Triple in Asthma Dose Finding

This was a dose-finding, phase II, multicentre, randomised, double-blind, active-controlled, 3-way cross-over of 6 weeks, balanced incomplete block and multiple dose study. Since each patient serves as his/her own control, the cross-over design reduces the effect of potentially confounding variables and allows for greater statistical power with fewer subjects. This study was designed to evaluate the efficacy of a free combination of CHF 5259 at 3 dose levels (25 μg, 50 μg or 100 μg daily) plus Foster vs. Foster alone, administered via pMDI over a 6-week treatment period in patients with uncontrolled asthma. A total of 220 patients were targeted for randomisation to ensure that a minimum of 164 completed the study (assuming an estimated non-evaluable rate of 25%). There were 4 treatments, but as it was a cross-over incomplete block design, each patient took only 3 treatments out of 4, according to the randomisation list of sequences: A-C-B; B-D-C; C-A-D and D-B-A. . The four treatments were: * Treatment A = CHF 5259 (GB 25 μg/day) plus Foster (BDP 400/FF 24 μg/day); * Treatment B = CHF 5259 (GB 50 μg/day) plus Foster (BDP 400/FF 24 μg/day); * Treatment C = CHF 5259 (GB 100 μg/day) plus Foster (BDP 400/FF 24 μg/day); * Treatment D = Foster (BDP 400/FF 24 μg/day) alone. Foster was used during the study as the control despite an indication in "patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled rapid-acting β2-agonist" (and not in patients with uncontrolled asthma). No risks for the patients were foreseen owing to the short study duration (6 weeks), the possibility of using salbutamol as rescue medication and the close medical monitoring during the entire study period. The Foster dose (400/24 μg daily) for the run-in and wash-out periods was selected as this is a standard dosing regimen marketed for the use of Foster in the treatment of asthma. This study comprised a total of 11 visits and a follow-up phone call: * A Pre-Screening visit (Visit 0 \[V0\]), carried out in order to fully explain the study to potential patients, to obtain their written informed consent and to instruct them on Screening visit procedures (such as fasting and medication restrictions). This visit occurred one week maximum prior to the Screening visit.A Screening visit (V1), carried out to establish the eligibility of patients for inclusion in the study and to instruct them on study procedures (such as fasting, medication restrictions, recognition of asthma exacerbations and use of the pMDI device, of the e-diary and of the e-peakflow meter). This visit was followed by a 2-week (±2 days) open-label run-in period on Foster. A 2-week run-in period on Foster prior to randomisation was deemed sufficient to standardise the patient population on the same concomitant treatment without leading to a deterioration of the disease. * An investigational phase, which lasted approximately 21 weeks and comprised 3 treatment periods (Period \[P\] 1, P2 and P3) of 6 weeks each (±2 days) separated by an open-label wash-out period of 1 week on Foster. Each 6-week treatment period allowed for adequate assessment of efficacy variables. Each treatment period comprised 3 visits (Day \[D\] 1, Day 14 and Day 42) during which efficacy and safety assessments were performed. Patients were also re-instructed on study procedures. Patients underwent the following visits: * A Randomisation visit at Visit P1D1 (V2); * Eight subsequent visits: Day 1 of the second and third treatment period (day of the first dosing): Visit P2D1 (V5) and Visit P3D1 (V8); Day 14 of each treatment period: Visit P1D14 (V3), Visit P2D14 (V6) and Visit P3D14 (V9); Day 42 of each treatment period (day of last dosing): Visit P1D42 (V4), Visit P2D42 (V7) and Visit P3D42 (V10). These visits were followed by a 1-week wash-out period with Foster. • A safety follow-up phone call was made one week after Visit P3D42 (V10) (or 1 week after the last dose intake and/or last visit in case of premature discontinuation of the patient) to check any unresolved or new adverse events (AEs)/serious adverse events (SAEs).