Efficacy of LAMA Added to ICS in Treatment of Asthma (ELITRA)

A Multicentre, Randomised, Double-blind, Placebo-controlled, 2-way Cross-over Study to Evaluate the Efficacy and Safety of CHF 5259 (Glycopyrrolate Bromide) pMDI on Top of QVAR® pMDI for the Treatment of Patients With Uncontrolled Asthma on Low-Medium Dose of Inhaled Corticosteroids.

Primary objective

The primary objective was to evaluate the superiority of CHF 5259 (glycopyrronium bromide [GB]) in a pressurised metered dose inhaler (pMDI) (50 μg total daily dose) versus placebo in terms of forced expiratory volume in the first second (FEV1) area under the curve between time 0 and 12 hours (AUC0-12h) normalised by time on Day 42.

Key secondary objective

The key secondary objective was to evaluate the superiority of CHF 5259 pMDI (50 μg total daily dose) versus placebo in terms of peak FEV1 on Day 42.

Secondary objectives

The secondary objectives were:

• To evaluate the effect of CHF 5259 pMDI on other lung function parameters and on clinical outcome measures;
• To assess the safety and tolerability of study medications.

This was a phase IIb, multicentre, randomised, double-blind, placebo-controlled, 2-way crossover study consisting of two 6-week treatment periods (42 days each ±2 days), separated by a 1-week washout period (+2 days). The study employed a complete block design and a multiple-dosing regimen. It was designed as an add-on therapy to evaluate the efficacy and safety of CHF 5259 pMDI when used in combination with Qvar® pMDI in patients with uncontrolled asthma on low-to-medium doses of inhaled corticosteroids (ICS).

The crossover design was chosen because each patient serves as their own control, thereby reducing variability caused by inter-patient differences and minimizing the effects of potential confounding factors. This design improve statistical power, allowing for estimation of comparisons between treatments with a smaller sample size compared to a parallel arms study. The study aimed to randomise 98 patients to ensure at least 68 evaluable participants, accounting for an estimated 30% dropout or non-evaluable rate.

The study included the following phases:

• Pre-Screening Phase (Visit [V] 0): Conducted within 7 days prior to the Screening Visit, this visit aimed to explain the study to potential participants, obtain informed consent, and instruct patients on procedures for the Screening Visit.
• Screening Phase (Visit 1): This visit assessed eligibility for inclusion in the study and transitioned participants from their previous ICS therapy to a clinically equivalent dose of Qvar® pMDI (ranging from 50 μg to 400 μg daily). The Qvar® regimen was maintained as background therapy throughout the study. The Screening Visit was followed by a 2-week open-label run-in phase (±2 days) with Qvar® pMDI to ensure baseline standardization without compromising disease control.
• Investigational Phase:

Comprised two treatment periods:

1. Treatment Period 1 (P1): Spanning 42 days, starting at randomisation (Visit 2) and ending at Day 42 (Visit 3).
2. Treatment Period 2 (P2): Spanning another 42 days, starting at Visit 4 (Day 1 of Period 2) and concluding at Visit 5 (Day 42 of Period 2).

During these periods, patients received two puffs of their assigned treatment (CHF 5259 or placebo) twice daily (morning and evening), in addition to their stable Qvar® therapy.

A 1-week washout period (+2 days) was implemented between the two treatment periods to minimize the potential for carryover effects from the first treatment period.

• Follow-Up Phase: One week (+2 days) after the final treatment visit (Visit 5) or early termination, a follow-up phone call was conducted to assess unresolved adverse events (AEs) and document any new AEs or concomitant medications.

Overall, the study lasted 17 weeks per participant, including a 1-week pre-screening period; the 2-week run-in period; two 6-week treatment periods, and the follow-up phase. The two 6-week treatment periods allowed sufficient time for the evaluation of efficacy endpoints, while the 1-week washout period was deemed adequate to eliminate residual treatment effects.

Inclusion Criteria:

1. Patient's written informed consent obtained prior to any study related procedures;
2. Male or female patients aged ≥18 and ≤75 years;
3. History of asthma ≥5 year and diagnosed before the age of 40 years;
4. Patients with uncontrolled asthma on low medium doses of ICS (200 - 1000 μg daily dose BDP non-extrafine or estimated clinical comparable dose) at a stable dose for at least 4 weeks prior to Screening visit;
5. Patients with a pre bronchodilator FEV1 ≥40% and <90% of their predicted normal value, after appropriate washout from bronchodilators, at Screening visit and the end of the run in period;
6. Patients with a positive response to the reversibility test at Screening visit within 30 minutes after administration of 400 μg of salbutamol pMDI, defined as ΔFEV1 ≥12% and ≥200 mL over baseline; Note: In case this reversibility threshold was not met, the test could have been performed once before randomisation.
7. Patients with uncontrolled asthma evidenced by a score at the Asthma Control Questionnaire® (ACQ) ≥1.5 (criterion had to be met at Screening visit and the end of the run in period);
8. Patients with a co-operative attitude and ability to be trained to correctly use the pMDI and the electronic peak flow meter (e-peak flow meter). At the Screening visit (V1), all the above mentioned inclusion criteria were checked. At the Randomisation visit (V2), the following inclusion criteria were re checked: 5, 7 and 8.

