Randomized, Placebo Controlled, Crossover Study in an Environmental Challenge Chamber to Assess Safety & Efficacy of Three Oral Doses of BI 671800 Versus Fluticasone Propionate and Montelukast in Sensitive Seasonal Allergic Rhinitis Patients Out of Season

Study Overview
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Brief Summary
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The objective of the current study is to investigate the efficacy, safety and tolerability of BI 671800 ED using three dose levels of BI 671800 ED (50 mg, 200 mg and 400 mg), administered twice daily compared to FP (fluticasone propionate) nasal 100 mcg per nostril qd in the morning or Montelukast 10 mg qd am given for 2 weeks in patients with SAR (seasonal allergic rhinitis) out of season using an environmental exposure chamber in patients known to be sensitive to the aero-allergen Dactylis glomerata.

Official Title
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Randomised, Double-blind, Triple Dummy, Partial Cross-over (Each Active Treatment With Placebo) Study Using an Environmental Challenge Chamber (ECC) to Assess the Safety and Efficacy of 2 Weeks of Oral BI 671800 ED 50, 200 or 400 mg Bid, Compared to Montelukast 10 mg qd, Fluticasone Propionate Nasal Spray 200 µg qd (2 Nasal Actuations Each Nostril of 50 µg) Versus Placebo in Seasonal Allergic Rhinitis Patients Out of Season, Sensitive to Dactylis Glomerata.

Conditions
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Rhinitis, Allergic, Seasonal, Asthma

Intervention / Treatment
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* Drug: BI 67100 ED 25 mg
* Drug: BI 671800 ED placebo
* Drug: montelukast placebo tablet
* Drug: montelukast placebo tablet
* Drug: fluticasone propionate placebo nasal spray
* Drug: fluticasone propionate placebo nasal spray
* Drug: fluticasone propionate placebo nasal spray
* Drug: BI 671800 ED 100 mg
* Drug: BI 671800 ED placebo
* Drug: BI 671800 ED placebo
* Drug: BI 671800 ED placebo
* Drug: BI 671800 ED 100 mg
* Drug: 671800 ED placebo
* Drug: montelukast placebo tablet
* Drug: montelukast placebo tablet
* Drug: montelukast placebo tablet
* Drug: montelukast 10 mg tablet
* Drug: fluticasone propionate placebo nasal spray
* Drug: fluticasone propionate nasal spray placebo
* Drug: Fluticasonepropionate nasal spray 200 mcg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent consistent with ICH-GCP guidelines (International Conference on Harmonisation for Good Clinical Practice) and local legislations prior to any study-related procedures, which includes medication washout and restrictions. Male or female, with a diagnosis of seasonal allergic rhinitis by a physician with a positive skin prick test to Dactylis glomerata within 12 months prior to Visit 2 TNSS (total nasal symptom score) of less or equal than 2 before start of challenge at Visit 2 and a TNSS of > 5 at least once during the 2h-baseline ECC exposure 18 to 65 years of age (age inclusive) Non-smoker or ex-smoker with a cigarette smoking history of less or equal than 10 pack-years (and smoking cessation for at least one year prior to enrolment) with negative urinary cotinine at screening (Visit 1) Ability to comply with requirements, medication restrictions (see 4.2.2) and procedures of the study protocol including AM1® device and rescue medication use. Pre-bronchodilator FEV1 (forced expiratory volume in one second) equal or greater than 80% of predicted value (European Community for Steel and Coal) at screening BMI between 18 and 35 (Body Mass Index) Negative breath -alcohol, urine -cotinine and -drug tests at screening (Visit 1) Exclusion Criteria: Significant pulmonary disease other than allergic rhinitis (or mild intermittent asthma managed by SABA (short acting bronchodilator) alone) or other medical conditions* that may, in the opinion of the investigator result in the any of the following: put the patient at risk because of participation in the study influence the results of the study (as determined by medical history, examination and clinical investigations at screening) cause concern regarding the patient's ability to participate in the study. *e.g. cardiac, gastro-intestinal, hepatic, renal, metabolic, dermatologic, neurological, haematological, oncological and