Efficacy and Safety of CHF 1535 200/6µg in Not Adequately Controlled Asthmatic Patients

A 12-week, Multinational, Multicentre, Randomised, Double-blind, Double-dummy, 2-arm Parallel Group Study Comparing the Efficacy and Safety of CHF 1535 200/6µg Versus Beclomethasone Dipropionate in Adult Asthmatic Patients Not Adequately Controlled on High Dose of Inhaled Corticosteroids or on Medium Dose of Inhaled Corticosteroids Plus Long-acting β2 Agonists

Primary objective

To show the superiority of CHF 1535 (BDP/FF) pMDI (800/24 μg per day) over BDP HFA pMDI (800 μg per day) in terms of change from baseline to the entire treatment period in average pre-dose morning peak expiratory flow (PEF) in adult asthmatic patients not adequately controlled on high doses of ICS or on medium doses of ICS plus LABA.

Secondary objective

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.

This was a phase III, multinational, multicentre, randomised, double-blind, double-dummy, active-control, 2-arm parallel group study designed to demonstrate the superiority of CHF 1535 (200/6 μg FDC; 800/24 μg/day) vs. BDP (100 μg; 800 μg/day).

The study included the following phases:

• Pre-Screening Phase (Visit 0): conducted within a maximum of two weeks before the screening visit (Visit 1), aimed to explain the study to patients, obtain informed consent, and provide instructions on screening procedures, including medication restrictions.
• Screening Phase (Visit 1, Week -2): Patients were assessed for eligibility and transitioned to a 2-week open-label run-in period on beclomethasone dipropionate (BDP) pMDI 800 μg/day to establish a baseline .
• Randomisation Phase (Visit 2, Week 0): Patients were randomised in a 1:1 ratio to receive either CHF 1535 (800/24 µg/day) or BDP (800 µg/day) for 12 weeks, with allocation centrally assigned through an Interactive Web Response System (IWRS) to ensure balanced treatment groups.
• Investigational Phase (Treatment Period: Weeks 0-12): included six scheduled visits at Weeks 2, 4, 6, 8, 10, and 12 (end of treatment) to monitor efficacy and safety. Throughout this period, patients recorded their pre-dose morning and evening peak expiratory flow (PEF), rescue medication use, and asthma symptoms daily using an electronic peak flow meter. At each visit, key assessments were conducted to evaluate lung function (FEV1, FVC, and PEF), asthma symptom scores, and the use of both rescue and study medications. Vital signs, including heart rate and blood pressure, were monitored, while safety evaluations covered adverse events, serious adverse events, and laboratory assessments.
• Follow-Up Phase: conducted one week (+2 days) after the final visit (Visit 8) or early termination, the follow-up phase included a phone call to assess any unresolved adverse events (AEs) or new concomitant medications.

The total study duration for each participant was 16 weeks, including the 2-week run-in period, 12-week treatment phase, and 1-week follow-up. This design allowed sufficient time to evaluate the primary and secondary endpoints while ensuring a standardized baseline before randomisation.

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 (1000-2000 μg daily dose BDP non-extrafine or equivalent) or medium doses of ICS+LABA (500-1000 μg daily dose BDP non-extrafine or equivalent plus formoterol 24 μg or salmeterol 100 μg) at a stable dose for at least 4 weeks prior to screening; Equivalence to Medium dose High dose BDP non-extrafine 500-1000 μg > 1000-2000 μg BDP extrafine 200-400 μg > 400-800 μg Budesonide 400-800 μg > 800-1600 μg Ciclesonide 160-320 μg > 320-1280 μg Fluticasone 250-500 μg > 500-1000 μg Mometasone 400-800 μg > 800-1200 μg

4. Patients with a FEV1 > = 40% and < 80% of patient's predicted normal value and an absolute value of at least 0.9 L, 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 ≥ 200 mL over baseline, within 30 minutes after administration of 400 μg of salbutamol pMDI. In case this reversibility threshold was not met, the FEV1 reversibility test could 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 was acceptable;

6. Patients with not adequately controlled asthma evidenced by:

   a. At least one of the following at any week in the 2 previous weeks (in addition to

   FEV1 < 80% of the predicted normal value) had to be present:

   i. Daytime symptoms more than twice/week; ii. Any limitations of activities; iii. Nocturnal symptoms/awakening; iv. Need for reliever/rescue treatment more than twice/week;

   b. And a score at the Asthma Control Questionnaire© (ACQ) > 0.75. Both of the above had to 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 cooperative 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 could be included in the study.

Exclusion Criteria:

Patients were not enrolled in the study if one or more of the following criteria were present:

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 sensitiser;

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, could have placed the patient at undue risk;

4. Hospitalisation, emergency room (ER) admission or use of systemic corticosteroids for asthma exacerbation in the 4 weeks prior to the 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 could have interfered with data evaluation;

7. Patients who suffered from Chronic Obstructive Pulmonary Disease (COPD) as defined by the current Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines;

8. Current smokers or ex-smokers with total cumulative exposure equal or more than 5 pack-years and/or who 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 the screening visit;

10. Patients who were treated with anti-IgE antibodies;

11. Patients who were treated with long acting anti-cholinergics (tiotropium);

12. Patients who used any of the following medications prior to the screening visit and had not met the specified minimum wash-out period:

    1. Short-acting β2-agonists: 6 hours;
    2. LABA: 12 hours;
    3. Fixed combinations of an anti-cholinergic and short-acting β2-agonist: 12 hours;
    4. Short-acting anti-cholinergic: 12 hours;
    5. Systemic corticosteroids: 4 weeks;
    6. 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:

    1. Surgical sterilisation (e.g. bilateral tubal ligation, hysterectomy);
    2. Hormonal contraception (implantable, injectable, patch, oral);
    3. Double-barrier methods (any double combination of: intrauterine device, 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 levels > 40 mIU/mL, could be enrolled. A serum pregnancy test was performed at the screening visit in women of childbearing potential;

14. Patients who had 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, could have placed the patient at undue risk;

16. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that could have increased the risk associated with study participation or study drug administration and, in the judgment of the Investigator, would have made the patient inappropriate for entry into this study, placed the patients at undue risk or potentially compromised the results or interpretation of the study;

17. Patients with a clinically significant abnormality at 12-lead electrocardiogram (ECG) or presenting a Fridericia-correct QT (QTcF) interval value > 450 msec in males or > 470 msec in females;

18. Patients who received a live-attenuated virus vaccination within 2 weeks prior to screening or during the run-in (inactivated influenza vaccination was acceptable provided it was 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 beta-2-agonists, ICSs or propellant gases/excipients;

22. Patients with major surgery in the 3 months prior to the screening visit and/or planned surgery during the trial;

23. Patients treated with non-potassium sparing diuretics (association with potassium sparing diuretics was allowed), non-selective beta-blocking drugs, quinidine, quinidine-like anti arrhythmics, or any medication with a corrected QT (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 were receiving any therapy that could have interfered with the study drugs according to the Investigator's opinion.