A Study Testing the Superiority of CHF 1535 pMDI 800/24µg Total Daily Dose Compared With CHF 718 pMDI 800µg Total Daily Dose in Adults With Asthma on Medium or High-Dose Inhaled Corticosteroid

A 12 Week, Randomized, Double-blind, Multicenter, Active Controlled, 2-Arm Parallel Group Study Testing the Superiority of CHF 1535 pMDI 800/24µg Total Daily Dose (Fixed Combination of Extrafine Beclomethasone Dipropionate Plus Formoterol Fumarate) Compared to CHF 718 pMDI 800µg Total Daily Dose (Extrafine Beclomethasone Dipropionate) in Adults With Asthma on Medium or High-Dose Inhaled Corticosteroid

Compare the superiority of CHF 1535 versus CHF 718 in subjects with asthma who are on medium or high dose inhaled corticosteroids.

This was a phase III, multicenter, randomized, double-blind active controlled 2-arm parallel group to compare superiority of CHF 1535 pressurised metered dose inhaler (pMDI) compared with CHF 718 pMDI, in subjects with asthma on medium or high dose inhaled corticosteroids, with regard to change from baseline in forced expiratory volume in the first second (FEV1) Area under the Curve Calculated Between Time 0 and 12 Hours (AUC0-12h) at Week 12.

After screening, eligible subjects entered a 2-week run-in period using CHF 718 (BDP) pMDI 100µg, followed by a 12-week double-blind, treatment period. Screened subjects who were on a medium dose inhaled corticosteroid (ICS) or medium dose ICS-long-acting β2-adrenergic receptor agonists (LABA) prior to the study, received CHF 718 pMDI 100µg 2 inhalations twice daily (BID) i.e. total daily dose (TDD) 400µg) during the 2-week run in period. Screened subjects who were on a high dose ICS prior to the study received CHF 718 pMDI 100µg 4 inhalations BID (TDD 800µg) during the 2-week run in period.

Following the run-in period, eligible subjects were randomized to one of two study drug arms (using a 1:1 allocation ratio) for 12 weeks. A total of 6 clinic visits (V), (V0-V5) and a follow-up call (V6) were performed during the study.

During the study, daily symptoms, rescue medication use, and compliance with the study drug were recorded via a subject-specific electronic diary (eDiary). Concomitant medications and adverse events (AEs) were assessed and recorded throughout the study. Vital signs measurements, physical exam, 12-lead electrocardiogram (ECG), peak expiratory flow (PEF), and spirometry measurements, including serial spirometry were performed and recorded. Symptoms were assessed using disease specific questionnaires. Routine hematology, blood chemistry, and urine pregnancy testing were performed before enrolment and at the end of study.

CHF 1535 pMDI = 200/6 μg pressurised metered dose inhaler (fixed combination of extrafine beclomethasone dipropionate [BDP] plus formoterol fumarate [FF]).

CHF 718 pMDI = 100 μg pressurised metered dose inhaler (extrafine beclomethasone dipropionate [BDP]).

Inclusion Criteria (IC):

1. Informed consent: A signed and dated written informed consent obtained prior to any study-related procedures.

2. Sex and age: Male or female aged ≥18 and ≤75 years.

3. Diagnosis of asthma: A documented history of asthma for at least 1 year, with onset before age 40

4. Stable asthma therapy: Use of medium-dose ICS with or without a LABA or high-dose ICS alone for 3 months (at a stable dose for at least 4 weeks prior to screening).

5. Lung function: Subjects with a pre-bronchodilator FEV1 ≥40% and ≤85% of predicted, after appropriate washout from bronchodilators, at the screening and randomization visits. In addition, the absolute value of the first pre-dose FEV1 at randomization (V2) must be at least 80% of the pre-bronchodilator value attained at screening.

6. Reversibility post-bronchodilator: Subjects with a positive reversibility to bronchodilator at screening, defined as an increase in FEV1 > 12% and > 200mL compared to baseline within 30 minutes after 4 inhalations of albuterol hydrofluoroalkane (HFA) pMDI 90µg/actuation.

   Note for IC#5 and IC#6: In case the reversibility and/or quality threshold is not met at screening, the test can be performed once before randomization.

7. Female subjects:

   a. Women of childbearing potential (WOCBP) fulfilling one of the following criteria: i. WOCBP with fertile male partners: they and/or their partner must be willing to use a highly effective birth control method from the signing of the informed consent form and until the follow-up contact or ii. WOCBP with non-fertile male partners (contraception is not required in this case).

   b. Female subjects of non-childbearing potential defined as physiologically incapable of becoming pregnant (i.e. post-menopausal or permanently sterile as per definitions given in Appendix 2). Tubal ligation or partial surgical interventions are not acceptable. If indicated, as per investigator's request, post-menopausal status may be confirmed by follicle-stimulating hormone levels (according to local laboratory ranges).

