improvement of asthma control in patients with ICS plus LABA pretreatment may be explained by a number of factors including provision of FP/FORM in a fixed combination rather than as concurrent treatments [32], use of a pMDI rather than a dry
TE D
powder inhaler [33], the high and consistent fine particle fraction of FP/FORM [34], and the rapid onset of action of formoterol [18] (which is likely to promote adherence [35]). However, the possible improvement of the patients’ treatment adherence upon study inclusion cannot
EP
be ruled out. It was notable that, for almost all effectiveness outcomes, the improvement associated with FP/FORM therapy was already evident one month after treatment initiation
AC C
and that this degree of benefit was then sustained for the duration of the study. These data demonstrate that the FP/FORM therapy results in rapid benefit, which is sustained during long-term treatment. Certainly, patient satisfaction with both the efficacy and tolerability of their asthma treatment increased from baseline to the end of the study. These data are supported by the fact that 70% of patients intended to continue using FP/FORM therapy after the observational period. The decrease in the incidence of severe asthma exacerbations in this study (a 10-fold reduction) was particularly marked. Predictors of future exacerbations include a history of exacerbations, poor asthma control, activity limitation and low FEV1 values [36], many of 14
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
which were prevalent in the study population at baseline (Tables 1–3, Supplementary Table 2). The effectiveness of FP/FORM in management of exacerbation risk was recently highlighted by Papi et al. [36], who found that the incidence of corticosteroid-requiring exacerbations in patients receiving long-term FP/FORM therapy (2.1%) was considerably
RI PT
lower than the incidence in patients receiving other ICS/LABA combinations (9.5–16.7%). Although trial duration varied in the studies reviewed by Papi et al., the studies involving FP/FORM therapy were generally of similar or longer duration than many of the studies
involving other ICS/LABA combinations with which they were compared [36]. Papi et al.
SC
could find no study-related explanations for the difference in exacerbation incidence between FP/FORM and other ICS/LABA combinations. They thus suggested that the relatively low
M AN U
exacerbation rate in FP/FORM-treated patients may be related to the favourable pharmacological and mechanistic characteristics of fluticasone propionate and formoterol. Although half of the patients enrolled in this study had relatively good lung function at baseline, both FEV1 and PEF improved during the 12 months of treatment in the overall
TE D
population (Table 3). The improvement in PEF (0.55 L/s [9.6%] increase), which was more pronounced than the improvement in FEV1 (0.15 L [6.1%] increase), exceeded the average minimal patient perceivable improvement of 0.31 L/s [37]. The increase in PEF over the
EP
course of the study also matched or exceeded the minimal perceivable improvement in all the lung function subgroups (FEV1, 40–60%: 0.93 L/s; FEV1, 60–80%: 0.70 L/s; FEV1, >80%:
AC C
0.31 L/s). The increase in FEV1 exceeded the minimal perceivable improvement of 0.23 L in all but the patients with FEV1 >80% at baseline (FEV1, 40–60%: 0.41 L; FEV1, 60–80%: 0.23 L). For both FEV1 and PEF, the magnitude of the improvement was inversely related to the severity of the pulmonary impairment at baseline. In all subgroups, the majority of the improvement in lung function occurred prior to the 4–6 week visit, lung function then remaining stable for the duration of the observation period, reflecting the changes seen for asthma control and quality of life. This confirms the results of an open-label study with FP/FORM over 12 months, in which the lung function improvements were seen within the first two months and were sustained throughout the whole study [20]. 15
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
The clinical improvements associated with initiation of FP/FORM therapy were accompanied by a substantial reduction in the number of days on which asthma caused patients to be absent from work or education or unable to perform everyday activities. When compared with the results of other studies, the annualised rates of asthma-related unscheduled
RI PT
physician visits, emergency visits, hospital admissions and days spent in hospital appeared to be low. For example, data from the German Statutory Health Insurance database showed annual rates of asthma-related hospital admissions and days of hospitalisation in 2010 of 0.08 and 0.56, respectively [38]. In our study, the mean numbers of asthma-related hospital
SC
admissions and days spent in hospital were 0.02 and 0.12 per year, respectively.