psychiatric. Patients with malignancy for which the patient has undergone resection, radiation or chemotherapy within past 5 years. Patients with treated basal cell carcinoma or fully cured squamous cell carcinoma are allowed. Any other nasal and sinusoidal diseases or conditions by discretion of the investigator (i.e. nasal polyps, frequent nose bleeding) which may influence the study results Respiratory tract infection or asthma exacerbation in the 4 weeks prior to Visit 1 or during the screening and baseline period. Thoracotomy with pulmonary resection. Previous participation in this study (receipt of randomized treatment) or active participation in a current interventional study. Patients with a clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis at screening, if the abnormality defines a significant disease as defined in exclusion criterion No. 1. Patients will not be randomised if they have increased liver transaminases (AST or ALT greater than two fold the upper limit of normal at screening). Laboratory testing may be repeated once before randomization. Significant alcohol or drug abuse within past 2 years (see exclusion criteria No. 1) Patients with known hypersensitivity to any component of the investigational treatment (see section 4.1.1) or to fluticasone propionate nasal spray or montelukast or salbutamol or components. Patients taking CYP2C8 substrates such as -but not restricted to- amiodarone, amodiaquine, paclitaxel, rosiglitazone, pioglitazone, and repaglinide and CYP2C9 substrates such as -but not restricted to- warfarin, tolbutamide, phenytoin, losartan and acenocoumarol. Patients who have been treated with any of the following medications in the given interval before the respective Visit: Before Visit 2 An investigational drug within 1 month or six half lives (whichever is greater) Any immunomodulatory therapy since specific positive skin prick test. A biological based antagonist therapy including Omalizumab, or immune modulator therapy within 6 months A systemic (intravenous, intramuscular or oral) corticosteroid within 3 months The following medications within 4 weeks: topical steroids, change in prescription medications The following medications within 2 weeks: LABA (long acting beta agonist), methylxanthines, leukotriene modifiers, any antihistamines, oral decongestants, any anti-rhinitis therapies (i.e., decongestants, herbals, anticholinergics), and hay-fever medications, tricyclic antidepressants, aspirin and any NSAIDs (non steroidal anti inflammatory drugs) (for occasional pain relief, only paracetamol may be used), oral beta 2 agonists Before Visit 1: Short acting bronchodilator within 6 hours of baseline pulmonary function testing Patients with a risk for prolonged QT interval effects including: A marked baseline prolongation of the QT interval in the electrocardiogram by demonstration of a QTcB interval (Bazett's correction formula) > 450 ms A history of additional risk factors for TdP (Torsades de pointes) e.g., heart failure, hypokalemia, family, history of Long QT Syndrome, etc. The use of concomitant medications known to prolong the QT/QTc interval Pregnant or nursing women Women of childbearing potential not using a highly effective method of birth control.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 671800 ED 100 mg<br>2 capsules of BI 671800 ED 25 mg plus 2 capsules of BI 671800 ED placebo (bid in the morning and evening) plus 1 over-encapsulated montelukast placebo tablet (qd in the morning) plus fluticasone propionate placebo nasal spray (2 puffs each nostril qd in the morning) | Drug: BI 67100 ED 25 mg<br>* 2 capsules of BI 671800 ED 25 mg<br>Drug: BI 671800 ED placebo<br>* 2 capsules of BI 671800 ED placebo (bid in the morning and evening)<br>Drug: montelukast placebo tablet<br>* 1 over-encapsulated montelukast placebo tablet (qd in the morning)<br>Drug: fluticasone propionate placebo nasal spray<br>* fluticasone propionate placebo nasal spray (2 puffs each nostril qd in the morning)<br>|
