Seasonal Allergic Rhinoconjunctivitis, Asthma
Conditions
Keywords
Bilastine, Montelukast, total symptom score, AQLQ
Brief summary
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
Detailed description
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.
Interventions
Sponsors
Menarini International Operations Luxembourg SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
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.
Intervention model description
The study was a randomised (1:1:1), double-blind, double-dummy, interventional, active-controlled, parallel groups (three groups), multi-centre, multi-national, superiority clinical trial. The study plan included a 7-day (± 4) run-in period to ensure wash-out from previous forbidden treatments and to perform the tests required to ensure appropriate patient enrolment into the study. The active treatment period was 12 weeks (85 days) with a follow-up visit (phone call) at 28 days (± 4) after the End of Treatment.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline With Montelukast+Bilastine Compared With Bilastine Monotherapy in SARC Symptoms | 4 weeks of treatment (from baseline to 4 weeks of treatment) | To demonstrate that concomitant administration of montelukast and bilastine is superior to bilastine monotherapy in SARC symptoms, as assessed by Total Symptoms Scores (TSS) after 4 weeks of treatment. Total Symptoms Scores (TSS) assesses nasal (nasal congestion, rhinorrhea, nasal itching, sneezing) and non nasal symptoms (ocular redness, ocular itching, tearing) of rhinoconjuctivits. Each of the 7 symptoms is scored from 0 (absent) to 3 (severe) as follows: * 0 (absent) Symptom not present * 1 (mild) Symptom is clearly present but easily tolerated, a nuisance, minimal awareness * 2 (moderate) Symptom is bothersome but tolerable, does not interfere with daily activities or sleep * 3 (severe) Symptom is hard to tolerate and interferes with daily activities or sleep. TSS assessment comprises of scoring (0-3) of all 7 above mentioned symptoms. Final TSS scores is in a range from 0-21. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline With Montelukast+Bilastine Compared With Montelukast and Bilastine Monotherapies in Asthma Control | After 4 weeks of treatments | To evaluate the efficacy of concomitant montelukast and bilastine compared with montelukast and bilastine monotherapies in asthma control, as assessed by Asthma Quality of Life Questionnaire (AQLQ) after 4 weeks. The AQLQ was developed to measure the functional problems (physical, emotional, social and occupational) that are most troublesome to adults (17-70 years) with asthma. Each of the 32 questionnaire's items will be scored on a 7-point scale (where 7 means not impaired at all and 1 means severely impaired). The overall AQLQ score is the mean of all 32 responses (https://www.qoltech.co.uk/aqlq.html). The change in AQLQ score from baseline to 4 weeks after treatment - AQLQ score at baseline for patients with both available values has been the secondary endpoint. |
| Change From Baseline With Montelukast+Bilastine Compared With Montelukast and Bilastine Monotherapies in SARC Symptoms (DNSS) | After 4 weeks of treatment (from baseline) | To evaluate the efficacy of concomitant montelukast and bilastine compared with montelukast and bilastine monotherapies in daytime symptoms of SARC, as assessed by Daytime Nasal Symptom Score (DNSS) after 4 weeks of treatment. Daytime Nasal Symptom Score (DNSS) is the average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing of rhinoconjuctivits. Each of the 4 symptoms is scored from 0 (absent) to 3 (severe) as follows: * 0 (absent) Symptom not present * 1 (mild) Symptom is clearly present but easily tolerated, a nuisance, minimal awareness * 2 (moderate) Symptom is bothersome but tolerable, does not interfere with daily activities or sleep * 3 (severe) Symptom is hard to tolerate and interferes with daily activities or sleep. DNSS assessment comprises of scoring (0-3) of all 4 above mentioned symptoms. Final DNSS scores is in a range from 0-12. |