M AN U
The prevalence of AEs in this study (33.2% of patients with ≥1 AE) is similar to that reported in an open-label study in which 413 patients received FP/FORM 100/10 µg or 250/10 µg for up to 12 months (AEs in 36.9% of patients) [20]. However, the percentages of patients reporting serious AEs and who discontinued therapy as a result of AEs were higher in the current study than in the open-label study (4.0% vs. 2.1% and 6.5% vs. 3.0%, respectively).
TE D
The reasons for these differences may relate to the strict patient selection criteria or study environment in clinical trials [24, 39]. The current study did not reveal any new safety signals in patients treated with FP/FORM. The most frequently reported treatment-related AE was
EP
dysphonia, which is common in patients with asthma who have been treated with ICS [40]. One of the strengths of this study lies in its prospective, non-interventional design. Due to
AC C
restrictive inclusion/exclusion criteria of randomised clinical trials they may not accurately reflect the situation in clinical practice [22, 23]. For example, it has been estimated that only approximately 5% of the asthma patients seen in clinical practice would have been eligible for many of the major asthma randomised clinical trials [39, 41]. Another difference between real-life and controlled trials relates to the level of patient monitoring, which tends to lead to better adherence in clinical trials than in real-life studies [24, 25, 42, 43]. Data from prospective, non-interventional studies such as this one complement the results of clinical trials [24, 25] by providing data from patients in routine clinical practice.
16
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
This study did have a number of limitations, mainly based on its non-interventional character. These include the absence of a control arm in which patients’ medication remained unchanged from baseline, so the potentially beneficial effect on patients of involvement in the study could not be assessed. Additionally, it cannot be ruled out that the physicians may
RI PT
have influenced the patients’ perception of the drug’s effectiveness and that this led to an improved treatment adherence. A further feature was the emphasis on having few exclusion criteria, which may have allowed unmeasured confounding factors to influence the outcome in some patients. The dropout rate of 30.2% during the study is only a bit higher than in two
SC
other non-interventional asthma studies over 12 months (18.0%, 26.7%) [45, 46] and lies within the range reported in 12-month non-interventional omalizumab studies [44]. The
M AN U
dropout rate should be taken into account when interpreting the data, as patients with less treatment benefit and more adverse events are often more likely to drop out than patients with improvement of disease control. In addition, patients with seasonal asthma tend to use their medication only in the period in which they have asthma symptoms. These patients
TE D
may also have dropped out before study end. The study population showed diversity in age, gender and asthma severity, but not in ethnic origin. It is hoped that future studies will allow exploration of any ethnicity-based differences in treatment response, because differences in
EP
the response to treatment among asthmatic patients of different ethnic backgrounds and
AC C
genotypes have been reported [47, 48].
We can nevertheless conclude from this study that initiation of FP/FORM, or substitution of FP/FORM for participants’ usual therapy was associated with substantial and clinically important improvements in asthma status in a diverse population of patients in routine clinical practice.
Acknowledgments and conflict of interest We are indebted to the physicians who documented the patients in this study and thank the patients who participated. The study was sponsored by Mundipharma GmbH, who provided 17
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
funding for data analysis and medical writing support. We thank the Contract Research Organization Scope International AG for the operational conduct of the study and data analyses and Physicians World Europe GmbH for medical writing assistance. OS received payments for lectures and consultancy from Astellas, AstraZeneca, Berlin-
RI PT
Chemie, Boehringer Ingelheim, Chiesi, GSK, Mundipharma, and Roche. WP declares receiving payments for lectures from Boehringer Ingelheim, MEDA, AstraZeneca and Mundipharma. GH received educational grants and payments for lectures from Allergopharma, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Mundipharma, Novartis,
SC
and Teva. FK received payments for consultancy and lectures from Chiesi, Mundipharma,
M AN U
Novartis, and Teva. PO and BLB are employees of Mundipharma.
