| 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 | 20.0 |
| 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 demonstrate the superiority of CHF 5993 200/6/12.5 pMDI compared to CHF 1535 200/6 pMDI in terms of change from baseline in pre-dose FEV1 at Week 26.
- To demonstrate the reduction of moderate and severe asthma exacerbations rate with CHF 5993 200/6/12.5 pMDI compared to CHF 1535 200/6 pMDI during the entire 52-week treatment period.
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| E.2.2 | Secondary objectives of the trial |
Key Secondary Objectives:
- To demonstrate the superiority of CHF 5993 200/6/12.5 pMDI compared to CHF 1535 200/6 pMDI in terms of change from baseline in peak FEV1 within 3 hours post-dose at Week 26.
- To demonstrate the superiority of CHF 5993 200/6/12.5 compared to CHF 1535 200/6 in terms of change from baseline in morning PEF averaged over 26-week treatment period.
- To demonstrate the reduction of severe asthma exacerbations rate with CHF 5993 200/6/12.5 pMDI compared to CHF 1535 200/6 pMDI during the entire 52-week treatment period in the pooled analysis of CCD-05993AB1-03 and CCD-05993AB2-02 trials.
Safety Objective:
- To assess the safety and 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 greater than or equal to 18 and ≤75 years.
3. Patients must have a documented history of asthma for at least 1 year and asthma must have been diagnosed before the patient’s age of 40.
4. Patients with uncontrolled asthma with double therapy only on high doses of ICS (>1000 daily dose BDP non-extrafine or estimated clinical comparable dose) in combination with a β2 long-acting bronchodilator (LABA) at a stable dose for at least 4 weeks prior to screening. LABA daily dose: patients under formoterol 24 μg or salmeterol 100 μg or vilanterol 25 µg or other approved dose of LABA as clinically comparable to the others in the list can be included.
5. Patients with a pre-bronchodilator FEV1 <80% of their predicted normal value, after appropriate washout from bronchodilators, at the screening and randomization visits.
6. Patients with a positive response to a reversibility test at screening, defined as ΔFEV1>12% and >200mL over baseline 10-15 minutes after inhaling 400 μg of salbutamol pMDI.
7. Patients with uncontrolled asthma evidenced by a score at the Asthma Control Questionnaire 7 © (ACQ-7) ≥1.5 (this criterion must be met at screening and at the end of the run-in period).
8. A documented history of one or more asthma exacerbations requiring treatment with systemic corticosteroids or emergency department visit or in-patient hospitalization in the previous 12 months.
9. A co-operative attitude and ability:
- to be trained to correctly use the pMDI inhalers;
- to perform all trial related procedures including technically acceptable pulmonary function tests;
- to correctly use the electronic diary/peak flow meter.
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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. Run-in compliance < 50% at randomisation.
3. History of near fatal asthma or of a past hospitalisation for asthma in intensive care unit which, in the judgement of the investigator, may place the patient at undue risk.
4. Hospitalisation, emergency room admission or use of systemic corticosteroids for an asthma exacerbation in the 4 weeks prior to screening visit or during the run-in period.
5. Patients with any asthma exacerbation or respiratory tract infection in the 4 weeks prior to the screening visit or during run-in period.
6. Any change in dose, schedule or formulation of the combination ICS plus LABA in the 4 weeks prior to screening visit.
7. Patients using systemic corticosteroid medication in the 4 weeks prior to screening or slow release corticosteroids in the 12 weeks before screening.
8. Patients who suffer from COPD as defined by the current GOLD guidelines.
9. History of a diagnosis of cystic fibrosis, bronchiectasis or alpha-1 antitrypsin deficiency, or any other significant lung disease which may interfere with study evaluations.
10. Current smokers or ex-smokers with total cumulative exposure equal or more than 10 pack-years or having stopped smoking one year or less prior to screening visit.
11. Patients who have clinically significant cardiovascular condition according to investigator’s judgement
12. 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.
13. Patients whose electrocardiogram (12-lead ECG) shows QTcF >450 ms for males or QTcF >470 ms for females at screening or at randomisation visits (criterion not applicable for patient with pacemaker or permanent atrial fibrillation).
14. Patients with a medical history or current diagnosis of narrow-angle glaucoma, symptomatic prostatic hypertrophy, urinary retention bladder neck obstruction that, in the opinion of the investigator, would prevent use of anticholinergic agents.
15. Other severe acute or chronic medical or malignancy or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
16. Patients having received a vaccination within 2 weeks prior to screening or during the run-in.
17. Patients mentally or legally incapacitated, or patients accommodated in an establishment as a result of an official or judicial order.
18. Patients with a history of alcohol or drug abuse within two years prior to the start of the study.
19. Patients with known intolerance/hypersensitivity or contra-indication to treatment with ß2-agonists, inhaled corticosteroids, anticholinergics or propellant gases/excipients.
20. Patients with major surgery in the 3 months prior to screening visit or planned surgery during the trial.
21. Patients treated with non-potassium sparing diuretics (unless administered as a fixed-dose combination with a potassium conserving drug or changed to potassium sparing before the screening), non-selective beta-blocking drugs, quinidine, quinidine-like anti arrhythmics, or any medication with a QTc prolongation potential or a history of QTc prolongation.
22. Patients treated with monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants.
23. Patients being treated with monoclonal antibodies (e.g. anti-IgE or anti-IgG antibodies) or biological drugs.
24. Patients who are receiving any therapy that could interfere with the study drugs according to investigator’s opinion.
25. Pregnant or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) unless are willing to use one or more highly effective contraceptive measures.
26. Patients who have received an investigational drug within 2 months or six half-lives (whichever is greater) prior to screening visit, or have been previously randomized in this trial, or are currently participating in another clinical trial.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- Change from baseline in pre-dose FEV1 at Week 26
- Moderate and severe exacerbations rate over 52 weeks of treatment |
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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 (within 3 hours post dosing) at Week 26.
- Change from baseline in morning PEF measured by patients at home over the 26-week treatment period.
- Severe exacerbations rate over 52 weeks of treatment in a pre-specified pooled analysis of the two pivotal studies CCD-5993AB1-03 and CCD-05993AB2-02
- Safety variables, AEs, ADRs |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
26 weeks and 52 weeks
Safety throughout the study |
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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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Treatment arms A and B are double-blind; Treatment arm C is open-label |
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| 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 | 3 |
| 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 | 34 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 162 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Belarus |
| Bulgaria |
| Czech Republic |
| Germany |
| Hungary |
| Italy |
| Lithuania |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Slovakia |
| Spain |
| Turkey |
| Ukraine |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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