| Change From Baseline With Montelukast + Bilastine Compared With Montelukast and Bilastine Monotherapies in SARC Symptoms (DNNSS) | After 4 weeks of treatment (from baseline) | To evaluate the efficacy of concomitant montelukast and bilastine compared with montelukast and bilastine monotherapies in daytime symptoms of SARC, as assessed by Daytime Non Nasal Symptom Score (DNNSS) after 4 weeks of treatment. Daytime Non Nasal Symptom Score (DNSS) is the average of individual scores of ocular redness, ocular itching and tearing of rhinoconjuctivits. Each of the 3 symptoms is scored from 0 (absent) to 3 (severe) as follows: * 0 (absent) Symptom not present * 1 (mild) Symptom is clearly present but easily tolerated, a nuisance, minimal awareness * 2 (moderate) Symptom is bothersome but tolerable, does not interfere with daily activities or sleep * 3 (severe) Symptom is hard to tolerate and interferes with daily activities or sleep. DNNSS assessment comprises of scoring (0-3) of all 3 above mentioned symptoms. Final DNNSS scores is in a range from 0-9. |
| Usage of Relief Medication for SARC | From baseline to 4 weeks of treatment | Number of days without any relief medication for SARC |
| Usage of Relief Medication for Asthma | From baseline to 4 weeks of treatment | Number of days without any relief medication for Asthma. |
Countries
Croatia, Czechia, Germany, Italy, Latvia, Poland, Romania, Slovakia
Participant flow
Recruitment details
The recruitment started on 13 April 2016 and termineted on 23 November 2016. 454 patients with SARC and mild to moderate asthma as comorbidity were screened. 420 patients were randomised of which 388 patients completed the study.
Pre-assignment details
454 patients were enrolled but 34 patients did not met inclusion/exclusion critera.
Participants by arm
| Arm | Count |
|---|---|
| Bilastine+Montelukast Bilastine 20mg
Montelukast 10mg | 143 |
| Bilastine Monotherapy Bilastine 20mg
Placebo Montelukast 10mg | 140 |
| Montelukast Monotherapy Montelukast 10mg
Placebo Bilastine 20mg | 137 |
| Total | 420 |
Baseline characteristics
| Characteristic | Bilastine+Montelukast | Bilastine Monotherapy | Montelukast Monotherapy | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 143 Participants | 140 Participants | 137 Participants | 420 Participants |
| Age, Continuous | 34.9 years STANDARD_DEVIATION 11.1 | 35.5 years STANDARD_DEVIATION 11 | 35.4 years STANDARD_DEVIATION 10.7 | 35.2 years STANDARD_DEVIATION 10.9 |
| Sex: Female, Male Female | 69 Participants | 83 Participants | 73 Participants | 225 Participants |
| Sex: Female, Male Male | 74 Participants | 57 Participants | 64 Participants | 195 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 143 | 4 / 140 | 14 / 137 |
| serious Total, serious adverse events | 0 / 143 | 0 / 140 | 1 / 137 |
Outcome results
Primary
Change From Baseline With Montelukast+Bilastine Compared With Bilastine Monotherapy in SARC Symptoms
To demonstrate that concomitant administration of montelukast and bilastine is superior to bilastine monotherapy in SARC symptoms, as assessed by Total Symptoms Scores (TSS) after 4 weeks of treatment. Total Symptoms Scores (TSS) assesses nasal (nasal congestion, rhinorrhea, nasal itching, sneezing) and non nasal symptoms (ocular redness, ocular itching, tearing) of rhinoconjuctivits. Each of the 7 symptoms is scored from 0 (absent) to 3 (severe) as follows: * 0 (absent) Symptom not present * 1 (mild) Symptom is clearly present but easily tolerated, a nuisance, minimal awareness * 2 (moderate) Symptom is bothersome but tolerable, does not interfere with daily activities or sleep * 3 (severe) Symptom is hard to tolerate and interferes with daily activities or sleep. TSS assessment comprises of scoring (0-3) of all 7 above mentioned symptoms. Final TSS scores is in a range from 0-21.
