A Study to Assess Intranasal Repeat Dose Effect of Levocabastine in the Subjects With Allergic Rhinitis

Study Overview
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Brief Summary
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This study will be a randomized, double blind, placebo controlled, 3-way cross over design in allergic rhinitis subjects. Subjects will receive repeat doses of intra-nasal levocabastine for 7 days in each period and the duration of the study will be about 13 weeks. An Environmental Exposure Chamber (EEC) will be used in this study. The primary objective of the study is to investigate the non-inferiority effect of 7 days treatment with levocabastine on nasal symptoms elicited by an EEC when administered once daily (QD) compared with twice daily (BID). Also study will be conducted to investigate the superiority of effect of 7 days treatment with levocabastine (QD and BID) on nasal symptoms elicited by an EEC in subjects compared to placebo.

Official Title
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A Randomized, Double-blind, Placebo Controlled, 3 Way Cross Over Study in Subjects With Allergic Rhinitis to Assess the Effect of Intranasal Repeat Doses of Levocabastine When Administered Once Daily or Twice Daily on the 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: Levocabastine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Allergic Rhinitis (AR), as determined by the presence of seasonal or perennial rhinitis symptoms 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 at the baseline screening allergen challenge. Total nasal symptom score is the sum of nasal congestion, rhinorrhoea, nasal itch and sneeze, each of which are scored on a scale from 0 to 3. 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 4 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, laboratory tests and cardiac monitoring. 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 kilogram (kg) and body mass index (BMI) within the range 19 - 30 kg per meter square (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 (MlU/mL) and estradiol <40 picogram (pg)/mL (<147 picomol per liter [pmol/L]) is confirmatory); child-bearing potential with negative pregnancy test as determined by urine human chorionic gonadotropin (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 (ALP) and bilirubin <=1.5 x 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 QTc (QTcF) <450 milliseconds (msec). Exclusion Criteria: Nasal abnormalities likely to affect the outcome of the study, i.e. nasal septal perforation, nasal polyps, sinusitis and other nasal malformations. History of frequent nosebleeds. Subjects 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 subject's participation in the study. History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360mL) of beer, 5 ounces (150mL) of wine or 1.5 ounces (45ml) of 80 proof distilled 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. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period. Lactating females. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Exposure to more than four new chemical entities within 12 months prior to the first dosing day. Chronic oral steroids discontinued less than 6 months prior to screening. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. Subjects who are using some of the medications below on an as needed basis, may participate in the study if they remain free of medication for the following periods of time prior to screening and prior to dosing (study drugs): Nasal antihistamines: 72 hours, Oral antihistamines A (cetirizine, fexofenadine, loratadine, desloratadine): 72 hours, Oral antihistamines B (all others): 72hours, Eye and Nasal Levocasbastine: 7 days, Nasal decongestants: 24 hours, Oral decongestants: 24 hours, Nasal glucocorticosteroids: 7 days, Inhaled glucocorticoids: 1 week, Oral glucocorticosteroids: 12 weeks, Oral leukotriene receptor antagonists: 7 days, Oral 5-lipoxygenase inhibitors: 7 days, Oral methylxanthines: 7 days Subjects with recent upper respiratory tract infections (URTIs) will be allowed in the study only if their nasal symptoms associated with the URTI have been completely resolved for more than 3 weeks prior to screening.

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: Levocabastine Arm<br>Subjects will be assigned to one of six treatment sequences (ABC, BCA, CAB, ACB, BAC, CBA) in accordance with the randomisation schedule. A = Two, 50 microgram (mcg) sprays per nostril of levocabastine QD in the morning. Total dose of 200 mcg. Two, 0 mcg sprays from placebo to match vehicle in the evening; B = Two, 50 mcg sprays per nostril of levocabastine BID in the morning and evening. Total dose of 400 mcg; C = Two, 0 mcg sprays per nostril from placebo vehicle in morning and evenings. | Drug: Levocabastine<br>* Intranasal aqueous 50 mcg microsuspension of levocabastine supplied in an amber glass bottle fitted with a white top actuated plastic metering atomising spray pump filled with a uniform white suspension<br>Drug: Placebo<br>* Intranasal aqueous 0 mcg microsuspension supplied in an amber glass bottle fitted with a white top actuated plastic metering atomising spray pump filled with a uniform white suspension<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 | 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 13 Weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weighted Mean of the Symptom Scores for the Four Individual Components of the Total Nasal Symptom Score (TNSS) (Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing) (0-4) Hours Post Start of the Allergen Chamber Challenge on Day 8 | TNSS contains symtom scores for the four individual components (nasal congestion [NACG], rhinorrhea [RHSCR], nasal itching [NAITS] and sneezing [SNZS]), each scored on a 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 is administered in a sealed chamber to evaluate the efficacy of antihistamines/other treatments. The participants recorded their symptom scores on an e-diary. The mean score for each participant was calculated using the available diary data from the assessment periods, taking the average of non-missing data during the period. Weighted mean of the individual symptoms of theTNSS were 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 13 Weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allergic rhinitis, levocabastine, allergen challenge