| Experimental: BI 671800 ED 400 mg<br>2 capsules of BI 671800 ED 100 mg plus 2 capsules of placebo (bid in the morning and evening) plus 1 over-encapsulated montelukast placebo tablet (qd in the morning) plus fluticasone propionate nasal spray placebo (2 puffs each nostril qd in the morning) | Drug: fluticasone propionate placebo nasal spray<br>* fluticasone propionate placebo nasal spray (2 puffs each nostril qd in the morning)<br>Drug: BI 671800 ED 100 mg<br>* 2 capsules of BI 671800 ED 100 mg (bid in the morning and evening)<br>Drug: 671800 ED placebo<br>* 2 capsules of BI 671800 ED placebo (bid in the morning and evening)<br>Drug: montelukast placebo tablet<br>* 1 over-encapsulated montelukast placebo tablet (qd in the morning)<br>|
| Active Comparator: Montelukast 10 mg<br>1 over-encapsulated montelukast 10 mg tablet (qd in the morning) plus 4 capsules of BI 671800 ED placebo (bid in the morning and evening) plus fluticasone propionate placebo nasal spray (2 puffs each nostril qd in the morning) | Drug: fluticasone propionate placebo nasal spray<br>* fluticasone propionate placebo nasal spray (2 puffs each nostril qd in the morning)<br>Drug: BI 671800 ED placebo<br>* 4 capsules of BI 671800 ED placebo (bid in the morning and evening)<br>Drug: montelukast 10 mg tablet<br>* 1 over-encapsulated montelukast 10 mg tablet (qd in the morning)<br>|
| Active Comparator: Fluticasonepropionate nasal spray 200¿g<br>Fluticasonepropionate nasal spray 200 mcg (qd, 2 puffs of 50 ¿g per nostril) plus 4 capsules of BI 671800 ED placebo (bid in the morning and evening) plus 1 overencapsulated montelukast placebo tablet (qd in the morning) | Drug: BI 671800 ED placebo<br>* 4 capsules of BI 671800 ED placebo (bid in the morning and evening)<br>Drug: montelukast placebo tablet<br>* 1 over-encapsulated montelukast placebo tablet (qd in the morning)<br>Drug: Fluticasonepropionate nasal spray 200 mcg<br>* Fluticasonepropionate nasal spray 200 mcg (qd, 2 puffs of 50 mcg per nostril)<br>|
| Placebo Comparator: BI 671800 ED placebo<br>4 capsules of BI 671800 ED placebo (bid in the morning and evening), plus 1 over-encapsulated montelukast placebo tablet (qd in the morning) plus fluticasone propionate placebo nasal spray (2 puffs each nostril qd in the morning) | Drug: montelukast placebo tablet<br>* 1 over-encapsulated montelukast placebo tablet (qd in the morning)<br>Drug: BI 671800 ED placebo<br>* 4 capsules of BI 671800 ED placebo (bid in the morning and evening)<br>Drug: fluticasone propionate placebo nasal spray<br>* fluticasone propionate placebo nasal spray (2 puffs each nostril qd in the morning)<br>|
| Experimental: BI 671800 ED 800 mg<br>4 capsules of BI 671800 ED 100 mg (bid in the morning and evening) plus 1 over-encapsulated montelukast placebo tablet (qd in the morning) plus fluticasone propionate nasal spray placebo (2 puffs each nostril qd in the morning) | Drug: BI 671800 ED 100 mg<br>* 4 capsules of BI 671800 ED 100 mg (bid in the morning and evening)<br>Drug: montelukast placebo tablet<br>* 1 over-encapsulated montelukast placebo tablet (qd in the morning)<br>Drug: fluticasone propionate nasal spray placebo<br>* fluticasone propionate nasal spray placebo (2 puffs each nostril qd in the morning)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Nasal Symptom Score (TNSS) as AUC (area under the curve) of values over the entire period from 0-6 hours (h) in the ECC (Environmental Challenge Chamber) |  | After 2 wks of active treatment compared to 2 wks treatment with placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Symptom Score (TSSc) as AUC of values for the following periods: 0-2h; 2-4h; 4-6h; 2-6h; 0-6h; 0h-tmax; tmax-6h and hourly |  | After 2 wks of active treatment compared to 2 wks treatment with placebo | 
| TNSS as AUC of values for the following periods: 0-2h; 2-4h; 4-6h; 2-6; 0h-tmax; tmax-6h and hourly |  | After 2 wks of active treatment compared to 2 wks treatment with placebo | 
| Total Ocular Symptom Score (TOSS) as AUC of values for the following periods: 0-2h; 2-4h; 4-6h; 2-6h; 0-6h; 0h-tmax; tmax- 6h and hourly |  | After 2 wks of active treatment compared to 2 wks treatment with placebo | 
| Nasal and ocular sub-scores (single symptoms of TNSS and TOSS) as AUC of values for the following periods: 0-2h; 2-4h; 4-6h; 2-6h; 0-6h; 0h-tmax; tmax-6h and hourly |  | After 2 wks of active treatment compared to 2 wks treatment with placebo | 
| Flow rate from rhinomanometry as AUC of values obtained at 2, 4 and 6 h |  | After 2 wks of active treatment compared to 2 wks treatment with placebo |