AC C
EP
TE D
® FLUTIFORM is a registered trade mark of Jagotec AG and is used under licence.
18
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
References
[1] M. Masoli, D. Fabian, S. Holt, R. Beasley, P. Global Initiative for Asthma, The global burden of asthma: executive summary of the GINA Dissemination Committee report, Allergy 59(5) (2004) 469-78.
RI PT
[2] GINA, Global Strategy for Asthma Management and Prevention.
M AN U
SC
[4] K.B.K. Bundesärztekammer (BÄK), Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF),, Nationale VersorgungsLeitlinie Asthma – Long version, 2nd edition. version 5. 2013 (http://www.leitlinien.de/mdb/downloads/nvl/asthma/asthma-2aufl-vers5-lang.pdf, accessed Sep 2016). [5] J.A. van Noord, A.J. Schreurs, S.J. Mol, P.G. Mulder, Addition of salmeterol versus doubling the dose of fluticasone propionate in patients with mild to moderate asthma, Thorax 54(3) (1999) 207-12.
TE D
[6] P.M. O'Byrne, P.J. Barnes, R. Rodriguez-Roisin, E. Runnerstrom, T. Sandstrom, K. Svensson, A. Tattersfield, Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial, Am. J. Respir. Crit. Care Med. 164(8 Pt 1) (2001) 1392-7.
EP
[7] R.A. Pauwels, C.G. Lofdahl, D.S. Postma, A.E. Tattersfield, P. O'Byrne, P.J. Barnes, A. Ullman, Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group, N. Engl. J. Med. 337(20) (1997) 1405-11.
AC C
[8] A. Woolcock, B. Lundback, N. Ringdal, L.A. Jacques, Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids, Am. J. Respir. Crit. Care Med. 153(5) (1996) 1481-8. [9] A.P. Greening, P.W. Ind, M. Northfield, G. Shaw, Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & Hanburys Limited UK Study Group, Lancet 344(8917) (1994) 219-24. [10] T.E. Delea, M. Hagiwara, R.H. Stanford, D.A. Stempel, Effects of fluticasone propionate/salmeterol combination on asthma-related health care resource utilization and costs and adherence in children and adults with asthma, Clin. Ther. 30(3) (2008) 560-71. [11] S.W. Stoloff, D.A. Stempel, J. Meyer, R.H. Stanford, J.R. Carranza Rosenzweig, Improved refill persistence with fluticasone propionate and salmeterol in a single inhaler compared with other controller therapies, J. Allergy Clin. Immunol. 113(2) (2004) 245-51.
19
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
[12] C.J. Cates, L.S. Wieland, M. Oleszczuk, K.M. Kew, Safety of regular formoterol or salmeterol in adults with asthma: an overview of Cochrane reviews, Cochrane Database Syst Rev 2 (2014) Cd010314. [13] D.S. Pearlman, C.F. LaForce, K. Kaiser, Fluticasone/Formoterol combination therapy compared with monotherapy in adolescent and adult patients with mild to moderate asthma, Clin. Ther. 35(7) (2013) 950-66.
RI PT
[14] T. Pertseva, S. Dissanayake, K. Kaiser, Superiority of fluticasone propionate/formoterol fumarate versus fluticasone propionate alone in patients with moderate-to-severe asthma: a randomised controlled trial, Curr. Med. Res. Opin. 29(10) (2013) 1357-69.
SC
[15] J. Corren, L.E. Mansfield, T. Pertseva, V. Blahzko, K. Kaiser, Efficacy and safety of fluticasone/formoterol combination therapy in patients with moderate-to-severe asthma, Respir. Med. 107(2) (2013) 180-95.
