Clinical Effectiveness of Budesonide/Formoterol Fumarate Easyhaler^® for Patients with Poorly Controlled Obstructive Airway Disease: a Real-World Study of Patient-Reported Outcomes

This real-world, multicenter, open-label, non-randomized, non-interventional study was conducted by 200 pulmonologists across 200 Hungarian centers and was a nationwide assessment of inhaler effectiveness in patients diagnosed with asthma, COPD and ACO who started using the Bufomix Easyhaler^®, including those who switched from their current inhaler. The trial was registered with the National Pharmaceutical Institute of Hungary (registration no. OGYÉI/13,942-5/2016). Test devices were distributed from Orion Pharma to participating centers prior to the start of the study, which was conducted between 1 May 2016 and 31 December 2017. Patients made three visits to their pulmonologist; all measurements were evaluated as change from baseline (visit 1, when patients switched from their current inhaler to Bufomix Easyhaler^®) to visit 3 (after 12 weeks’ treatment with Bufomix Easyhaler^®). The dose and dosing regimen were agreed between the patient and their pulmonologist at the first visit. The following doses (μg/inhalation of budesonide/formoterol) were used, according to the Bufomix Easyhaler summary of product characteristics (SPC) [23, 24]: 160/4.5 in patients with asthma receiving 2 × 1 inhalations per day or patients with COPD receiving 2 × 2 inhalations per day; 320/9 in patients with asthma receiving 2 × 1 or 2 × 2 inhalations per day or patients with COPD receiving 2 × 2 inhalations per day. Patients with ACO were treated in accordance with Global Initiative for Asthma (GINA) guidelines [2]. The daily dose, per patient, was the same across the whole study period.

Demographic data, spirometry, current medication and smoking history were recorded using asthma and COPD assessment forms, completed during each visit by recruiting physicians (see supplementary material).

Patients were identified based on their attendance at routine clinical appointments at widespread centers in Hungary that met Good Clinical Practice requirements. Eligible patients were adults (> 18 years old) with a physician-led diagnosis of asthma or COPD (according to GINA or Global Initiative for Chronic Obstructive Lung Disease therapeutic guidelines [2, 10]) or ACO (also according to GINA guidelines) and without an exacerbation in the 4 weeks prior to enrollment. Additionally, patients whose disease could not be controlled with pre-existing therapy, whose proficiency in the usage of the previously prescribed inhaler was unsatisfactory, or who did not feel comfortable with their device, were also eligible for this study. Patients were excluded from the study if they had a hypersensitivity to budesonide, formoterol or lactose or if they were pregnant or breastfeeding [16]. The study was approved by the National Scientific and Research Ethics Committee of Hungary.

All procedures were performed in accordance with the ethical standards of the National Scientific and Research Ethics Committee of Hungary (the study was approved by this body) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants included in the study prior to study commencement.

Primary outcomes were change in patient-reported outcome (PRO) measures after 12 weeks of treatment; PRO measures were assessed using the following co-primary end points: the Asthma Control Test (ACT) [25], mini-Asthma Quality of Life Questionnaire (mini AQLQ) [26], COPD Assessment Test (CAT) [27] and modified Medical Research Council dyspnea scale (mMRC) [28]. All other outcomes were assessed as secondary end points.

Disease control was assessed during each visit using either the ACT (ACT score ≤ 19 indicates poorly or not well controlled asthma) or the CAT (CAT score of > 20 indicates a high impact of COPD on their daily life); health-related quality of life (HRQoL) measures were assessed using the mini-AQLQ (mini-AQLQ score < 4 indicates very limited daily life due to asthma) and the mMRC (mMRC score > 1 indicates difficulty in walking due to breathlessness).

To evaluate the usage of a previous inhaler (if it existed) and the Bufomix Easyhaler^® in everyday life, patients received a previously validated questionnaire (e.g., how easy was it to learn, use, clean and inhale from the inhaler, how much the inhaler use helped in everyday activities such as sports, walking, etc., and patients’ perception/preference for their inhaler) [29]. This self-assessment was completed during all visits (Table 1). Additionally, patient satisfaction using a previous inhaler (if it existed) or the Bufomix Easyhaler^® was analyzed at visit one using closed questions scored on a six-point scale: one (very good) to six (unsatisfactory). Before the start of the study, participating pulmonologists were trained in how to use the Bufomix Easyhaler^® by Orion Pharma staff; physicians then showed individual patients how to handle the device at the first visit, according to the SPC [23, 24]. After training the patient in using the Bufomix Easyhaler^®, physicians were asked to assess the ease of use (through visits 1–3) and the time taken to teach the patient how to use the device (at visit 1) (Table S1). For patients whose disease could not be controlled with pre-existing therapy, or whose proficiency in the usage of their previous inhaler was unsatisfactory, pulmonologists assessed the use of the previous device by asking the same questions provided for the Bufomix Easyhaler^®.

