E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
ADULTS ASTHMATIC PATIENTS NOT ADEQUATELY CONTROLLED ON HIGH DOSES OF INHALED CORTICOSTEROIDS OR ON MEDIUM DOSE OF INHALED CORTICOSTEROIDS PLUS LONG-ACTING β2 AGONISTS |
|
E.1.1.1 | Medical condition in easily understood language |
NOT CONTROLLED ASTHMATIC PATIENTS |
|
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 | 14.1 |
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 |
|
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 show the superiority of CHF 1535 (BDP/FF) pMDI (800/24µg per day) over BDP HFA (Qvar®) pMDI (800µg per day) in terms of lung function considering change from baseline to the entire treatment period in average pre-dose morning PEF in adult asthmatic patients not adequately controlled on high doses of ICS or on medium dose of ICS+LABA. |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the effect of CHF 1535 pMDI on clinical outcome measures and other lung function parameters and to evaluate the safety and tolerability profile |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A subset of patients (15% of the randomised patients) will undergo a 24h serum cortisol evaluation. This assessment will take place during the 24h preceding V2 and during the 24h following V8. |
|
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 persistent asthma not optimally controlled (GINA 2010 ‘Management Approach Based on Control’) on high doses of ICS (1000-2000µg daily dose BDP non-extrafine or equivalent) or medium dose of ICS+LABA (500-1000µg daily dose BDP non-extrafine or equivalent plus formoterol 24 µg or salmeterol 100µg) at a stable dose for at least 4 weeks prior to screening.
4.Patients with a FEV1 ≥40% and <80% of patient’s predicted normal value and an absolute value of at least 0.9L, 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, defined as ΔFEV1 ≥12% and ≥200mL over baseline, within 30 minutes after administration of 400μg of salbutamol pMDI. In case this reversibility threshold is not met, the FEV1 reversibility test can be performed once before randomisation, after an appropriate wash-out from bronchodilators. Alternatively, a documented positive response to reversibility, as defined above, within the 3 months prior to the screening visit is acceptable.
6.Patients with not adequately controlled asthma evidenced by:
at least one of the following at any week in the 2 previous weeks (other than FEV1 <80% of the predicted normal value) must be present:
-daytime symptoms more than twice/week;
-any limitations of activities;
-nocturnal symptoms/awakening;
-need for reliever/rescue treatment more than twice/week.
and a score at the Asthma Control Questionnaire© (ACQ) >0.75.
Both of the above must be met at screening and at the end of the run-in period.
7.Presence of at least 7 available pre-dose morning PEF measurements in the run-in period.
8.Patients with a co-operative attitude and ability to be trained to correctly use the pMDI and a portable electronic peak flow meter.
9.For France only: only patients registered under a social welfare can be included in the study.
|
|
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.Seasonal (intermittent) asthma or asthma occurring only during episodic exposure to an allergen or a chemical sensitizer.
3.History of near fatal asthma or of a past hospitalisation for asthma in Intensive Care Unit or of frequent exacerbations (3 or more asthma exacerbations/ year) 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 asthma exacerbation in the 4 weeks prior to screening visit and during the run-in period.
5.Lower Respiratory Tract Infection in the 4 weeks before the screening visit.
6.History of cystic fibrosis, bronchiectasis or alpha-1 antitrypsin deficiency, or any other significant lung disease which may interfere with data evaluation.
7.Patients who suffer from COPD as defined by the current GOLD guidelines.
8.Current smokers or ex-smokers with total cumulative exposure equal or more than 5 pack-years and /or having stopped smoking one year or less prior to screening visit.
9.Any change in dose, schedule, formulation of ICS or ICS + LABAs in the 4 weeks prior to screening visit.
10.Patients being treated with anti-IgE antibodies.
11.Patients being treated with long acting anti-cholinergics (tiotropium).
12.Patients had used any of the following medications prior to screening visit and have not met the specified minimum wash-out period:
-short-acting β2-agonists: 6 hours,
-long-acting β2-agonists: 12 hours,
-fixed combinations of an anti-cholinergics and short-acting β2-agonist: 12
hours,
-short-acting anti-cholinergic: 12 hours,
-systemic corticosteroids: 4 weeks,
-slow release corticosteroids: 12 weeks.
13.Pregnant or lactating women or women at risk of pregnancy i.e. not using one or more of the following acceptable methods of contraception:
-surgical sterilization (e.g. bilateral tubal ligation, hysterectomy)
-hormonal contraception (implantable, injectable, patch, oral)
-double-barrier methods (any double combination of: IUD, male or female
condom with spermicidal gel, diaphragm, sponge, cervical cap)
(Post-menopausal women, i.e. women with at least 12 months of natural
(spontaneous) amenorrhea or at least 6 months of spontaneous
amenorrhea with documented serum follicle-stimulating hormone (FSH)
levels >40 mIU/mL, can be enrolled).
A serum pregnancy test will be performed at screening visit in women of childbearing potential.
14.Patients who have received an investigational drug within 2 months before screening visit.
15.Patients with a significant history or current evidence of heart failure, cardiomyopathy, coronary artery disease, myocardial infarction, severe uncontrolled hypertension, cardiac arrhythmias or any other significant cardiovascular disease which, in the judgement of the investigator, may place the patient at undue risk.
16.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.
17.Patients with a clinically significant abnormality at 12-lead ECG or presenting a QTcF interval value >450 msec in males or >470 msec in females.
18.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).
19.Patients mentally or legally incapacitated.
20.Patients with a history of alcohol or drug abuse.
21.Patients with known intolerance/hypersensitivity or contra-indication to treatment with β2-agonists, inhaled corticosteroids or propellant gases/excipients.
22.Patients with major surgery in the 3 months prior to screening visit and/or planned surgery during the trial.
23.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.
24.Patients treated with monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants, unless already taken at stable doses for at least 4 weeks before the screening visit and evidence of a normal QTc interval under these medications.
25.Patients who are receiving any therapy that could interfere with the study drugs according to investigator’s opinion.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline to the entire treatment period in average pre-dose morning PEF. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
PEF performed during all study period since V2(Week0 Randomisation visit) to V8 (study end) for a total of about 12weeks |
|
E.5.2 | Secondary end point(s) |
-Change from baseline in pre-dose morning FEV1 and FVC at each clinic visit.
-Change from baseline to each inter-visit period in average pre-dose morning PEF.
-Change from baseline to each inter-visit period and to the entire treatment period in:
-average pre-dose evening PEF and daily PEF variability;
-percentage of rescue-use free days;
-average use of rescue medication (number of puffs/day);
-average total day-time and night-time asthma symptom scores;
-percentage of asthma symptoms-free days;
-percentage of asthma control days (days without asthma symptoms and
rescue use).
-Change from baseline in ACQ score.
-Number of moderate / severe asthma exacerbations.
Safety end points:
- Adverse events and adverse drug reactions.
- Vital signs (heart rate, systolic and diastolic blood pressure).
- 12-lead ECG.
- Standard haematology and blood chemistry.
- Serum cortisol AUC0-24h and Cmin (in a subset of patients)
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
-PEF performed during all study period since V2(Week0 Randomisation visit) to V8 (study end) for a total of about 12 weeks.
-Pre-dose morning FEV1 and FVC evaluated at eache study visits (total of 8 evaluations)
- ACQ evaluated atV1, V2 and at V8
- Labs and ECG at V1 and V8
- Vital signs at all visits since V1
- Serum cortisol, where applicable, at V2 and at V8
- AE at all visits |
|
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 | 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 | 2 |
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 | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 84 |
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 |
Russian Federation |
Ukraine |
|
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
|
|
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 | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |