| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of a free combination of CHF 5259 (glycopyrrolate bromide [GB]) at 3 dose levels plus Foster 100/6 µg (fixed combination of beclomethasone dipropionate [BDP] plus formoterol [FF]) in a metered dose inhaler by comparison with Foster 100/6 µg in terms of FEV1 AUC0-12h normalised by time on Day 42. |
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| E.2.2 | Secondary objectives of the trial |
Key secondary objective
To evaluate the efficacy of the free combination CHF 5259 plus Foster 100/6 µg by comparison with Foster 100/6 µg in terms of Peak FEV1 on Day 42.
Secondary objectives
To evaluate the effect of the free combination of CHF 5259 plus Foster 100/6 µg on other lung function parameters and on clinical outcome measures.
To assess the safety and the tolerability of the study treatments
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Patient’s written informed consent obtained prior to any study-related procedures.
2.Male or female patients aged ≥18.
3.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
4.Patients with a pre-bronchodilator FEV1 ≥40% and <80% of their predicted normal value, after appropriate washout from bronchodilators, at screening and at the end of the run-in period.
5.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 ≥200mL over baseline.
Note: In case the reversibility threshold is not met, the test can be performed once before randomisation.
6.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).
7.Patients with a co-operative attitude and ability to be trained to correctly use the pMDI.
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| E.4 | Principal exclusion criteria |
1.Inability to carry out pulmonary lung function testing, to comply with study procedures or with study treatment intake.
2.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 place the patient at undue risk.
3.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.
4.Lower respiratory tract infection in the 4 weeks before the screening visit or during the run-in period.
5.Patients who are in therapy for gastroesophageal reflux disease (GERD) and/or patients with a medical history of GERD that leads to asthma symptoms.
6.Patients with a seasonal worsening of asthma and who cannot complete the study outside the relevant allergen season.
7.History of cystic fibrosis, bronchiectasis or alpha-1 antitrypsin deficiency, or any other significant lung disease which may interfere with data evaluation.
8.Patients who suffer from COPD as defined by the current GOLD guidelines.
9.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.
10.Any change in dose, schedule, formulation of ICS + LABAs in the 4 weeks prior to screening visit.
11.Patients used to be or being treated with inhaled long-acting antimuscarinic drugs.
12.Patients being treated with anti-IgE antibodies
13.Pregnant or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) UNLESS are using one or more reliable methods of contraception
14.Patients who have received an investigational drug within 2 months before screening visit.
15.Patients who have clinically significant cardiovascular condition according to investigator’s judgement
16.An abnormal and clinically significant 12-lead ECG that results in active medical problem which may impact the safety of the patient according to investigator’s judgement.
17.Patients whose electrocardiogram (12-lead ECG) shows QTcF >450 ms for males or QTcF >470 ms for females at screening or at randomisation visits.
18.Medical diagnosis of narrow-angle glaucoma, clinically relevant prostatic hypertrophy or bladder neck obstruction that, in the opinion of the investigator, would prevent use of anticholinergic agents.
19.Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration and, in the judgment of the investigator, would make the patient inappropriate for entry into this study, place the patients at undue risk or potentially compromise the results or interpretation of the study.
20.Patients having received a live-attenuated virus vaccination within two weeks prior to screening or during the run-in (inactivated influenza vaccination is acceptable provided it is not administered less than 48 hours prior to screening).
21.Patients mentally or legally incapacitated.
22.Patients with a history of alcohol or drug abuse.
23.Patients with known intolerance/hypersensitivity or contra-indication to treatment with ß2-agonists, inhaled corticosteroids, anti-cholinergics or propellant gases/excipients.
24.Patients with major surgery in the 3 months prior to screening visit and/or planned surgery during the trial.
25.Patients treated with non-potassium sparing diuretics (association with potassium sparing diuretics is allowed), non-selective beta-blocking drugs, quinidine, quinidine-like anti arrhythmics, or any medication with a QTc prolongation potential or a history of QTc prolongation.
26.Patients treated with monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants.
27.Patients who are receiving any therapy that could interfere with the study drugs according to investigator’s opinion.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| FEV1 AUC0-12h normalised by time (FEV1 AUC0-12h absolute value / 12 hours) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Change from Baseline in Peak FEV1
Safety (Adverse Events and Adverse Drug Reactions)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Day 42 for peak FEV1 and across the study for the safety |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Last follow up phone contact, 1 week after Visit 10 |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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