Health & Medical Lung Health

Beclomethasone/Formoterol vs Fluticasone/Salmeterol in COPD

Beclomethasone/Formoterol vs Fluticasone/Salmeterol in COPD

Methods

Patients


This study was carried out in 76 outpatient respiratory clinics throughout Europe and included patients aged ≥ 40 years with a diagnosis of moderate to severe COPD. Inclusion criteria were: smoking history ≥ 10 pack years; regular bronchodilator use in the previous 2 months; post-bronchodilator forced expiratory volume measured in the first second (FEV1) < 60% of predicted; post-bronchodilator FEV1/forced vital capacity (FVC) < 0.7; an increase in FEV1 ≥ 5% from baseline following administration of 400 μg of salbutamol; a Baseline Dyspnoea Index (BDI) focal score ≤ 10 at the screening and randomisation, and a history of ≤ one COPD exacerbation treated with antibiotics or systemic corticosteroids in the previous 12 months. Patients were excluded if they had been diagnosed with asthma, other respiratory disorders, or any other clinically relevant condition that could have interfered with the evaluation of results.

The study was performed in accordance with the principles of the Declaration of Helsinki and with the Good Clinical Practice guidelines recommended by the International Conference on Harmonization of Technical Requirements. The protocol was approved by the Institutional Review Board of each centre (a list is shown in Additional file 1), and informed written consent was obtained from each participant prior to study entry.

Study Design


This was a randomised, double-blind, double-dummy, 2-arm parallel group study. After a screening visit, patients entered a 2-week run-in period, where they received inhaled ipratropium bromide (Atrovent® Inhaler CFC-Free 20 μg) as maintentance treatment administered 4 times/day. Patients were then randomised to a 12-week treatment period with either extrafine BDP/FF 100/6 μg in a hydrofluoralkane pressurised metered dose inhaler (pMDI; FOSTER®, Chiesi Farmaceutici, Parma, Italy) or FP/S 500/50 μg, in a dry-powder inhaler (DPI; Seretide®, Accuhaler® GlaxoSmithKline, Middlesex, UK). Randomization was performed according to a pre-determined balanced-block, computer generated, randomisation list stratified by country. BDP/FF was administered as two puffs twice daily (daily dose 400 μg BDP/24 μg FF), while FP/S was administered as one inhalation twice daily (daily dose 1000 μg FP/100 μg S). Clinic visits were performed at monthly intervals. Inhaled rescue salbutamol use was permitted during the whole study period (including run-in), but no other COPD medications were permitted.

Protocol Outcome Measures


The two co-primary efficacy variables were Transition Dyspnoea Index (TDI) score at the end of the study (week 12), and Area Under the Curve (AUC0–30min) standardized by time of change from pre-dose in FEV1 after drug inhalation during the morning of baseline visit. In order to demonstrate the equivalence between BDP/FF and FP/S in terms of TDI, dyspnoea was assessed at baseline with the Baseline Dyspnoea Index (BDI) score and by TDI score at week 12. Pulmonary function tests (PFTs) were performed, in accordance with ATS/ERS standards, at the screening visit before (pre-bronchodilator) and after (post-bronchodilator) salbutamol inhalation and at each clinic visit. At baseline and week 12, PFTs were performed before study drug inhalation (pre-dose) and then 5, 15 and 30 minutes after (post-dose). At week 4 and 8, spirometry was performed at pre-dose only. PFTs were all performed at least 12 hours after the previous evening dose and 6 hours after previous salbutamol use. Each site was provided with the same spirometer FlowScreen® CT that directly transferred PFTs values to the e-CRF.

A diary card was used each morning at home to record COPD symptom scores, the number of inhalations of study medication (run-in medication included) and salbutamol use; the diary card is shown in Additional file 1. Symptoms assessed with the diary card included ability to perform usual daily activities, breathlessness, night waking caused by respiratory symptoms, breathlessness on rising, cough and sputum production; each was assigned a score ranging from 0 (no symptoms) to 3 (worst), giving a maximum total score of 18/day; this questionnaire has been used previously in a COPD clinical trial, but has not been formally validated for this purpose.

Occurrence of COPD exacerbations and adverse events were evaluated by the Investigator at all visits, by diary review and asking the patient. Health status was assessed using the St. George's Respiratory Questionnaire (SGRQ) at baseline and at week 12. All patient-reported outcomes were gathered pre-dose in the morning. The six-minute walking test (6MWT) was carried out following ATS guidelines at pre-dose and post-dose, both at baseline and week 12.

Statistics


Data are expressed as mean and standard deviation (SD), unless otherwise specified. The study was powered to detect a mean difference between treatments of 0.080 L in the AUC0–30min standardized by time of change from pre-dose in FEV1 at baseline visit, assuming a SD of 0.16 L and using a two-sample t-test with two-sided significance level of 0.05 (further details are in Additional file 1). Superiority for AUC0–30min was demonstrated if the two-sided 95% confidence interval (CI) for the adjusted mean difference between the two drugs lied entirely above 0. Equivalence in TDI score was demonstrated if the two-sided 95% CI for the adjusted mean difference lied entirely within the equivalence margins fixed at ± 1, assuming the true mean difference in TDI score between treatments is 0 and the standard deviation is 2.7.

For all parameters, the analysis of covariance, with treatment and country as factors, and baseline value (pre-dose at randomisation visit) as a linear covariate, was applied. All analyses were performed with SAS™ System (SAS Institute Inc, Cary, NC), version 9.2. Statistical significance was set at 0.05 two tailed, and all analyses were performed on the intention-to-treat population (ITT). Imputation of missing data was completed following last observation carried forward method for post-baseline data. According to the current indication for ICS/LABA use in COPD, a pre-defined analysis was performed in patients with FEV1 < 50% of predicted for all efficacy variables.

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