M AN U
[16] R.A. Nathan, A. D'Urzo, V. Blazhko, K. Kaiser, Safety and efficacy of fluticasone/formoterol combination therapy in adolescent and adult patients with mild-tomoderate asthma: a randomised controlled trial, BMC Pulm. Med. 12 (2012) 67. [17] A. Bodzenta-Lukaszyk, G. Pulka, A. Dymek, D. Bumbacea, T. McIver, B. Schwab, H. Mansikka, Efficacy and safety of fluticasone and formoterol in a single pressurized metered dose inhaler, Respir. Med. 105(5) (2011) 674-82.
TE D
[18] A. Bodzenta-Lukaszyk, A. Dymek, K. McAulay, H. Mansikka, Fluticasone/formoterol combination therapy is as effective as fluticasone/salmeterol in the treatment of asthma, but has a more rapid onset of action: an open-label, randomized study, BMC Pulm. Med. 11 (2011) 28.
EP
[19] A. Bodzenta-Lukaszyk, J. Van Noord, W. Schröder-Babo, Kombinationstherapie mit Fluticason/Formoterol in einem Dosieraerosol hat vergleichbare Wirksamkeit wie die freie Konbination Fluticason und Formoterol, Pneumologie 66(3) (2012) 29.
AC C
[20] A.H. Mansur, K. Kaiser, Long-term safety and efficacy of fluticasone/formoterol combination therapy in asthma, J. Aerosol Med. Pulm. Drug Deliv. 26(4) (2013) 190-9. [21] A. Bodzenta-Lukaszyk, R. Buhl, B. Balint, M. Lomax, K. Spooner, S. Dissanayake, Fluticasone/formoterol combination therapy versus budesonide/formoterol for the treatment of asthma: a randomized, controlled, non-inferiority trial of efficacy and safety, J. Asthma 49(10) (2012) 1060-70. [22] L. Cazzoletti, A. Marcon, C. Janson, A. Corsico, D. Jarvis, I. Pin, S. Accordini, E. Almar, M. Bugiani, A. Carolei, I. Cerveri, E. Duran-Tauleria, D. Gislason, A. Gulsvik, R. Jogi, A. Marinoni, J. Martinez-Moratalla, P. Vermeire, R. de Marco, Asthma control in Europe: a realworld evaluation based on an international population-based study, J. Allergy Clin. Immunol. 120(6) (2007) 1360-7. [23] P. Demoly, B. Gueron, K. Annunziata, L. Adamek, R.D. Walters, Update on asthma control in five European countries: results of a 2008 survey, Eur. Respir. Rev. 19(116) (2010) 150-7. 20
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
[24] S. Saturni, F. Bellini, F. Braido, P. Paggiaro, A. Sanduzzi, N. Scichilone, P.A. Santus, L. Morandi, A. Papi, Randomized Controlled Trials and real life studies. Approaches and methodologies: a clinical point of view, Pulm. Pharmacol. Ther. 27(2) (2014) 129-38. [25] D. Price, G. Brusselle, N. Roche, D. Freeman, A. Chisholm, Real-world research and its importance in respiratory medicine, Breathe (Sheff) 11(1) (2015) 26-38.
RI PT
[26] flutiform® summary of product characteristics (http://www.medicines.ie; accessed March 2016). [27] R.A. Nathan, C.A. Sorkness, M. Kosinski, M. Schatz, J.T. Li, P. Marcus, J.J. Murray, T.B. Pendergraft, Development of the asthma control test: a survey for assessing asthma control, J. Allergy Clin. Immunol. 113(1) (2004) 59-65.
M AN U
SC
[28] E.F. Juniper, K. Svensson, A.C. Mork, E. Stahl, Modification of the asthma quality of life questionnaire (standardised) for patients 12 years and older, Health Qual Life Outcomes 3 (2005) 58. [29] M. Schatz, M. Kosinski, A.S. Yarlas, J. Hanlon, M.E. Watson, P. Jhingran, The minimally important difference of the Asthma Control Test, J. Allergy Clin. Immunol. 124(4) (2009) 71923.e1. [30] E.F. Juniper, G.H. Guyatt, A. Willan, L.E. Griffith, Determining a minimal important change in a disease-specific Quality of Life Questionnaire, J. Clin. Epidemiol. 47(1) (1994) 81-7.