Forced expiratory volume in 1 s (FEV₁) was determined using spirometry through visits 1–3 (measured as a pre-bronchodilator assessment), according to the American Thoracic Society/European Respiratory Society task force guidelines [30, 31] and expressed as FEV₁% predicted normal.

All questionnaires were provided in e-format case report forms (CRFs) by VIT Ltd., Hungary; scores were input into these CRFs by the pulmonologist at each visit after they read each question to the patient.

All statistical analyses were performed using SAS^® software, version 9.4 for Windows (SAS Institute Inc., Cary, NC, USA).

Overall, 1498 patients with obstructive airway disease were evaluated (asthma: n = 621; COPD: n = 778; ACO: n = 99). Baseline characteristics are summarized in Table 2. Patients with asthma were younger, with a mean age of 53.2 years [standard deviation (SD), 16.3], than those with COPD (mean age 64.1 years; SD, 9.9) and ACO (mean age 61.9 years; SD 10.6). Overall, patients had a mean FEV₁ % predicted of 62.2% (21.8). The majority of patients were female (60.4%), had a smoking history (59.0%) and were educated up to high school (88.9%).

At baseline (visit 1), 455 (30.4%) patients were new to inhaler use, and 1043 (69.6%) patients switched to the Bufomix Easyhaler^® from other inhalers. The three most commonly used inhalers were the Metered Dose Inhaler (MDI), Turbuhaler^® and Diskus^® (Fig. S1). At baseline, most of the 1498 participants had poorly controlled asthma or experienced a high impact of COPD on their daily life. Accordingly, 398 (64.1%) patients with asthma, 563 (72.4%) patients with COPD and 82 (82.8%) patients with ACO were using a maintenance medication at baseline.

After switching to the Easyhaler^® from other devices, significant improvement occurred in all groups of patients with asthma and COPD, including inhaler-naïve patients (Tables 3, 4). Patients with asthma had a mean (SD) ACT score of 14.2 (4.1) at baseline; disease control was significantly improved by visit 3 (p < 0.001), when the mean (SD) ACT score was 21.0 (2.7). By visit 3, 73.2% of all patients with asthma (asthma and ACO) had ‘well-controlled’ disease (Fig. 1a). Furthermore, a marked reduction in reliever inhaler use was observed at visit 3; 87.2% of all patients with asthma reportedly used their reliever inhaler no more than once a week compared with 32.2% of patients at visit 1 (Fig. 2).

Patients with COPD had a mean (SD) CAT score of 24.2 (5.7) at baseline. Disease control was significantly improved by visit 3 (p < 0.001) when the mean (SD) CAT score was 18.2 (5.1). By visit 3, 67.7% of all COPD patients (COPD and ACO) experienced low-medium disease impact on their QoL (CAT ≤ 20; Fig. 1b).

Overall, twelve weeks of treatment with the Bufomix Easyhaler^® resulted in a significant improvement in lung function (FEV₁% predicted). In total, mean (SD) FEV₁% predicted increased from 62.2% (21.8) at baseline to 69.9% (23.1) at visit 3 (p < 0.001). Similar improvements in lung function were observed in all patient groups; patients with asthma, COPD and ACO (Tables 3, 4). Most importantly, significant improvement in lung function was observed in patients who switched to the Bufomix Easyhaler^® from another inhaler.

Patients with asthma had a mean (SD) mini-AQLQ score of 3.8 (0.9) at baseline, indicating a moderate impairment of QoL from asthma. A significant improvement in mini-AQLQ score, indicating some impairment, was observed by visit 3 [5.2 (0.7); p < 0.001] (Table 3).

Patients with COPD had a mean (SD) mMRC score of 1.9 (0.9) at baseline, indicating that most patients walk more slowly than people of the same age because of breathlessness or must stop for breath when walking at their own pace. A significant improvement in the mMRC score was observed by visit 3 [1.2 (0.8); p < 0.001] (Table 4).

Patients were asked to describe their perceptions of different attributes of their current treatment from the multiple-choice questions (Table 1). Overall, patient satisfaction was higher for the Bufomix Easyhaler^® than for the other inhalers (Fig. 3). Furthermore, more than 90.0% of physicians described the Bufomix Easyhaler^® as easy to teach, with 98.9% of their patients having learned the technique within 10 min and 73.8% within 5 min of teaching (Fig. 4).