| 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 | 14.0 |
| 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 that CHF 1535 50/6 μg pMDI (daily dose: BDP 200 μg/FF 24 μg) is superior to the corresponding monotherapy with beclomethasone dipropionate 50 μg pMDI (daily dose: BDP 200 μg) and non-inferior relative to the corresponding free combination of beclomethasone dipropionate 50 μg pMDI (daily dose: BDP 200 μg) plus formoterol fumarate 6 μg pMDI (daily dose: FF 24 μg) (all treatments administered via the AeroChamber Plus™ spacer device) in terms of pulmonary function (change from baseline in pre-dose morning FEV1 after a 12-week treatment period) in children patients with “partly controlled” persistent asthma |
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| E.2.2 | Secondary objectives of the trial |
- To evaluate the effect of the treatments on additional lung function parameters and on clinical outcome measures;
- To assess the safety and the tolerability of the administered treatments |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent obtained from the parents/legal representatives (according to the local regulation) and written or verbal assent by the patient (when appropriate) prior to any study related procedures.
For France: only patients registered under a social welfare can be included in the study.
2. Prepuberal male and female outpatients, aged ≥ 5 and < 12 years in Tanner stages I and II according to Investigator's assessment.
3. Clinical diagnosis of asthma (GINA revised 2009) at least six months prior to screening visit.
4. Evidence of “partly controlled” asthma during the 2-week run-in period defined as following (GINA revised 2009), i.e. at least one of the following:
- daytime symptoms more than twice/week,
- any limitations of activities,
- any nocturnal symptoms / awakening,
- need for reliever/rescue treatment more than twice a week.
5. Treated with inhaled β2-agonists as required.
6. Symptomatic asthmatic patients treated with inhaled beclomethasone dipropionate (BDP) up to 400 μg or equivalent at a stable dose for at least 4 weeks prior to screening visit.
Equivalence to:
BDP non-extrafine ≤ 400 μg
BDP extrafine ≤ 200 μg
Budesonide ≤ 400 μg
Ciclesonide ≤ 320 μg
Flunisolide ≤ 1250 μg
Fluticasone ≤ 500 μg
Mometasone ≤ 400 μg
Triamcinolone ≤1200 μg
Patients under combination ICS-LABA or ICS-LTRA can enter into the study at the corresponding ICS dose, according to GINA guidelines (i.e. maximum 200 μg of non-extrafine BDP or equivalent).
7. A documented positive response to the reversibility test, defined as ΔFEV1 ≥ 12% over baseline, 15 minutes after 400 μg salbutamol pMDI via a Volumatic™ spacer device (ATS/ERS taskforce 2005) within 6 months prior to the screening must be provided. If not available, this test must be done at screening.
8. Forced Expiratory Volume during the first second (FEV1) ≥ 60% and ≤ 95% of predicted normal values at the screening visit and at the randomisation visit.
9. A cooperative attitude/ability and physical capacity to use a pMDI and a spacer device and perform lung functions. |
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| E.4 | Principal exclusion criteria |
1. Patients with two or more admissions to hospital for asthma exacerbation in the past 12 months or any admission to intensive care ever.
2. Any concomitant disease requiring additional treatment with systemic glucocorticosteroids.
3. Regular use of anticholinergics.
4. Allergy to one component of medications used.
5. Intolerance or contra-indication to treatment with β2-agonists and/or inhaled corticosteroids.
6. Having received an investigational drug within 2 months before the current study.
7. Patients and/or parents unlikely to comply with the study protocol or unable to understand the nature and scope of the study or the possible benefits or unwanted effects of the study treatments.
8. Occurrence of acute asthma exacerbations or lower respiratory tract infections in the 4 weeks preceding the screening visit or during the run-in period.
9. History of cystic fibrosis, bronchiectasis, primary ciliary dyskinesia, bronchopulmonary dysplasia, or previous premature children with less than 36 weeks of gestational age.
10. History of near fatal asthma (e.g. brittle asthma, hospitalisation for asthma exacerbation in Intensive Care Unit).
11. Diagnosis of restrictive lung disease.
12. Significant medical history and/or treatments for cardiac, renal, neurological, hepatic, endocrine diseases, or any laboratory abnormality indicative of a significant underlying condition, that may interfere with patient’s safety, compliance, or study evaluations, according to the investigator’s opinion.
13. QTc interval (Fridericia’s formula) higher than 450 msec (for boys) and 470 msec (for girls) at screening visit and randomisation visit.
14. Current smokers. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline to end of treatment (Week 12, V5) in pre-dose morning FEV1 (L). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| V2 (week 0) and V5 (week 12) |
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| E.5.2 | Secondary end point(s) |
- change from baseline in pre-dose morning FEV1 and FVC at each clinic visit;
- mean change from baseline in pre-dose morning FEV1 and FVC;
- change from baseline in pre-dose morning and evening PEF (measured with electronic manual spirometer);
- change from baseline in daily PEF variability;
- change from baseline in daytime and night-time asthma symptom scores;
- change from baseline in percentage of symptom-free days;
- change from baseline in daytime and night-time use of rescue salbutamol (number of inhalations);
- change from baseline in percentage of rescue salbutamol-free days;
- change from baseline in percentage of asthma control days.
- change from baseline in Standardised Paediatric Asthma Quality of Life Questionnaire (PAQLQ(S)) score;
- number of asthma exacerbations, number of patients with asthma exacerbations and asthma exacerbation rate;
- FeNO parameter expressed as percentage of baseline (as explorative evaluation in a subgroup of 10% of patients in pre-selected centres).
- Adverse events and adverse drug reactions.
- Heart rate, systolic and diastolic blood pressure in sitting position, pre-dose (V1 to V5) and 30 min post-dose at each visit (V2 to V5).
- Standard haematology and blood chemistry at V2 and V5.
- 12-lead ECG (including QTc interval corrected by Fridericia’s formula), pre-dose at V1, pre-dose and 30 min post-dose at V2 and V5.
- 12-hour overnight urinary free cortisol/creatinine ratio at V2 and V5. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy end points will be evaluated at study visits according to the schedule of assessment reported in the study protocol.
PAQLQ, Routine haematology and blood chemistry and FeNO test will be evaluated at V2 (week =) and V5 (week12).
12-lead ECG will be evaluated at V1 (week -2), V2 (week 0) and V5 (week 12) |
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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 | Yes |
| 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 |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 79 |
| 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 |
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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
|
| Last Visit of the Last Subject |
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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 | 2 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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