| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patient with severe asthma |
|
| 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 |
|
| 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 |
| In symptomatic patients on high-doses ICS (Inhaled Corticosteroid) beclomethasone diproprionate (two puffs b.i.d.), to demonstrate the superiority of CHF 1535 200/6 (two puffs b.i.d.) versus a high dose of BDP (beclomethasone diproprionate 2000 μg/day) given as monotherapy, in terms of pulmonary function (change from baseline in pre-dose morning FEV1 measured at clinic) and asthma control (change from baseline in percentage of complete days without asthma symptoms), and the non-inferiority versus Seretide® 500/50 (one inhalation b.i.d.), in terms of pulmonary function (change from baseline in pre-dose morning FEV1 measured at clinic) during a 24-week treatment period. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the effect of the treatments on additional lung function parameters and clinical outcome measures, to assess the achievement of asthma control (according to the criteria established in GINA revised 2006), to assess the safety and the tolerability of CHF 1535 200/6 and to perform a pharmaco-economic evaluation in the perspective of the HealthCare System. |
|
| 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 2 sub-studies included in the protocol (not all sites will participate to those substudies):
- a subgroup of subjects (30% of all patients) will be selected for 12-h overnight urinary cortisol and adrenocorticotropic hormone (ACTH) test.
12-h overnight urine (which will be collected for free cortisol and creatinine excretion) and plasma response to ACTH injection will be used as diagnostic tests to assess the potential effect of inhaled corticosteroids to cause suppression of the hypothalamic-pituitary-adrenal axis.
- a subgroup of subjects (10% of all patients) will be selected for a 24-h Holter monitoring.
24-hour Holter monitoring will be performed to assess whether electrophysiologic effects (heart rate and rythm) could be observed in patients receiving inhaled medications. |
|
| E.3 | Principal inclusion criteria |
Patient will be enrolled at Visit 1 into the run-in period if they meet each and every one of the following criteria:
1. Subject’s written informed consent and written informed consent by parents/legal
representatives (adolescent patients).
2. Outpatients of both sexes aged ≥ 18 and ≤ 70 years.
3. Evidence of asthma demonstrated by a documented positive response to the reversibility test, defined as ΔFEV1 ≥ 12% and ≥ 200 mL over baseline, within 30 minutes after administration of 400 μg of salbutamol pMDI. In case this is not achieved, a historically documented FEV1 reversibility within the previous 12 months is acceptable.
4. Patients with severe persistent asthma diagnosed according to GINA guidelines (revised 2006).
5. Levels of asthma control, during each of the two previous weeks (to be checked at screening and at randomisation visits), defined as:
→ 1 or more of the following:
- Daytime symptoms → more than twice/ week;
- Limitations of activities → any;
- Nocturnal symptoms/awakening → any;
- Need for reliever/rescue treatment → more than twice/ week.
6. Patients on previous treatment with high doses of ICS (> 1000 μg BDP CFC daily or equivalent) or ICS + LABA fixed or free combinations (daily dose of budesonide 800 μg/fluticasone 500 μg or equivalent ICS doses plus formoterol 24 μg or salmeterol 100μg) at a stable dose for at least 2 months prior to inclusion.
7. Patients who meet the following requirement: FEV1 ≥ 40% and < 80% of predicted normal values and at least 0.9 L, after appropriate washout from bronchodilators.
8. A cooperative attitude and ability to be trained in the proper use of a pMDI, an
Accuhaler® and a portable electronic peak flow meter (SpirotelTM). |
|
| E.4 | Principal exclusion criteria |
Patient will not be enrolled at Visit 1 into the run-in period and will not be randomized to treatments at Visit 2 (i.e. these criteria will be also reviewed at Visit 2) if they meet one or more of the following criteria:
1. Pregnant or lactating women. Females of childbearing potential without an efficient contraception (e.g. oestro-progestatives, condoms).
2. Having received an investigational drug within 2 months.
3. Inability to comply with study procedures or with study treatment intake.
4. Seasonal asthma or asthma occurring only during episodic exposure to an allergen or a chemical sensitizer.
5. History of cystic fibrosis, bronchiectasis or alpha-1 antitrypsin deficiency, or any other significant lung disease.
6. Patients who suffer from COPD as diagnosed by the GOLD guidelines (2006).
7. Previous or current smokers who have a smoking history greater than 5 pack years, (defined as the number of packs of 20 cigarettes smoked per day multiplied by number of years the patient smoked).
8. Diagnosis of restrictive lung disease (e.g. kyphoscoliosis, ankylosing spondylitis).
9. Patients who have an uncontrolled cardiovascular (e.g., uncontrolled hypertension), respiratory, hematologic, immunologic, renal, neurologic, hepatic, endocrine (e.g., uncontrolled diabetes mellitus) or other disease, or any condition that might, in the judgment of the Investigator, place the patients at undue risk or potentially compromise the results or interpretation of the study.
10. Patients who have a history of coronary artery disease, cerebrovascular disease, and cardiac arrhythmias.
11. Patients who have a concomitant disease of poor prognosis (e.g., cancer).
12. Clinically relevant laboratory abnormalities such as (but not limited to) hypokalemia that might compromise patient's safety or compliance, interfere with evaluation, or preclude, completion of the study in judgment of the investigator. Patients with uncontrolled diabetes including patients with a history of blood glucose levels consistently out of the normal range or HbA1C >8.0% measured at Visit 1.
13. Patients who have an abnormal QTc interval value value in the Screening visit ECG test (i.e., > 450 msec in males or > 470 msec in females).
14. Patients having received a live-attenuated virus vaccination within two weeks prior to screening or during the run-in.
15. Patients mentally or legally incapacitated.
16. Patients who abuse alcohol.
17. Intolerance/hypersensitivity or contra-indication to treatment with β2-agonists and/or inhaled corticosteroids.
18. Major surgery in the previous 3 months.
19. Any change in dose, schedule, formulation or product of previous ICS or fixed/free combination ICS + LABAs in the 2 months prior to screening visit.
20. Any change in dose, schedule, formulation or product of other concomitant asthma treatments in the 2 months prior to screening visit.
21. Moderate/severe exacerbations and/or intake of oral corticosteroids during the 2-week run-in period.
22. Patients treated with slow-release corticosteroids in the 3 months prior to screening visit.
23. Patients treated with non-potassium sparing diuretics, 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 at the screening visit.
25. Patients who are receiving therapy that could interact with steroids, such as enzyme inhibitors (macrolide antibiotics, antifungal oral therapy) or induced (anticonvulsants, rifampin).
26. Patients being treated with anti-IgE antibodies.
27. Patients who have had a respiratory tract infection within 2-months prior to Visit 1. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Two co-primary variables are defined:
- Change from baseline to end of treatment in pre-dose morning FEV1 (L) (measured
at clinic visit).
- Change from baseline to end of treatment in percentage of complete days without
asthma symptoms (asthma symptom scores recorded daily at home on electronic
peak flow meter). |
|
| 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 | Yes |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 95 |
| 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 |
|
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 22 |
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