A Proof of Concept Study to Assess Effect of Fluticasone Furoate (FF)/Levocabastine Fixed Dose Combination (FDC) Compared With Levocabastine and FF Alone in Subjects With Allergic Rhinitis (AR)

Study Overview
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Brief Summary
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This study will be a randomised, double blind, placebo controlled, 3-way, incomplete block crossover study to evaluate the effect of single and repeat doses of levocabastine, FF, placebo and a FDC of FF/levocabastine administration in AR subjects. The total expected study duration for each individual participating in the study will be a maximum of up to 20 weeks (including the screening and follow-up). This will be a three period study and subjects will be assigned to a sequence of three treatments. There will be a wash-out period of 14-28 days between two treatment periods. The rational for this study is to demonstrate proof of concept with the FDC of FF and levocabastine compared with each of the components administered alone.

Official Title
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A Randomised, Double-blind, Placebo-controlled, 3 Way, Incomplete Block Cross Over Study in Subjects With Allergic Rhinitis to Assess the Effect of Once Daily Single and Repeat Doses of Intranasal Fluticasone Furoate/Levocabastine Fixed Dose Combination (FDC) Relative to Levocabastine and Fluticasone Furoate Alone on the Onset and Magnitude of Symptoms of Rhinitis in an Allergen Challenge Chamber

Conditions
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Rhinitis, Allergic, Perennial and Seasonal

Intervention / Treatment
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* Drug: FF/levocabastine
* Drug: FF
* Drug: levocabastine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of AR, as determined by the presence of rhinitis symptoms that last for several months per year, for more than 1 year and are not attributed to infections or nasal abnormalities. Subjects have a TNSS score of >=6 during the screening allergen challenge chamber. Subjects have a positive skin prick test (wheal >=4 millimeter [mm]) for seasonal pollen at or within the 12 months preceding the screening visit. Subjects have a positive radioallergosorbent test (RAST) (>=class 2) for seasonal pollen at or within the 12 months preceding the screening visit. There are no conditions or factors that would make the subject unlikely to be able to stay in the chamber for 5 hours. Male/females between 18 and 65 years of age inclusive, at the time of signing the informed consent. Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination and laboratory tests. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the Investigator agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Body weight >=50 kg and body mass index (BMI) within the range 19-30 kilogram per meter suare (kg/m^2) (inclusive). A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy [for this definition, documented refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records]; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone [FSH] >40 milli international unit per milliliter (MIU/milliliter [mL]) and estradiol <40 picogram per milliliter[pg/mL] (<147 picomole per liter [pmol/L]) is confirmatory). Child-bearing potential with negative pregnancy test as determined by urine beta-human chorionic gonadotropin (β-hCG) test at screening or prior to dosing and; Agrees to use one of the contraception methods for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until 1 week post-last dose Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Subjects should be non-smokers, which for this study is defined as having smoked <10 packs per year in their lifetime, and have not smoked in the 6 months prior to the screening visit. alanine aminotransferase (ALT), alkaline phosphatase and bilirubin <=1.5x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Based on single or averaged corrected QT interval (QTc) values of triplicate electrocardiogram (ECGs) obtained over a brief recording period: Fridericia's QTC (QTcF) <450 milliseconds (msec). Exclusion Criteria: Nasal abnormalities likely to affect the outcome of the study, that is nasal septal perforation, nasal polyps, sinusitis other nasal malformations. History of frequent nose bleeds Patients with rhinitis medicamentosa Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Significant renal impairment, which based on the opinion of the investigator, would preclude the subjects participation in the study. History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 gram of alcohol: a half-pint ( 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening A positive pre-study drug/alcohol screen. A positive test for human immunodeficiency virus (HIV) antibody.

