Foster 100/6 mg NEXThaler Versus Foster 100/6mg Pressurized Metered-dose Inhaler (pMDI) in Patients With Controlled Asthma.

A 12-week, Multicenter, Randomized, Double-blind, Double-dummy, 2-arm Parallel Group Study Comparing the Efficacy and Safety of Foster 100/6mg NEXThaler, 2 Inhalations b.i.d, Versus Foster 100/6mg pMDI, 2 Puffs b.i.d in Patients With Controlled Asthma.

Primary Objective

To demonstrate the non-inferiority of Foster® NEXThaler® 100/6 µg versus (vs.) Foster® pressurised metered dose inhaler (pMDI) 100/6 µg in terms of pulmonary function (change from baseline to the entire treatment period in average pre-dose morning peak expiratory flow [PEF]) in asthmatic patients.

Secondary Objectives

To evaluate the effect of the test treatments in terms of additional lung function parameters and clinical outcome measures, and to assess the safety and tolerability.

This was a phase III, multinational, multicentre, randomised, double-blind, double-dummy, active-control, 2-arm parallel group study designed to evaluate the non-inferiority of Foster® NEXThaler® 100/6 µg (400/24 µg/day) versus Foster® pMDI 100/6 µg (400/24 µg/day) in patients with controlled asthma.

The study included the following phases:

• Pre-Screening Phase (Visit 0): Conducted within a maximum of 7 days before the screening visit (Visit 1), this phase provided patients with study details, obtained informed consent, and outlined medication restrictions.
• Screening and Run-in Phase (Visit 1, Week -4 to Visit 2, Week -2): Patients underwent eligibility assessments and transitioned into a 4-week open-label run-in period with Foster® pMDI 100/6 µg (400/24 µg/day) to establish baseline parameters.
• Randomisation Phase (Visit 3, Week 0): Eligible patients were randomised in a 1:1 ratio to receive either Foster® NEXThaler® 100/6 µg 2 inhalations bid (for a total daily dose of 400/24 µg/day) or Foster® pMDI 100/6 µg, 2 puffs bid (for a total daily dose of 400/24 µg/day) for 12 weeks. The allocation was managed via an Interactive Web Response System (IWRS) to ensure balanced treatment groups.
• Investigational Phase (Treatment Period: Weeks 0-12): Patients attended scheduled visits at Weeks 2, 4, 6, 8, 10, and 12 to monitor efficacy and safety.

Daily, patients recorded pre-dose morning and evening Peak Expiratory Flow (PEF), rescue medication use, and asthma symptoms using an electronic peak flow meter and e-diary. At each visit, lung function (FEV1, FVC, and PEF), asthma symptom scores, and rescue medication use were assessed. Vital signs (heart rate, blood pressure) and safety outcomes (adverse events, serious adverse events, and laboratory assessments) were monitored.

• Follow-Up Phase: A safety follow-up phone call was conducted 7-10 days after the final visit (Week 12) or early termination to assess any unresolved adverse events (AEs) or new concomitant medications.

The total study duration per participant was 16 weeks, including the 4-week run-in period, 12-week treatment phase, and 1-week follow-up. This design ensured a standardized baseline before randomisation and provided sufficient time to assess both primary and secondary endpoints.

Salbutamol (purchased locally and provided by the Investigator site to the patient) was used as a rescue medication.

Inclusion Criteria:

1. Male or female outpatients, Chinese ethnicity aged ≥18 years, who signed an ICF prior to initiation of any study-related procedure;

2. Clinical diagnosis of asthma for a minimum of 6 months prior to V1 (Week -4) confirmed by a chest physician according to international guidelines updated 2018 (GINA) [1]. The evidence of asthma had to be confirmed through a documented positive response (in the last 24 months) either to a bronchial provocation test/challenge test or a reversibility test. In case the patient did not have any documented reversibility test or provocation/challenge test, a salbutamol reversibility test was performed at V1 (Week -4) within 10 to 30 minutes after administration of 400 µg of salbutamol pMDI [17]. Test response was positive if ΔFEV1 ≥12% and ≥200 mL over baseline.

   Note: In case the reversibility threshold was not met at V1 (Week -4), the test could have been repeated once before V2 or at V2 (Week -2);

3. FEV1 >80% of the predicted normal value after appropriate washout from bronchodilators (checked at V1 [Week -4] and at the randomisation visit [V3, Week 0]);

   Note: If this criterion was not met:

   • At V1 (Week -4), the test could have been repeated once before V2 or at V2 (Week -2);
   • At randomisation visit (V3, Week 0), the test could have been repeated once within 2 days after this visit;

4. ACQ-6 score <0.75 (checked at V1 [Week -4] and at the randomisation visit [V3, Week 0]);

5. Patients on previous regular treatment at a stable dose for at least 1 month prior to the screening visit (V1, Week -4) with either medium daily dose of ICS monotherapy (e.g. BDP-chlorofluorocarbons [CFC] >500-1000 µg/day or equivalent dose) or high daily dose of ICS monotherapy (e.g. BDP-CFC >1000 µg/day or equivalent dose) or low daily dose of ICS (e.g. BDP-CFC ≥200-500 µg/day or equivalent dose)/LABA free/fixed combination or medium daily dose of ICS (e.g. BDP-CFC >500-1000 µg/day or equivalent dose)/LABA free/fixed combination;

6. A cooperative attitude and ability to be trained to the proper use of DPI and pMDI inhalers and an electronic peak flow meter (checked at the screening visit [V1, Week -4] and at the randomisation visit [V3, Week 0]);

7. At least seven valid pre-dose morning PEF measurements in the last 14 days of the run-in period were necessary (checked at the randomisation visit [V3, Week 0]).