TE D
[31] B. Rogala, P. Majak, J. Gluck, T. Debowski, Asthma control in adult patients treated with a combination of inhaled corticosteroids and longacting beta2agonists: a prospective observational study, Pol Arch Intern Med 127(2) (2017) 100-106.
EP
[32] C. Marceau, C. Lemiere, D. Berbiche, S. Perreault, L. Blais, Persistence, adherence, and effectiveness of combination therapy among adult patients with asthma, J. Allergy Clin. Immunol. 118(3) (2006) 574-81.
AC C
[33] D. Price, N. Roche, J. Christian Virchow, A. Burden, M. Ali, A. Chisholm, A.J. Lee, E.V. Hillyer, J. von Ziegenweidt, Device type and real-world effectiveness of asthma combination therapy: an observational study, Respir. Med. 105(10) (2011) 1457-66. [34] B. Johal, M. Howald, M. Fischer, J. Marshall, G. Venthoye, Fine Particle Profile of Fluticasone Propionate/Formoterol Fumarate Versus Other Combination Products: the DIFFUSE Study, Comb Prod Ther 3 (2013) 39-51. [35] B.G. Bender, Overcoming barriers to nonadherence in asthma treatment, J. Allergy Clin. Immunol. 109(6 Suppl) (2002) S554-9. [36] A. Papi, A.H. Mansur, T. Pertseva, K. Kaiser, T. McIver, B. Grothe, S. Dissanayake, Long-Term Fluticasone Propionate/Formoterol Fumarate Combination Therapy Is Associated with a Low Incidence of Severe Asthma Exacerbations, J. Aerosol Med. Pulm. Drug Deliv. 29(4) (2016) 346-61.
21
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
[37] N.C. Santanello, J. Zhang, B. Seidenberg, T.F. Reiss, B.L. Barber, What are minimal important changes for asthma measures in a clinical trial?, Eur. Respir. J. 14(1) (1999) 23-7. [38] C. Jacob, B. Bechtel, S. Engel, P. Kardos, R. Linder, S. Braun, W. Greiner, Healthcare costs and resource utilization of asthma in Germany: a claims data analysis, Eur J Health Econ 17(2) (2016) 195-201.
RI PT
[39] J. Travers, S. Marsh, M. Williams, M. Weatherall, B. Caldwell, P. Shirtcliffe, S. Aldington, R. Beasley, External validity of randomised controlled trials in asthma: to whom do the results of the trials apply?, Thorax 62(3) (2007) 219-23. [40] H.E. Hassen, A.M. Abo Hasseba, Voice evaluation in asthma patients using inhaled corticosteroids, Kulak Burun Bogaz Ihtis Derg 26(2) (2016) 101-8.
M AN U
SC
[41] K. Herland, J.-P. Akselsen, O.H. Skjønsberg, L. Bjermer, How representative are clinical study patients with asthma or COPD for a larger “real life” population of patients with obstructive lung disease?, Respir. Med. 99(1) (2005) 11-19. [42] A. Kondla, T. Glaab, R. Pedersini, M. Lommatzsch, Asthma control in patients treated with inhaled corticosteroids and long-acting beta agonists: A population-based analysis in Germany, Respir. Med. 118 (2016) 58-64. [43] D. Price, M. Fletcher, T. van der Molen, Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey, NPJ Prim Care Respir Med 24 (2014) 14009.
TE D
[44] M. Caminati, G. Senna, G. Stefanizzi, R. Bellamoli, S. Longhi, F. Chieco-Bianchi, G. Guarnieri, S. Tognella, M. Olivieri, C. Micheletto, G. Festi, E. Bertocco, M. Mazza, A. Rossi, A. Vianello, g. North East Omalizumab Network study, Drop-out rate among patients treated with omalizumab for severe asthma: Literature review and real-life experience, BMC Pulm. Med. 16(1) (2016) 128.