Time frame: 4 weeks of treatment (from baseline to 4 weeks of treatment)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Bilastine+Montelukast | Change From Baseline With Montelukast+Bilastine Compared With Bilastine Monotherapy in SARC Symptoms | -3.2522 score on a scale |
| Bilastine Monotherapy | Change From Baseline With Montelukast+Bilastine Compared With Bilastine Monotherapy in SARC Symptoms | -3.4462 score on a scale |
p-value: 0.572195% CI: [-0.8693, 0.4813]ANCOVA
Secondary
Change From Baseline With Montelukast+Bilastine Compared With Montelukast and Bilastine Monotherapies in Asthma Control
To evaluate the efficacy of concomitant montelukast and bilastine compared with montelukast and bilastine monotherapies in asthma control, as assessed by Asthma Quality of Life Questionnaire (AQLQ) after 4 weeks. The AQLQ was developed to measure the functional problems (physical, emotional, social and occupational) that are most troublesome to adults (17-70 years) with asthma. Each of the 32 questionnaire's items will be scored on a 7-point scale (where 7 means not impaired at all and 1 means severely impaired). The overall AQLQ score is the mean of all 32 responses (https://www.qoltech.co.uk/aqlq.html). The change in AQLQ score from baseline to 4 weeks after treatment - AQLQ score at baseline for patients with both available values has been the secondary endpoint.
Time frame: After 4 weeks of treatments
Population: The Intention To Treat population (used for statistical analysis) was 419 patients because 1 patient in Montekukast Monotherapy arm was a drop-out.~The drop-out patient was, instead, included in a Safety Population (420 patients).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Bilastine+Montelukast | Change From Baseline With Montelukast+Bilastine Compared With Montelukast and Bilastine Monotherapies in Asthma Control | 0.6250 score on a scale |
| Bilastine Monotherapy | Change From Baseline With Montelukast+Bilastine Compared With Montelukast and Bilastine Monotherapies in Asthma Control | 0.6399 score on a scale |
| Montelukast Monotherapy | Change From Baseline With Montelukast+Bilastine Compared With Montelukast and Bilastine Monotherapies in Asthma Control | 0.5849 score on a scale |
p-value: 0.010595% CI: [-2.0379, -0.2725]ANCOVA
Secondary
Change From Baseline With Montelukast + Bilastine Compared With Montelukast and Bilastine Monotherapies in SARC Symptoms (DNNSS)
To evaluate the efficacy of concomitant montelukast and bilastine compared with montelukast and bilastine monotherapies in daytime symptoms of SARC, as assessed by Daytime Non Nasal Symptom Score (DNNSS) after 4 weeks of treatment. Daytime Non Nasal Symptom Score (DNSS) is the average of individual scores of ocular redness, ocular itching and tearing of rhinoconjuctivits. Each of the 3 symptoms is scored from 0 (absent) to 3 (severe) as follows: * 0 (absent) Symptom not present * 1 (mild) Symptom is clearly present but easily tolerated, a nuisance, minimal awareness * 2 (moderate) Symptom is bothersome but tolerable, does not interfere with daily activities or sleep * 3 (severe) Symptom is hard to tolerate and interferes with daily activities or sleep. DNNSS assessment comprises of scoring (0-3) of all 3 above mentioned symptoms. Final DNNSS scores is in a range from 0-9.
