Safety and Efficacy Study of Adding GSK2190915 to Low Dose Inhaled Corticosteroid Treatment for Asthma Subjects > or = 12 Years of Age

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy and safety of adding GSK2190915 100mg, GSK2190915 300mg or placebo tablets administered once daily to fluticasone propionate 100mcg inhalation administered twice daily in uncontrolled asthmatic subjects > or = 12 years of age over the course of 6 weeks treatment. The secondary objectives are to undertake an exploratory analysis of the efficacy and safety of adding montelukast 10mg administered once daily or salmeterol 50mcg administered twice daily to fluticasone propionate 100mcg inhalation administered twice daily and to investigate the pharmacokinetics and pharmacodynamics of GSK2190915 in uncontrolled asthmatic subjects > or = 12 years of age over the course of 6 weeks treatment.

Official Title
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A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Five-Treatment, Four 6-Week Period Cross-Over, Multi-Center Study to Evaluate the Effect of Adding GSK2190915 100mg, GSK2190915 300mg, Montelukast 10mg or Placebo Tablets Once Daily or Salmeterol 50mcg Inhalation Powder Twice Daily to Fluticasone Propionate 100mcg Inhalation Powder Twice Daily in Uncontrolled Asthmatic Subjects ≥ 12 Years of Age

Conditions
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Asthma

Intervention / Treatment
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* Drug: FP 100
* Drug: GSK2190915 100
* Drug: GSK2190915 300
* Drug: montelukast
* Drug: placebo
* Drug: FP/SAL 100/50


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 12 years of age or older Non-, former or current smokers with a documented smoking history of ≤ 10 pack years Asthma diagnosis as defined by the National Institutes of Health Best FEV1 of 50% to <80% of the predicted normal value Post-albuterol FEV1/FVC ratio of >0.70 at Visit 1/1a (between 5:00AM and 12:00 noon) ≥ 12% and ≥200mL reversibility of FEV1 Must have been using FP 100mcg inhalation powder BID for at least 2 weeks just prior to Visit 1. Must be able to replace their current short-acting beta2-agonists with albuterol inhalation aerosol Must be able and willing to give written informed consent to take part in the study. Must be able and willing to comply with all aspects of the study including completion of daily e-Diary. Exclusion criteria: History of life-threatening asthma Recent asthma exacerbation Concurrent respiratory disease Recent respiratory infection Liver disease Other concurrent diseases/abnormalities Oral candidiasis Drug allergy Milk protein allergy Immunosuppressive Medications Administration of systemic, oral or depot corticosteroids within 12 weeks of Visit 1 OATP1B1 substrates within 4 weeks of Visit 1 Cytochrome P450 3A4 (CYP 3A4) Inhibitors Cytochrome P450 3A4 (CYP 3A4) Inducers Investigational Medications Compliance: any infirmity, disability, or geographical location which seems likely (in the opinion of the Investigator) to impair compliance with any aspect of this study protocol Affiliation with Investigator's Site

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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Female