8. Cooperative attitude and ability to demonstrate correct use of the pMDI inhalers and eDiary/peak flow meter.

Exclusion Criteria:

1. Pregnancy or lactation: where pregnancy is defined as the state of a female after conception and until termination of the gestation, confirmed by a positive pregnancy test (serum and urine pregnancy test to be performed at screening visit and urine pregnancy test to be performed prior to randomization).
2. Poor compliance with run-in medication or eDiary completion <50% before randomization.
3. History of "at risk" asthma: History of near-fatal asthma or of a past hospitalization for asthma in intensive care unit which, in the judgement of the investigator, may place the subject at undue risk.
4. Recent asthma exacerbation: Hospitalization, emergency room admission or use of systemic corticosteroids for an asthma exacerbation in the 4 weeks prior to screening visit or during the run-in period.
5. Unresolved respiratory tract infection (RTI) in the 4 weeks prior to the screening visit or during run-in period. Documented coronavirus disease 2019 (COVID-19) diagnosis within the last 8 weeks or complications from this disease, which have not resolved within 14 days prior to screening.
6. Unstable ICS dose during the 4 weeks prior to screening visit, including any change in dose, schedule, or formulation.
7. Use of systemic corticosteroid medication in the 4 weeks prior to screening or slow-release corticosteroids in the 12 weeks before screening.
8. Respiratory disorders other than asthma: History of a diagnosis of cystic fibrosis, bronchiectasis, Chronic Obstructive Pulmonary Disease (COPD), (as defined by the current Global Initiative for Chronic Obstructive Lung Disease [GOLD] Report), alpha-1 antitrypsin deficiency, or any other significant lung disease which may interfere with study evaluations.
9. Smoking status: Current smokers or ex-smokers with total cumulative exposure equal to or more than 10 pack-years or having stopped smoking within one year prior to screening visit.
10. E-cigarette status: Current e-cigarettes users at the time of the screening visit.
11. Cannabis usage: Current use of inhaled or oral cannabis products (e.g. marijuana).
12. Substance abuse: Subjects with a history of alcohol or substance/drug abuse within 12 months prior to screening.
13. Cardiovascular diseases: Subjects who have clinically significant cardiovascular condition such as, but not limited to, unstable ischemic heart disease, New York Heart Association (NYHA) Class III/IV heart failure, acute ischemic heart disease within one year prior to study entry, known history of atrial fibrillation or history of sustained and non-sustained cardiac arrhythmias diagnosed within the last 6 months prior to screening, not controlled with a rate control strategy. Note: Subjects with Permanent Atrial Fibrillation (for at least 6 months) with a resting ventricular rate <100/min, controlled with a rate control strategy (i.e., selective β-blocker, calcium channel blocker, pacemaker placement, digoxin, or ablation therapy) can be considered for the enrollment.
14. ECG criteria: An abnormal and clinically significant 12-lead electrocardiogram (ECG) which may impact the safety of the subject according to Investigator's judgement. In terms of the QTcF, subjects with QTcF >450ms for males or QTcF >470ms for females at screening or at randomization visits (criterion not applicable for subject with pacemaker or permanent atrial fibrillation).
15. Other medical conditions: Other active severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
16. Vaccination: Subjects having received a vaccination within 2 weeks prior to screening or during the run-in period.
17. Subjects' wellbeing: Subjects mentally or legally incapacitated, including but not limited to subjects who are institutionalized or incarcerated.
18. Hypersensitivity: Subjects with known intolerance, hypersensitivity or contraindication to treatment with ß2-agonists, ICS, or propellant gases/excipients.
19. Surgery: Subjects with major surgery in the 3 months prior to the screening visit or planned surgery during the study.
20. Additional treatment: Subjects treated with non-potassium sparing diuretics (unless administered as a fixed-dose combination with a potassium conserving drug or changed to potassium sparing before the screening), non-selective beta-blocking drugs, quinidine, quinidine-like anti-arrhythmic, or any medication with a QTc prolongation potential or a history of QTc prolongation.
21. Subjects treated with monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants.
22. Subjects with concomitant immunosuppressive therapy, use of oral or injected corticosteroids, anti-immunoglobulin E (IgE), anti-IL5 or other monoclonal or polyclonal antibodies within 12 weeks prior to screening.
23. Subjects who are receiving any therapy that could interfere with the study drugs according to investigator's opinion.
24. Participating in other investigational trial: Subjects who have received an investigational drug within 1 month or 5 half-lives (whichever is greater) prior to screening visit, or have been previously randomized in this trial, or are currently participating in another clinical trial.
25. Spacer: The need to use a spacer for correct self-administration of a pMDI.