AC C
EP
[45] B. Stallberg, I. Naya, J. Ekelund, G. Eckerwall, Real-life use of budesonide/formoterol in clinical practice: a 12-month follow-up assessment in a multi-national study of asthma patients established on single-inhaler maintenance and reliever therapy, Int. J. Clin. Pharmacol. Ther. 53(6) (2015) 447-55. [46] C. Terzano, G. Cremonesi, G. Girbino, E. Ingrassia, S. Marsico, G. Nicolini, L. Allegra, 1-year prospective real life monitoring of asthma control and quality of life in Italy, Respir. Res. 13 (2012) 112. [47] M.E. Wechsler, M. Castro, E. Lehman, V.M. Chinchilli, E.R. Sutherland, L. Denlinger, S.C. Lazarus, S.P. Peters, E. Israel, N.A.C.R. Network, Impact of race on asthma treatment failures in the asthma clinical research network, Am. J. Respir. Crit. Care Med. 184(11) (2011) 1247-53. [48] M.E. Wechsler, S.J. Kunselman, V.M. Chinchilli, E. Bleecker, H.A. Boushey, W.J. Calhoun, B.T. Ameredes, M. Castro, T.J. Craig, L. Denlinger, J.V. Fahy, N. Jarjour, S. Kazani, S. Kim, M. Kraft, S.C. Lazarus, R.F. Lemanske, A. Markezich, R.J. Martin, P. Permaul, S.P. Peters, J. Ramsdell, C.A. Sorkness, E.R. Sutherland, S.J. Szefler, M.J. 22
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Walter, S.I. Wasserman, E. Israel, Effect of β2-adrenergic receptor polymorphism on response to longacting β2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial, The Lancet 374(9703) (2009) 1754-1764.
23
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Tables Table 1. Baseline characteristics Characteristic
Full analysis population N=1,410
Age, years
49.0 ± 17.6
RI PT
Gender, n (%) Male
557 (39.5)
Female
847 (60.1)
Missing
6 (0.4)
Ethnic origin, n (%) BMI, kg/m
1,377 (97.7)
SC
Caucasian 2
27.68 ± 5.64 10.9 ± 12.7
Treatment prior to Visit 1, n (%) ICS without LABA ICS plus LABA Free combination Fixed combination Other
M AN U
Asthma duration, years
191 (13.5) 555 (39.4) 93 (6.6) 462 (32.8) 664 (47.1)
Controlled (≥ 20)
TE D
ACT-Score at Visit 1, n (%)
428 (30.4) 359 (25.5)
Poorly controlled (≤ 15)
597 (42.3)
Unclassified
EP
Somewhat controlled (16-19)
26 (1.8)
FEV1 at Visit 1, n (% predicted)
AC C
40–60%
216 (15.3)
>60–80%
449 (31.8)
>80%
708 (50.2)
Unclassified
37 (2.6)
Smoking habit during study, n (%) Non-smoker1
857 (60.8)
Ex-smoker2
252 (17.9)
Smoker
3
220 (15.6)
Values shown are for mean ± standard deviation unless stated otherwise ACT, Asthma Control Test™; BMI, body mass index; FEV1; forced expiratory volume in one second; ICS, inhaled corticosteroid; LABA, long-acting beta2-agonist 24
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Never smoked before entering study and did not start smoking during study; 2Stopped smoking at least one year before entering study and did not start smoking during study; 3 Smoked when entering study and did not stop smoking during study.
AC C
EP
TE D
M AN U
SC
RI PT
1
25
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Table 2. Severe asthma exacerbations Full analysis population N=1,410 Within the 12 months prior to enrolment
Treatment-emergent
835 (59.2)
1, n (%)
299 (21.2)
2, n (%)
116 (8.2)
3, n (%)
49 (3.5)
≥4, n (%)
41 (2.9)
Mean (SD) severe asthma exacerbations per patient
70 (5.0) 0.72 (1.91)
67 (4.8)
10 (0.7) 6 (0.4) 0
0
0.07 (0.33)
M AN U
Missing assessments, n (%)
1,327 (94.1)
SC
0, n (%)
RI PT
Number of severe exacerbations
AC C
EP
TE D
n, number of patients; SD, standard deviation
26
ACCEPTED MANUSCRIPT
Schmidt et al.
