| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe symptomatic asthmatic patients aged ≥ 12 years under treatment with inhaled corticosteroids (< 2000 µg BDP or equivalent). |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
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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 via NEXT™DPI (beclomethasone dipropionate + formoterol fumarate 100 + 6 μg), 1 inhalation or 2 inhalations twice daily, for 12 weeks is non-inferior to the corresponding dose of CHF 1535 via HFA-134a “extrafine” pMDI in terms of pulmonary function (change from baseline in pre-dose morning FEV1) in moderate to severe symptomatic asthmatic patients aged ≥ 12 years under treatment with inhaled corticosteroids (< 2000 µg BDP or equivalent). |
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| E.2.2 | Secondary objectives of the trial |
• To show that CHF 1535 via NEXT™ DPI and CHF 1535 via HFA-134a “extrafine” pMDI 2 inhalations twice daily are superior to the corresponding CHF 1535 via NEXT™ DPI and CHF 1535 via HFA-134a “extrafine” pMDI 1 inhalation twice daily in terms of pre dose morning FEV1.
• To evaluate the effect of the CHF 1535 via NEXT™ DPI compared to CHF 1535 via HFA-134a “extrafine” pMDI on other lung function parameters, on clinical outcome measures, on safety and tolerability
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| 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 |
There is 3 sub-studies included in the protocol (not all site will participate in the sub-studies)
- at Visit 2 and Visit 5, spirometry will be performed post-dose at 10, 30 minutes and 1, 2, 3, 4, 6 and 8 hours post-dose in a subgroup of about 30% of subjects.
- 24-hours urinary cortisolassessments (at Visit 2 and Visit 5) (in a subgroup of about 30% of patients from pre-selected sites): urine collection will be done during the night preceding the visits. The urine should be kept by the patient in a refrigerator until the 24-hours collection is completed. Sample preparation, storage and shipping will be performed according to specific procedures provided by the central laboratory.
- the induced sputum eosinophils assessments (at Visit 2 and Visit 5) (in a subgroup of about 30% of patients) will be performed locally following the procedures described in protocol |
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| E.3 | Principal inclusion criteria |
1. Written informed consent obtained from the patient and/or the parents/legal representatives (according to the local laws)
2. Outpatients of both sexes, aged ≥ 12 years
3. Clinical diagnosis of moderate to severe symptomatic asthma treated with a stable daily dose of inhaled corticosteroids < 2000 µg BDP or equivalent for at least 4 weeks prior to inclusion.
4. Forced expiratory volume in the first second (FEV1) > 40% and < 80% of the predicted normal values following adequate wash-out from bronchodilators.
5. A documented positive response to the reversibility test at the screening visit, defined as ΔFEV1 ≥ 12% and ≥ 200 mL over baseline, 30 minutes after 400 μg salbutamol pMDI (ATS/ERS taskforce 2005).
6. Evidence for “partly controlled” asthma in the 2 weeks before inclusion according to the Classification of Asthma Severity and Levels of Asthma Control of the Global Strategy for Asthma Management and Prevention (GINA revised 2006) i.e. one or more of the following, other than FEV1 < 80% of the predicted normal value:
•daytime symptoms more than twice / week;
•any limitations of activities or nocturnal symptoms / awakening;
•need for reliever/rescue treatment more than twice / week.
7. Patients free of long-acting β2-agonists (LABAs) treatment at least for 2 weeks before the screening visit;
8. Daily dose of previous inhaled corticosteroids (ICS) treatment:
•< 2000 µg of CFC BDP or “non-extrafine” BDP
•< 800 µg of BDP “extrafine” HFA
•< 1600 µg of budesonide
•< 1000 µg of fluticasone
•< 2000 µg of flunisolide
•<1200 µg of mometasone
•< 1280 µg of ciclesonide
9. A minimum inspiratory flow ≥ 40 L/min evaluated with the In-Check Oral (at Visit 1).
10. Non-smokers or ex smokers with a cumulative tobacco exposure less than 5 pack years and who have stopped smoking since more than 1 year.
11. A cooperative attitude and ability to be trained in the proper use of a pMDI and a NEXT™DPI.
12. At visit 2 the “partly controlled” asthma will be checked with the Asthma Control Questionnaire to check symptoms in the last 7 days (ACQ score ≥ 1.5).
Evidence for “partly controlled” asthma in the 2 weeks run-in period according to the Classification of Asthma Severity and Levels of Asthma Control of the Global Strategy for Asthma Management and Prevention (GINA revised 2006) i.e. one or more of the following, other than FEV1 < 80% of the predicted normal value:
•daytime symptoms more than twice / week;
•any limitations of activities or nocturnal symptoms/awakening
•need for reliever/rescue treatment more than twice / week. |
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| E.4 | Principal exclusion criteria |
1. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive urinary β-HCG laboratory test (> 5 IU/ml)
2. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they meet the following definition of post-menopausal:
•12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/ml
•or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy
•or are using one or more of the following acceptable methods of contraception: surgical sterilization (e.g., bilateral tubal ligation), hormonal contraception (implantable, patch, oral), and double-barrier methods (any double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap). For females aged 12 to 17 years acceptable methods of contraception may include total abstinence at the discretion of the investigator. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Reliable contraception should be maintained throughout the study and for 30 days after study drug discontinuation.
3. Significant seasonal variation in asthma or asthma occurring only during episodic exposure to an allergen or a chemical sensitizer;
4. History of near fatal asthma (e.g. brittle asthma, hospitalisation for asthma exacerbation in Intensive Care Unit);
5. Occurrence of asthma exacerbations or respiratory tract infections in the 6 weeks preceding the screening visit;
6. Diagnosis of Chronic Obstructive Pulmonary Disease (COPD) as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (updated 2006);
7. History of cystic fibrosis, bronchiectasis or alpha-1 antitrypsin deficiency;
8. Diagnosis of restrictive lung disease
9. Patients treated with oral or parenteral corticosteroids in the previous 2 months (3 months for parenteral depot corticosteroids);
10. Intolerance or contra-indication to treatment with β2-agonists and/or inhaled corticosteroids;
11. Allergy to any component of the study treatments;
12. Any change in the dose, schedule, formulation or product of an inhaled corticosteroid in the 4 weeks prior to screening visit;
13. Having received an investigational drug within 2 months before the screening visit;
14. Inability to comply with study procedures or treatment;
15. Significant medical history of 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;
16. Any patient with active cancer or a history of cancer with less than 5 years disease free survival time (whether or not there is evidence of local recurrence or metastases). Localized basal cell carcinoma (without metastases) of the skin is acceptable.
17. Patients with abnormal QTc at screening visit (> 450 msec-Bazett formula). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Change from baseline measured at clinic visit V2 (end of run-in) to the end of treatment period (V5) in pre-dose morning FEV1 (L) measured at clinic.
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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 | 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.8.3 |
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 | 57 |
| 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 | Information not present in EudraCT |
| 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 |
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| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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