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: Arm 1<br>Each Subject will be assigned to a sequence of three treatments (e.g ABC, BCD, ACD): A=Two, 50 microliter (mcqL) sprays per nostril of FF, total dose 100 microgram (mcg); B=Two, 50 mcqL sprays per nostril of levocabastine, total dose 200 mcg; C=Two, 50 mcql sprays per nostril of FF/levocabastine FDC, total daily dose 100 mcg FF and 200 mcg levocabastine; D=Two, 50 mcql sprays per nostril of placebo. There will be a wash out period of 14-28 days between two treatment periods | Drug: FF/levocabastine<br>* FF/levocabastine (25mcg/50 mcg) will be supplied as intranasal aqueous microsuspension in an amber glass bottle fitted with a white top actuated plastic metering atomising spray pump filled with a uniform white suspension. Two sprays in each nostril in the morning in a fasted state will be administered.<br>Drug: FF<br>* FF (25mcg) will be supplied as intranasal aqueous microsuspension in an amber glass bottle fitted with a white top actuated plastic metering atomising spray pump filled with a uniform white suspension. Two sprays in each nostril in the morning in a fasted state will be administered.<br>Drug: levocabastine<br>* levocabastine (50mcg) will be supplied as intranasal aqueous microsuspension in an amber glass bottle fitted with a white top actuated plastic metering atomising spray pump filled with a uniform white suspension. Two sprays in each nostril in the morning in a fasted state will be administered.<br>Drug: Placebo<br>* Placebo will be supplied as intranasal aqueous microsuspension in an amber glass bottle fitted with a white top actuated plastic metering atomising spray pump filled with a uniform white suspension. Two sprays in each nostril in the morning in a fasted state will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weighted Mean of the Total Nasal Symptom Score (TNSS) (0-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 8 of Each Treatment Period | The TNSS (score of 0-12) is defined as the sum of the symptom scores for the four individual components (nasal congestion, rhinorrhea, nasal itch, and sneezing, each scored on 0-3 scale [0=none, 1=mild, 2=moderate, 3=severe]). TNSS was measured at the pre-allergen chamber challenge, and then every 15 minutes from 0 to 4 hours post start of the allergen chamber challenge. In the Environmental Exposure Chamber (EEC), aerosolized allergen was administered in a sealed chamber to evaluate the efficacy of antihistamines/other treatments. Weighted mean TNSS was calculated by dividing the value of the area under the response time curve over the 0-4 hours (calculated by trapezoidal rule) by the time interval of available data. | Day 8 of each treatment period (up to 80 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weighted Mean of the Magnitude of Symptom Relief on Total Nasal Symptom Score (TNSS) (2-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 1 of Each Treatment Period | Magnitude of symptom relief was assessed by calculating change from pre-dose weighted mean TNSS (2-4h) post start of the allergen chamber challenge at Day 1. The pre-dose value was the maximum of the three pre-dose measurements (1h 15 minutes (min), 1h 30 min and 1h 45 min post start of the allergen chamber challenge). The TNSS (score of 0-12) is defined as the sum of the symptom scores for the four individual components (nasal congestion, rhinorrhea, nasal itch and sneezing, each scored on 0-3 scale [0=none, 1=mild, 2=moderate, 3=severe]). | Day 1 of each treatment period (up to 80 days) | 
| Weighted Mean of the Magnitude of Symptom Relief on Total Ocular Symptom Score (TOSS) (2-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 1 of Each Treatment Period | Magnitude of symptom relief was assessed by calculating change from pre-dose weighted mean TOSS (2-4h) post start of the allergen chamber challenge at Day 1. The pre-dose value was the maximum of the three pre-dose measurements (1h 15 minutes (min), 1h 30 min and 1h 45 min post start of the allergen chamber challenge). The TOSS (score of 0-9) is defined as the sum of the symptom scores for the three individual components (red, itchy, and tearing eyes, each scored on 0-3 scale [0=none, 1=mild, 2=moderate, 3=severe], average of two eyes). | Day 1 of each treatment period (up to 80 days) | 
| Weighted Mean of the Total Ocular Symptom Score (TOSS) (0-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 8 of Each Treatment Period | The TOSS (score of 0-9) is defined as the sum of the symptom scores for the three individual components (red, itchy, and tearing eyes , each scored on 0-3 scale [0=none, 1=mild, 2=moderate, 3=severe], average of two eyes). TOSS was measured at the pre-allergen chamber challenge, and then every 15 minutes from 0 to 4 hours post start of the allergen chamber challenge. In the Environmental Exposure Chamber (EEC), aerosolized allergen was administered in a sealed chamber to evaluate the efficacy of antihistamines/other treatments. Weighted mean TOSS was calculated by dividing the value of the area under the response time curve over the 0-4 hours (calculated by trapezoidal rule) by the time interval of available data. | Day 8 of each treatment period (up to 80 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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levocabastine fixed dose combination, Rhinitis, Allergic, Perennial and Seasonal, Allergic Rhinitis, fluticasone furoate