Real-life effectiveness FP/FORM
Table 3. Lung function parameters in the overall population and stratified by lung function at baseline Baseline
4–6 weeks
Month 3
Month 6
Month 9
FEV1 (L)
2.45 (0.90)
2.63 (0.91)
2.61 (0.90)
2.61 (0.92)
2.58 (0.90)
FEV1 predicted (%)
80.2 (24.2)
85.6 (20.2)
85.3 (19.6)
85.6 (19.5)
PEF rate (L/s)
5.72 (2.09)
6.26 (2.19)
6.30 (2.20)
PEF rate predicted (%)
77.5 (23.1)
84.6 (23.4)
FEV1 (L)
1.57 (0.41)
1.92 (0.73)
FEV1 predicted (%)
52.6 (5.6)
65.0 (18.0)
PEF rate (L/s)
3.98 (1.49)
4.77 (1.99)
PEF rate predicted (%)
53.7 (16.4)
65.4 (23.7)
FEV1 (L)
2.23 (0.61)
2.49 (0.78)
FEV1 predicted (%)
71.3 (5.7)
PEF rate (L/s)
5.33 (1.66)
PEF rate predicted (%)
70.6 (16.9)
Month 12
End of study (LOCF)
Change from baseline to end of study (LOCF)
2.59 (0.89)
2.60 (0.90)
0.16 (0.56)*
84.8 (20.4)
85.2 (19.7)
85.2 (19.8)
4.9 (20.4)*
6.21 (2.23)
6.30 (2.29)
6.30 (2.25)
6.27 (2.26)
0.57 (1.43)*
85.1 (23.3)
84.5 (23.8)
85.2 (24.5)
85.5 (23.9)
84.9 (24.0)
7.5 (18.9)*
1.99 (0.75)
1.93 (0.72)
1.93 (0.76)
1.92 (0.76)
1.98 (0.79)
0.43 (0.57)*
66.5 (17.8)
65.5 (17.3)
65.8 (19.9)
65.2 (18.5)
66.2 (18.9)
13.7 (17.9)*
4.96 (1.96)
4.76 (1.85)
4.93 (2.16)
4.80 (2.05)
4.91 (2.09)
1.02 (1.72)*
67.3 (22.5)
65.5 (21.7)
67.8 (25.0)
66.0 (23.2)
66.7 (23.6)
13.9 (22.1)*
2.49 (0.81)
2.47 (0.82)
2.47 (0.81)
2.46 (0.79)
2.46 (0.81)
0.23 (0.46)*
78.5 (12.3)
78.4 (13.1)
7901 (12.3)
77.7 (13.3)
78.3 (13.4)
78.1 (13.8)
6.9 (13.8)*
6.01 (1.81)
6.12 (1.93)
5.93 (2.05)
6.19 (2.14)
6.14 (2.00)
6.03 (2.11)
0.69 (1.49)*
79.1 (18.0)
79.7 (18.4)
78.8 (20.5)
80.5 (20.6)
81.0 (19.7)
79.5 (20.7)
8.6 (19.5)*
2.98 (0.86)
2.94 (0.85)
2.94 (0.86)
2.92 (0.83)
2.92 (0.83)
2.93 (0.84)
0.02 (0.56)
RI PT
Full analysis population
M AN U
Overall population (N=1,410)
AC C
EP
TE D
FEV1 40–60% predicted (n=216)
FEV1 >60–80% predicted (n=449)
SC
Lung function parameter
FEV1 >80% predicted (n=708) FEV1 (L)
2.91 (0.88)
27
ACCEPTED MANUSCRIPT
Schmidt et al.
