A 52-Week Randomized Double-Blind Trial Comparing CHF5993 (Beclometasone Dipropionate, Formoterol Fumarate, Glycopyrronium Bromide) to Fluticasone Propionate/Salmeterol in Adolescents with Uncontrolled Asthma

The primary objective is to demonstrate the superiority of the investigational fixed‑dose combination inhaler compared with Seretide® Evohaler® in the change from baseline in pre‑dose FEV1 at Week 26, reflecting a clinically meaningful improvement in lung function for adolescents with uncontrolled asthma. Secondary objectives include:

• Superiority in change from baseline in 2‑hour post‑dose FEV1 at Week 26.
• Comparison of severe asthma exacerbation rates over the full 52‑week treatment period.
• Comparison of changes from baseline in the 7‑item Asthma Control Questionnaire (ACQ‑7) and the Asthma Quality of Life Questionnaire (AQLQ) at all scheduled visits.
• Comparison of changes from baseline in pre‑dose FEV1 at all applicable visits.
• Comparison of changes from baseline in 2‑hour post‑dose FEV1 at all applicable visits.
• Proportion of subjects classified as responders (≥100 mL increase in pre‑dose FEV1) at Weeks 26 and 52.
• Change from baseline in 48‑hour post‑dose morning FEV1 after the last dose at Week 52.
• Change from baseline in the weekly 5‑item Asthma Control Questionnaire (ACQ‑5) throughout the 52‑week period.
• Change from baseline in home spirometry parameters over the entire treatment duration.
• Safety and tolerability assessment, including adverse events, electrocardiograms, vital signs and laboratory tests, across the 52‑week study.

The trial enrolled 121 participants diagnosed with Uncontrolled Asthma, comprising both male and female adolescents aged 12 to <18 years. Subjects were required to have a documented asthma history of at least six months, be receiving stable medium‑dose inhaled corticosteroid/long‑acting β₂‑agonist therapy for a minimum of four weeks, and demonstrate a pre‑dose forced expiratory volume in one second (FEV₁) between 60 % and 90 % of predicted values after bronchodilator washout. Eligibility also required a positive bronchodilator reversibility response (≥12 % and ≥200 mL increase in FEV₁) and an ACQ‑7 score of 1.5 or higher, indicating uncontrolled disease, as well as at least one asthma exacerbation requiring systemic corticosteroids, emergency department care, or hospitalization in the prior year. Inclusion mandated written informed consent from parents or legal representatives and assent from the participants, together with the capacity to be trained in proper use of metered‑dose inhalers, adherence to home spirometry, and operation of an electronic diary. Subjects weighing 30 kg or more were eligible for the pharmacokinetic sub‑study. The population was selected based on these clinical and functional criteria, reflecting a cohort of adolescents with moderate to severe, inadequately controlled asthma.

The study is a 52‑week, randomized, double‑blind, double‑dummy, active‑controlled, two‑arm parallel‑group trial comparing CHF5993 pMDI (extrafine beclomethasone dipropionate, formoterol fumarate, glycopyrronium bromide) with Seretide® Evohaler® (fluticasone propionate/salmeterol) in adolescents with Uncontrolled Asthma. After obtaining informed consent, eligible participants undergo a screening visit to confirm eligibility criteria, including pulmonary function testing and asthma control assessment. Eligible subjects are then randomized in a 1:1 ratio and receive either the investigational product or the comparator, each administered with matching placebos to maintain blinding. Study visits are scheduled at baseline (randomisation), weeks 4, 12, 26, 39, and week 52, with each visit including pre‑dose and post‑dose spirometry, electronic diary review, safety assessments, and collection of secondary efficacy endpoints. The end‑of‑study visit occurs at week 52, concluding all efficacy and safety evaluations. Participants remain in the trial for approximately 53 weeks, encompassing the screening period and the 52‑week treatment phase. Early termination may occur if a participant experiences a serious adverse event, fails to comply with protocol procedures, withdraws consent, or requires prohibited concomitant therapy.

The experimental investigational medicinal product (IMP) is CHF5993 pMDI, a pressurised metered‑dose inhaler containing a fixed combination of beclometasone dipropionate (100 µg), formoterol fumarate dihydrate (6 µg), and glycopyrronium bromide (12.5 µg) per actuation. The formulation is a solution for inhalation, administered by inhalation use. Participants receive two actuations twice daily, delivering the specified microgram amounts of each active substance, for a total of 52 weeks. Compliance is monitored through dose‑counter checks at each study visit and review of electronic inhaler diaries.

The active comparator is Seretide Evohaler, a pressurised inhalation suspension delivering fluticasone propionate (25 µg) and salmeterol (125 µg) per metered dose. The inhaler is used via inhalation, with a dosing schedule of two actuations twice daily, consistent with standard asthma maintenance therapy. Dosing adherence is similarly assessed by dose‑counter verification and participant‑recorded dosing logs.

Two matched placebos are employed to maintain blinding: IMP Placebo and Comparator Placebo. Both are formulated as inert inhalation devices without active pharmaceutical ingredients, identical in appearance to the active inhalers. Placebo inhalations are administered on the same schedule as the corresponding active treatment to preserve the double‑dummy design.

Efficacy will be evaluated primarily by the change from baseline in pre‑dose FEV1 at Week 26, measured with standardized spirometry in accordance with ATS/ERS guidelines. Additional spirometric assessments include the change from baseline in 2‑hour post‑dose FEV1 at Week 26, the same measurements at all scheduled clinical visits, the 48‑hour post‑dose morning FEV1 after the final dose at Week 52, and home‑based spirometry parameters collected throughout the 52‑week treatment period. The proportion of responders will be determined at Weeks 26 and 52 based on a ≥100 mL increase in pre‑dose FEV1.

Patient‑reported outcomes will be captured using validated instruments: the Asthma Control Questionnaire (ACQ‑7) at Weeks 12, 26 and 52, and the ACQ‑5 on a weekly basis for the entire study duration; the Asthma Quality of Life Questionnaire (AQLQ) at the same three timepoints. Severe asthma exacerbation rate and time to first severe exacerbation will be recorded over the full 52‑week period. All efficacy data will be analyzed by comparing the change from baseline between the test and comparator arms using appropriate statistical models for continuous (e.g., FEV1, questionnaire scores) and time‑to‑event (e.g., first severe exacerbation) outcomes.