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.

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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).

Inclusion criteria

For inclusion into the study, patients were required to fulfil all of the following criteria:

• Patient's written informed consent obtained prior to any study-related procedures;
• Male or female patients aged ≥18;
• Patients with uncontrolled asthma on medium doses of ICS+LABA (>500-1000 μg daily dose BDP non-extrafine or equivalent plus formoterol 24 μg or salmeterol 100 μg) at a stable dose for at least 4 weeks prior to Screening; Drug* Medium daily dose BDP non-extrafine >500 - 1000 μg BDP extrafine >250 - 500 μg Budesonide >400 - 800 μg Ciclesonide >160 - 320 μg Fluticasone >250 - 500 μg Mometasone ≥400 μg - < 800 μg

*In this table (adapted from GINA 2012) the recommendations for doses of inhaled glucocorticosteroids are given as "μg/day budesonide or equivalent"

• Patients with a pre-bronchodilator FEV1 ≥40% and <80% of their predicted normal value, after appropriate wash-out from bronchodilators, at Screening and at the end of the run-in period;
• Patients with a positive response to the reversibility test at Screening within 30 minutes after administration of 400 μg of salbutamol pMDI, defined as ΔFEV1 ≥12% and ≥200 mL over Baseline; Note: In case the reversibility threshold is not met, the test can be performed once before randomisation.
• Patients with uncontrolled asthma evidenced by a score at the Asthma Control Questionnaire® (ACQ) ≥1.5 (criterion must be met at Screening and at the end of the run-in period);
• Patients with a co-operative attitude and ability to be trained to correctly use the pMDI.

At pre-Screening visit (V0) the patient's written informed consent (criterion 1) was obtained and then at the Screening visit (V1), all the above-mentioned inclusion criteria were checked. At the Randomisation visit (Visit P1D1 [V2]), the following inclusion criteria were re-checked: 4, 6 and 7.

Exclusion criteria

Patients were not enrolled if one or more of the following criteria were present:

• Inability to carry out pulmonary lung function testing, to comply with study procedures or with study treatment intake;
• History of near fatal asthma or of a past hospitalisation for asthma in intensive care unit or of frequent exacerbations which, in the judgement of the Investigator, may have placed the patient at undue risk;
• Hospitalisation, emergency room admission or use of systemic corticosteroids for asthma exacerbation in the 4 weeks prior to Screening visit and during the run-in period;
• Lower respiratory tract infection in the 4 weeks before the Screening visit or during the run-in period;
• Patients who were in therapy for gastroesophageal reflux disease (GERD) and/or patients with a medical history of GERD that led to asthma symptoms;
• Patients with a seasonal worsening of asthma and who were not able to complete the study outside the relevant allergen season;
• History of cystic fibrosis, bronchiectasis or alpha-1 antitrypsin deficiency, or any other significant lung disease which may have interfered with data evaluation;
• Patients who suffered from COPD as defined by the current Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines;
• Current smokers or ex-smokers with total cumulative exposure equal or more than 10 pack-years and /or having stopped smoking one year or less prior to Screening visit;
• Any change in dose, schedule, formulation of ICS + LABAs in the 4 weeks prior to Screening visit;
• Patients used to be or treated with inhaled long-acting antimuscarinic drugs;
• Patients treated with anti-IgE antibodies;
• Pregnant or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) UNLESS were using one or more of the following reliable methods of contraception:

• Placement of an intra uterine device (IUD) or intra uterine system (IUS);
• Hormonal contraception (implantable, patch, oral);
• Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical vaults/caps) with spermicidal foam/gel/film/cream/suppository. Reliable contraception was maintained throughout the study. Pregnancy tests were performed at study entry (a serum one at Screening visit and a urine one at Screening and Randomisation visits) in all women of childbearing potential. Any postmenopausal women (physiologic menopause defined as "12 consecutive months of amenorrhea") or women permanently sterilized (e.g. tubal occlusion, hysterectomy or bilateral salpingectomy) were allowed to be enrolled in the study.
• Patients who have received an investigational drug within 2 months before Screening visit;
• Patients who had clinically significant (CS) cardiovascular condition according to Investigator's judgement, such as but not limited to: congestive heart failure (New York Heart Association [NYHA] class >3), acute ischemic heart disease in the last year prior to study Screening, history of sustained cardiac arrhythmias or sustained and nonsustained cardiac arrhythmias diagnosed in the last 6 months (sustained means lasting more than 30 seconds and or ending only with external action, and or leads to hemodynamic collapse; non-sustained means > 3 beats < 30 seconds, and or ending spontaneously, and or asymptomatic), impulse conduction blocks. Similarly, patients affected by permanent or paroxysmal atrial fibrillation were not considered for enrolment;
• An abnormal and CS 12-lead electrocardiogram (ECG) that resulted in active medical problem which may have impacted the safety of the patient according to Investigator's judgement;
• Patients whose electrocardiogram (12-lead ECG) showed Fridericia-Corrected QTc (QTcF) >450 millisecond (ms) for males or QTcF >470 ms for females at Screening or at Randomisation visits;
• Medical diagnosis of narrow-angle glaucoma, clinically relevant prostatic hypertrophy or bladder neck obstruction that, in the opinion of the Investigator, would have prevented use of anticholinergic agents;
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may have increased the risk associated with study participation or study drug administration and, in the judgment of the Investigator, would have made the patient inappropriate for entry into this study, placed the patients at undue risk or potentially compromised the results or interpretation of the study;
• Patients having received a live-attenuated virus vaccination within two weeks prior to Screening or during the run-in (inactivated influenza vaccination was acceptable provided it was not administered less than 48 hours prior to Screening);
• Patients mentally or legally incapacitated;
• Patients with a history of alcohol or drug abuse;
• Patients with known intolerance/hypersensitivity or contra-indication to treatment with ß2-agonists, inhaled corticosteroids, anti-cholinergics or propellant gases/excipients;
• Patients with major surgery in the 3 months prior to Screening visit and/or planned surgery during the trial;
• Patients treated with non-potassium sparing diuretics (association with potassium sparing diuretics was allowed), non-selective β-blocking drugs, quinidine, quinidine-like anti arrhythmics, or any medication with a QTc prolongation potential or a history of QTc prolongation;
• Patients treated with monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants;
• Patients who were receiving any therapy that could have interfered with the study drugs according to Investigator's opinion.

At the Screening visit (V1), all the above-mentioned exclusion criteria were checked. At the Randomisation visit (Visit P1D1 [V2], the following exclusion criteria were re-checked: 1, 3, 4, 5, 13, 16, 17, 19, 20, 24 and 27.