Real-life effectiveness FP/FORM 96.2 (22.5)
97.8 (14.8)
97.3 (14.8)
97.1 (14.5)
97.3 (14.7)
97.3 (14.1)
96.6 (14.7)
0.5 (23.1)
PEF rate (L/s)
6.61 (1.99)
6.97 (2.16)
6.95 (2.18)
6.91 (2.15)
6.93 (2.16)
6.95 (2.18)
6.92 (2.14)
0.34 (1.25)*
PEF rate predicted (%)
90.6 (18.5)
95.1 (20.0)
95.6 (20.6)
95.1 (19.9)
95.6 (20.8)
95.7 (20.5)
95.0 (20.4)
4.6 (16.8)*
RI PT
FEV1 predicted (%)
All values represent mean (standard deviation) * p<0.0001 vs. baseline (one sample t-test)
AC C
EP
TE D
M AN U
SC
FEV1, forced expiratory volume in 1 second; LOCF, last observation carried forward; PEF, peak expiratory flow
28
Schmidt et al.
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Figure legends
Figure 1. Asthma Control Test™ (ACT) total score (full analysis population). *p<0.0001 vs. baseline (one-sample t-test), difference to baseline for all visits: p<0.0001
LOCF, last observation carried forward; SD, standard deviation.
RI PT
(repeated measures ANOVA).
LOCF, last observation carried forward.
SC
Figure 2. Asthma Control Test™ (ACT) total score classification (full analysis population).
M AN U
Figure 3. Asthma Quality of Life Questionnaire (AQLQ) total score and domain scores (full analysis population). The range of patient numbers with results is given for each visit. *
p<0.0001 vs. baseline (one-sample t-test), difference to baseline for all visits: p<0.0001
(repeated measures ANOVA).
AC C
EP
TE D
LOCF, last observation carried forward; SD, standard deviation.
29
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
*
*
*
*
*
*
Baseline
4-6 weeks
Month 3
Month 6
Month 9
Month 12
End of study (LOCF)
1,384
1,074
1,010
1,042
ACT total score (mean ± SD)
25
20
15
10
n
966
977
1,363
100 80
30.9
AC C
% patients with asthma control
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
54.5 60
67.1
65.3
62.4
20.1
19.3
21.0
15.7
12.8
15.4
16.7
Month 6
Month 9
Month 12
End of study (LOCF)
61.8
61.4
24.7
22.8
18.2
13.6
4-6 weeks
Month 3
25.9
40 27.3 20
43.1
0 Baseline
Poorly controlled (ACT ≤ 15) n
1,384
1,074
Somewhat controlled (ACT 16-19) 1,010
1,042
Controlled (ACT ≥ 20) 966
977
1,363
AQLQ scores (mean ± SD)
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
* * ** *
7
* * ** *
* * * * *
5.60 5.56 5.58 5.73 5.59
5.69 5.63 5.69 5.83 5.69
5.72 5.59 5.58 5.52 5.58
* * * * *
6 5.39 5.31 5.40 5.51 5.44
5 4.73
4
4.50
4.84 4.87 4.97
3 2 1
n
Baseline
4–6 week
Month 3
Month 12
Total score
Symptoms
Activities limitation
Emotional function
Environmental stimuli
991–998
953–968
1,356–1,366
1,350–1,371
1,068–1,082
End of study (LOCF)
Schmidt et al.
Highlights
Real-life effectiveness FP/FORM
ACCEPTED MANUSCRIPT
Real-life effectiveness of asthma treatment with a fixed-dose fluticasone/formoterol pressurised metered-dose inhaler – results from a non-interventional study
Highlights Prospective, non-interventional study in 1,563 community-based patients with
RI PT
•
asthma
First real-life data set with fluticasone propionate/formoterol fumarate (FP/FORM)
•
Clinically important improvement in asthma control and quality of life with FP/FORM
•
Decreased incidence of severe asthma exacerbations with FP/FORM
•
Improvements were evident 1 month after treatment start and sustained for 12
M AN U
SC
•
AC C
EP
TE D
months