Exclusion Criteria:

1. Pregnant or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) unless they were using one or more of the following highly effective contraceptive measures:

   • Placement of an intrauterine device or intrauterine hormone-releasing system;
   • Combined (oestrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal);
   • Progesterone-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable);
   • Bilateral tubal occlusion;
   • Vasectomised partner;
   • Sexual abstinence; Reliable contraception had to be maintained throughout the study. Any postmenopausal women (physiologic menopause defined as "12 consecutive months of amenorrhoea without an alternative medical cause") or women permanently sterilised (e.g. bilateral oophorectomy, hysterectomy or bilateral salpingectomy) could be enrolled in the study.

   Pregnancy testing was carried out during the course of the study in all women of childbearing potential: serum pregnancy test was performed at screening (V1, Week -4) and end of treatment (V9, Week 12), urine pregnancy test was performed at all visits except V0 (Week -5) and V9 (Week 12);

2. Intermittent asthma or asthma occurring only during episodic exposure to an allergen or a chemical sensitiser;

3. History of near fatal asthma (e.g. brittle asthma, hospitalisation for asthma exacerbation in an intensive care unit);

4. Diagnosis of chronic obstructive pulmonary disease as defined by the current global initiative for chronic obstructive lung disease (GOLD) guidelines updated 2016 [18];

5. Current smokers or ex-smokers with total cumulative exposure equal or more than 10 pack-years or having stopped smoking 1 year or less prior to screening (V1, Week -4);

6. Severe asthma exacerbation leading to intake of systemic corticosteroids (≥10 days) within 1 month prior to inclusion or moderate/severe asthma exacerbation (according to international guidelines updated 2018 [GINA] [1]) during the run-in period (checked at the screening visit [V1, Week -4] and at the randomisation visit [V3, Week 0]);

7. Lower respiratory tract infections (e.g. pneumonia) affecting the patient's asthma within 1 month prior to inclusion;

8. History of cystic fibrosis, bronchiectasis or alpha-1 antitrypsin deficiency, or any other significant lung disease;

9. Diagnosis of restrictive lung disease;

10. Patients treated with oral or parenteral corticosteroids in the previous 2 months before V1 (Week -4; 3 months for parenteral depot corticosteroids);

11. Intolerance or contra-indication to treatment with β2-agonists and/or ICS or allergy to any component of the study treatments;

12. Having received an investigational medication within 2 months before screening (V1, Week -4);

13. Patients who had a clinical or functional uncontrolled respiratory, haematological, immunologic, renal, neurologic, hepatic, endocrinal or other disease, or any condition (e.g. major surgery) that might have, in the judgment of the Investigator, represented for the patients an undue risk or that could have compromised the results or interpretation of the study;

14. History or current evidence of uncontrolled heart failure, clinically relevant coronary artery disease, recent myocardial infarction, severe hypertension, uncontrolled cardiac arrhythmias;

15. Clinically relevant laboratory abnormalities such as (but not limited to) hypokalaemia (<3.5 mEq/L), that might have compromised patient's safety or compliance, interfered with evaluation, or precluded completion of the study, in the judgment of the Investigator. Patients with uncontrolled diabetes including patients with a history of fasting plasma glucose levels consistently out of the normal range (>140 mg/dL) or HbA1C >8%;

16. Patients who had an abnormal 12-lead ECG (i.e. QRS interval [QRS] >120 ms and/or PR interval [PR] >210 ms and/or HR <45 beats per minute [bpm] and/or HR >110 bpm and/or Fridericia-corrected QT interval [QTcF] >450 ms for males or QTcF >470 ms for females) or 12-lead ECG evaluated as abnormal clinically significant (CS) by the Investigator, at screening (V1, Week -4);

17. Patients who had a concomitant disease of poor prognosis (e.g. cancer);

18. Patients treated with monoclonal antibodies (e.g. anti-immunoglobulin E [anti-IgE] antibodies);

19. Patients treated with non-potassium sparing diuretics (unless administered at a fixed dose combination with a potassium conserving medication), non-selective β1-blocking medications, quinidine, quinidine-like antiarrhythmics or any medication with a corrected QT interval (QTc) prolongation potential, or a history of QTc prolongation;

20. Patients treated with monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants, unless already taken at stable doses in the month before screening (V1, Week -4) and without any safety concern;

21. Patients who were receiving therapy that could interact with steroids, such as enzyme inhibitors (macrolides, antifungal therapy [not topical]) or inducers (anticonvulsants, rifampicin);

22. Inability to comply with study procedures or with study treatment intake.