The purpose of this study is to compare concomitant administration of Montelukast and Bilastine to Montelukast and Bilastine monotherapies in patients with SARC and asthma

The present study (SKY) was designed to show if once daily oral combination therapy with Montelukast 10 mg and Bilastine 20 mg is superior to monotherapy with Bilastine 20 mg in patients with Seasonal Allergic RhinoConjunctivitis (SARC) and comorbid mild to moderate asthma on total symptom scores (TSS) and if the combination therapy reflects an improvement in quality of life as assessed via the Asthma Quality of Life Questionnaire (AQLQ) over a longer time period when compared to monotherapies with Montelukast 10 mg and Bilastine 20 mg. Mild to moderate asthma was defined according to the criteria of the Global Initiative for Asthma, i.e., GINA criteria 2 and 3 (GINA, 2012). The study population included patients inadequately controlled on inhaled corticosteroids and in whom "as-needed" short acting beta-agonists provided inadequate clinical control.

INCLUSION CRITERIA

1. Patients aged 18 years or older;

2. Patients with at least 2 years history of SARC prior to the study and mild to moderate asthma (GINA criteria 2 and 3) inadequately controlled on inhaled corticosteroids and in whom "as-needed" short acting beta-agonists provide inadequate clinical control;

3. Forced expiratory volume at one second (FEV1) > 70% of the predicted normal value demonstrable at least 6 hours after last short acting β-2 agonist use or 12 hours after last long acting β-2 agonist (LABA) use;

4. Nasal Symptoms Score (NSS) at baseline ≥ 3. Baseline NSS will be defined as the mean of the 6 last assessments of the patients' diary (3 last days before randomization);

5. Positive results of skin prick test on at least one seasonal allergen within the last 3 years;

6. Patients who provided a signed written informed consent form;

7. Patients who are able and willing to complete web-based Patient's Diary;

8. Patients who agree to maintain consistency in their surroundings throughout the study period;

9. Women of childbearing potential (WOCBP) including peri-menopausal women who have had a menstrual period within 1 year have to have a negative pregnancy test. Results have to be available until the Visit 2 and negative for the patient to be entered in the study.

10. WOCBP have to use an effective method of birth control throughout the study period and for 4 weeks after study completion (defined as a method which results in a failure rate of less than 1% per year) such as:

    • combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
    • progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
    • intrauterine device (IUD)
    • intrauterine hormone-releasing system (IUS)
    • bilateral tubal occlusion
    • vasectomised partner (provided that partner is the sole sexual partner of the trial participant and that the vasectomised partner has received medical assessment of the surgical success)
    • sexual abstinence In each case of delayed menstrual period (over one month between menstruations) confirmation of absence of pregnancy is strongly recommended. This recommendation also applies to WOCBP with infrequent or irregular menstrual cycles.

EXCLUSION CRITERIA

1. Patients with hypersensitivity to any component of the study medications;

2. Patients with non-allergic rhinoconjunctivitis (e.g. vasomotor, infectious, drug-induced);

3. Presence of nasal polyps or any clinically important nasal anomaly;

4. History of acute and/or chronic sinusitis within 30 days of Visit 2;

5. History of eye surgery within 3 months of Visit 2;

6. History of intranasal surgery within 3 months of Visit 2;

7. Immunotherapy within 6 months prior to Visit 1;

8. Upper respiratory infections including cold and systemic infections within 3 weeks of Visit 2;

9. Patients with moderate to severe renal impairment and taking P-gp inhibitors (e.g. ketoconazole, erythromycin, cyclosporine, ritonavir, diltiazem) within 7 days prior to the first dose of study medication;

10. Patients requiring daily "controller" medications with cromolyn-type drugs or leukotriene antagonists;

11. Patient required daily "controller" medication with Inhaled corticosteroids (ICS) or LABA at medium /high dosage defined by GINA criteria;

12. Patients with clinically important (based on principal investigator's judgment) hepatic impairment;

13. Patients with severe concomitant disease (based on principal investigator's judgment) that could interfere with treatment response;

14. Patients with QT syndrome;

15. Patients with Galactose intolerance, Lapp lactase deficiency or glucose- galactose malabsorption;

16. Pregnant or breast-feeding women;

17. Patients with a mental condition rendering the subject unable to understand the nature, scope and possible consequences of the study (based on principal investigator's judgment);

18. Patients who had a recent history (within previous 12 months) of drug addiction or alcohol abuse based on Principal investigator's judgment ;

19. Patients participating in or having participated in another clinical trial within the previous three months;

20. Patients unable to take relief medications due to contraindications or intolerance;

21. Patients who are taking or have taken any of the following medications prior to randomisation in the study and have not complied with the specified washout period:

    • Antihistaminic drugs or montelukast (7 days)
    • Systemic or intranasal corticosteroids (4 weeks)
    • Delayed-release corticosteroids (3 months)
    • Ketotifen (2 weeks)
    • Macrolides antibiotics and imidazolic antifungals (systemic)(7 days)
    • Anticholinergics (7 days)
    • Drugs with antihistamine properties (phenothiazine) (7 days)
    • Intranasal and systemic decongestants (3 days)
    • Lodoxamide (7 days)

22. Patients who will be operating heavy machinery or need to drive motor vehicles as an essential part of their profession.

23. Patients who are planning to travel outside the study area during the course of the study.

The principal investigator and study staff, subjects and monitors remained blinded to the treatment until study closure in this double-blind, double-dummy study. The identity of the study drug was revealed only if the subject experienced a medical emergency the management of which would be improved by the knowledge of the blinded treatment assignment.

As the combination therapy of Bilastine + Montelukast consisted of two tablets in contrast to monotherapy with either Bilastine or Montelukast, the double-dummy technique was applied with matching placebo for each Investigation Medicinal Product (IMP) (monotherapy with Bilastine or Montelukast) to ensure the maintenance of double-blind conditions. Therefore, each patient took 2 tablets with each dose administered.

As by randomisation list, each Patient Kit consisted of two IMP treatments (either active + placebo or active + active) in separate blisters packed in two different boxes.