Exclusion Criteria:

1. Inability to carry out pulmonary lung function testing, to comply with study procedures or with study medication intake;

2. History of near fatal asthma or of a past hospitalisation for asthma in intensive care unit or of frequent exacerbations in the last year which, in the judgement of the Investigator, may have placed the patient at risk;

3. Hospitalisation, emergency room admission or use of systemic corticosteroids for asthma exacerbation in the 4 weeks prior to Screening visit or during the run-in period;

4. Lower respiratory tract infection in the 4 weeks before Screening visit or during the run-in period;

5. Patients who were in current therapy for gastroesophageal reflux disease (GERD) or patients with a medical history of GERD that led to asthma symptoms;

6. Patients with a seasonal worsening of asthma and who were not able to complete the study outside the relevant allergen season;

7. History of cystic fibrosis, bronchiectasis or alpha 1 antitrypsin deficiency, bronco carcinoma, lung carcinoma or any other significant lung disease which may have interfered with data evaluation;

8. Patients with a medical history or current diagnosis of COPD as defined by the Global Initiative for chronic obstructive lung disease (GOLD) guidelines (2014);

9. Current smokers or ex-smokers with total cumulative exposure equal or more than 10 pack years or having stopped smoking one year or less prior to Screening visit;

10. Any change in dose, schedule or formulation of ICS in the 4 weeks prior to Screening visit;

11. Patient had used any of the following treatments 4 weeks before Screening visit: inhaled LABAs, inhaled LAMAs, inhaled ICS/LABA fixed combinations, theophylline,leukotriene modifiers, cromolyn sodium, nedocromil sodium, systemic anticholinergics, systemic corticosteroids (12 weeks for slow release corticosteroids);

12. Pregnant or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) unless are using at least one or more of the following reliable methods of contraception:

    1. Placement of an intrauterine device or intrauterine system;
    2. Hormonal contraception (implantable, injectable, patch, oral);
    3. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical vaults/caps) with spermicidal foam/gel/film/cream/suppository;
    4. Male sterilisation (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); Reliable contraception was maintained throughout the study and for 1 week after the last study dose. Pregnancy tests were performed at study entry (a serum test at Screening visit and a urinary test at Screening and Randomisation visits) in all women of childbearing potential.

    Any postmenopausal women (physiologic menopause defined as "12 consecutive months of amenorrhea") or women permanently sterilised (e.g. tubal occlusion, hysterectomy or bilateral salpingectomy) were enrolled in the study.

13. Patients who received any investigational new drug or participated in clinical study either within the last 8 weeks (or 5 half-lives for biologic products with slow elimination) before Screening visit;

14. Patients who had clinically significant (CS) cardiovascular condition according to Investigator's judgement such as but not limited to: congestive heart failure (New York Heart Association [NYHA] class >3), acute ischemic heart disease in the last year prior to study Screening, history of sustained cardiac arrhythmias or sustained and non-sustained cardiac arrhythmias diagnosed in the last 6 months (sustained means lasting more than 30 seconds or ending only with external action, or leads to hemodynamic collapse; non-sustained means >5 beats <30 seconds), impulse conduction blocks. Similarly, patients affected by permanent or paroxysmal atrial fibrillation were not considered for enrolment;

15. An abnormal and CS 12-lead electrocardiogram (ECG) that resulted in active medical problem which may have impacted the safety of the patient according to Investigator's judgement;

16. Patients whose electrocardiogram (12-lead ECG) showed Fridericia corrected QT (QTcF) >450 ms for males or QTcF >470 ms for females at Screening or at Randomisation visits;

17. Medical diagnosis of narrow angle glaucoma, clinically relevant prostatic hypertrophy or bladder neck obstruction that, in the opinion of the Investigator, prevented use of anticholinergic agents;

18. Unstable concurrent disease: e.g. uncontrolled hyperthyroidism, uncontrolled diabetes mellitus or other endocrine disease; significant hepatic impairment; with moderate to severe renal impairment (known creatinine clearance of ≤50 mL/min); uncontrolled gastrointestinal disease (e.g. active peptic ulcer); uncontrolled neurological disease; uncontrolled haematological disease; uncontrolled autoimmune disorders, or other laboratory abnormality that may have increased the risk associated with study participation or study medications administration and, in the judgment of theInvestigator, made the patient inappropriate for entry into this study, or placed the patients at undue risk or potentially compromised the results or interpretation of the study;

19. Patients having received a live attenuated virus vaccination within two 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);

20. Patients mentally or legally incapacitated;

21. Patients with a history of alcohol or drug abuse;

22. Patients with known intolerance/hypersensitivity or contra indication to treatment with β2 agonists, inhaled corticosteroids, anti cholinergics or propellant gases/excipients;

23. Patients with major surgery in the 3 months prior to Screening visit or planned surgery during the trial;

24. Patients treated with anti IgE antibodies;

25. Patients treated with non-potassium sparing diuretics (unless administered as a FDC with a potassium conserving drug), non-selective beta blocking drugs (except if taken at stable regimen for at least 2 months before Screening), quinidine, quinidine like anti arrhythmics, or any medication with a QTc prolongation potential or a history of QTc prolongation;

26. Patients treated with monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants;

27. Patients who are receiving any therapy that could have interfered with the study medications according to Investigator's opinion. At the Screening visit (V1), all the above mentioned exclusion criteria were checked. At the Randomisation visit (V2), the following exclusion criteria were re-checked: 1, 2, 3, 4, 5, 12, 15, 16, 18, 19, 23 and 27.