Time frame: After 4 weeks of treatment (from baseline)
Population: The Intention To Treat population (used for statistical analysis) was 419 patients because 1 patient in Montekukast Monotherapy arm was a drop-out.~The drop-out patient was, instead, included in a Safety Population (420 patients).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Bilastine+Montelukast | Change From Baseline With Montelukast + Bilastine Compared With Montelukast and Bilastine Monotherapies in SARC Symptoms (DNNSS) | -1.2824 score on a scale |
| Bilastine Monotherapy | Change From Baseline With Montelukast + Bilastine Compared With Montelukast and Bilastine Monotherapies in SARC Symptoms (DNNSS) | -1.3185 score on a scale |
| Montelukast Monotherapy | Change From Baseline With Montelukast + Bilastine Compared With Montelukast and Bilastine Monotherapies in SARC Symptoms (DNNSS) | -1.1574 score on a scale |
p-value: 0.8103295% CI: [-0.3319, 0.2596]ANCOVA
Secondary
Change From Baseline With Montelukast+Bilastine Compared With Montelukast and Bilastine Monotherapies in SARC Symptoms (DNSS)
To evaluate the efficacy of concomitant montelukast and bilastine compared with montelukast and bilastine monotherapies in daytime symptoms of SARC, as assessed by Daytime Nasal Symptom Score (DNSS) after 4 weeks of treatment. Daytime Nasal Symptom Score (DNSS) is the average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing of rhinoconjuctivits. Each of the 4 symptoms is scored from 0 (absent) to 3 (severe) as follows: * 0 (absent) Symptom not present * 1 (mild) Symptom is clearly present but easily tolerated, a nuisance, minimal awareness * 2 (moderate) Symptom is bothersome but tolerable, does not interfere with daily activities or sleep * 3 (severe) Symptom is hard to tolerate and interferes with daily activities or sleep. DNSS assessment comprises of scoring (0-3) of all 4 above mentioned symptoms. Final DNSS scores is in a range from 0-12.
Time frame: After 4 weeks of treatment (from baseline)
Population: The Intention To Treat population (used for statistical analysis) was 419 patients because 1 patient in Montekukast Monotherapy arm was a drop-out.~The drop-out patient was, instead, included in a Safety Population (420 patients).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Bilastine+Montelukast | Change From Baseline With Montelukast+Bilastine Compared With Montelukast and Bilastine Monotherapies in SARC Symptoms (DNSS) | -1.9713 score on a scale |
| Bilastine Monotherapy | Change From Baseline With Montelukast+Bilastine Compared With Montelukast and Bilastine Monotherapies in SARC Symptoms (DNSS) | -2.1106 score on a scale |
| Montelukast Monotherapy | Change From Baseline With Montelukast+Bilastine Compared With Montelukast and Bilastine Monotherapies in SARC Symptoms (DNSS) | -1.8678 score on a scale |
p-value: 0.488595% CI: [-0.5342, 0.2557]ANCOVA
Secondary
Usage of Relief Medication for Asthma
Number of days without any relief medication for Asthma.
Time frame: From baseline to 4 weeks of treatment
Population: The Intention To Treat population (used for statistical analysis) was 419 patients because 1 patient in Montekukast Monotherapy arm was a drop-out.~The drop-out patient was, instead, included in a Safety Population (420 patients).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bilastine+Montelukast | Usage of Relief Medication for Asthma | 53.2548 Days | Standard Error 2.0193 |
| Bilastine Monotherapy | Usage of Relief Medication for Asthma | 52.4177 Days | Standard Error 2.0212 |
| Montelukast Monotherapy | Usage of Relief Medication for Asthma | 50.7146 Days | Standard Error 2.0768 |
p-value: 0.745295% CI: [-5.8968, 4.2228]ANOVA
Secondary
Usage of Relief Medication for SARC
Number of days without any relief medication for SARC
Time frame: From baseline to 4 weeks of treatment
Population: The Intention To Treat population (used for statistical analysis) was 419 patients because 1 patient in Montekukast Monotherapy arm was a drop-out.~The drop-out patient was, instead, included in a Safety Population (420 patients).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bilastine+Montelukast | Usage of Relief Medication for SARC | 15.0057 Days | Standard Error 0.826 |
| Bilastine Monotherapy | Usage of Relief Medication for SARC | 15.8416 Days | Standard Error 0.8326 |
| Montelukast Monotherapy | Usage of Relief Medication for SARC | 15.4179 Days | Standard Error 0.8411 |
p-value: 0.370495% CI: [-0.9969, 2.6688]ANOVA