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FP 100mcg BID plus GSK2190915 100mg QD (AM)<br>FP 100mcg BID plus GSK2190915 100mg QD (AM) | Drug: FP 100<br>* FP 100mcg BID<br>Drug: GSK2190915 100<br>* GSK2190915 100mg QD (AM)<br>|
| Experimental: FP 100mcg BID plus GSK2190915 300mg QD (AM)<br>FP 100mcg BID plus GSK2190915 300mg QD (AM) | Drug: FP 100<br>* FP 100mcg BID<br>Drug: GSK2190915 300<br>* GSK2190915 300mg QD (AM)<br>|
| Active Comparator: FP 100mcg BID plus montelukast 10mg QD (PM)<br>FP 100mcg BID plus montelukast 10mg QD (PM) | Drug: FP 100<br>* FP 100mcg BID<br>Drug: montelukast<br>* montelukast 10mg QD (PM)<br>|
| Active Comparator: FP 100mcg BID plus placebo BID<br>FP 100mcg BID plus placebo BID | Drug: FP 100<br>* FP 100mcg BID<br>Drug: placebo<br>* placebo BID<br>|
| Active Comparator: FP/SAL 100/50mcg BID plus placebo BID<br>FP/SAL 100/50mcg BID plus placebo BID | Drug: placebo<br>* placebo BID<br>Drug: FP/SAL 100/50<br>* FP/SAL 100/50mcg BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough (AM Pre-dose and Pre-rescue Bronchodilator) Forced Expiratory Volume in 1 Second (FEV1) at the End of the 6-week Treatment Period | FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 was measured electronically using spirometry, prior to study medication and any rescue albuterol (bronchodilator) use. At the end of the 6-week treatment period, FEV1 was measured approximately 24 hours after the participant's last morning dose of study medication and approximately 12 hours after the evening dose of study medication. Trough FEV1 was analyzed using mixed effect analysis of covariance (ANCOVA) model for treatment effects, incorporating fixed effects of baseline, period, age, center, smoking status, and random effect of participant. Intent-to-Treat Population is defined as all participants who were randomized and received at least one dose of study drug. | End of Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily Trough (Morning Pre-dose and Pre-rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Averaged Over the Last 3 Weeks of the 6-week Treatment Period | The PEF is a measure of lung function and measures how fast a person can breathe out. Trough PEF was measured every morning prior to study medication dose and any rescue albuterol (bronchodilator) use. Participants recorded PEF in a daily electronic diary (eDiary). Daily trough morning PEF was averaged over the last 3 weeks of the 6-week treatment period, and analyzed using mixed effect ANCOVA model for treatment effects, incorporating fixed effects of baseline, period, age, center, smoking status, and random effects of participant. | Week 4 to Week 6 | 
| Daily Evening PEF Averaged Over the Last 3 Weeks of the 6-week Treatment Period | The PEF is a measure of lung function and measures how fast a person can breathe out. PEF was measured every evening prior to study medication dose and any rescue albuterol (bronchodilator) use. Participants recorded PEF in a daily eDiary. Daily evening PEF was averaged over the last 3 weeks of the 6-week treatment period, and analyzed using mixed effect ANCOVA model for treatment effects, incorporating fixed effects of baseline, period, age, center, smoking status, and random effects of participant. | Week 4 to Week 6 | 
| Daily (Average of Morning and Evening) PEF Averaged Over the Last 3 Weeks of the 6 -Week Treatment Period Between GSK2190915 and Montelukast Groups | The PEF is a measure of lung function and measures how fast a person can breathe out. PEF was measured every morning and evening prior to study medication dose and any rescue albuterol (bronchodilator) use. Participants recorded PEF in a daily eDiary. Daily average of morning and evening PEF was averaged over the last 3 weeks of the 6-week treatment period, and analyzed using mixed effect ANCOVA model for treatment effects, incorporating fixed effects of baseline, period, age, center, smoking status, and random effects of participant. This outcome measure explored the efficacy between GSK2190915 and montelukast due to the dosing time difference. | Week 4 to Week 6 | 
| Daily Asthma Symptom Score Averaged Over the Last 3 Weeks of the 6-week Treatment Period | Daytime and night time asthma symptoms were recorded every evening at bedtime and every morning upon rising, respectively, before taking any rescue or study medication and before assessing the PEF. Symptoms were recorded on scales ranging from '0' (implying no symptoms) to either 5 (for daytime symptoms) or 4 (for night time symptoms) (implying severe symptoms). Participants recorded the symptoms in a daily eDiary. 24-hour period asthma symptom scores were averaged over the last 3 weeks of the 6-week treatment period, and analyzed using mixed effect ANCOVA model for treatment effects, incorporating fixed effects of baseline, period, age, center, smoking status, and random effects of participant. | Week 4 to Week 6 | 
| Daily Rescue Short-acting beta2-agonist (SABA) Use Averaged Over the Last 3 Weeks of the 6-week Treatment Period | A SABA (albuterol) was provided to participants as a rescue medication, to use as needed for symptomatic relief of asthma symptoms. Participants were required to record their albuterol use in the morning and in the evening. Participants recorded the number of inhalations of rescue medication in a daily eDiary. The daily rescue SABA use was averaged over the last 3 weeks of the 6-week treatment period, and analyzed using mixed effect ANCOVA model for treatment effects, incorporating fixed effects of baseline, period, age, center, smoking status, and random effects of participant. | Week 4 to Week 6 | 
| Percentage of Symptom-free Days During the Last 3 Weeks of the 6-week Treatment Period | Daytime asthma symptoms were recorded every evening at bedtime, before taking any rescue or study medication and before assessing the PEF. Symptoms were recorded on a 6-point scale ranging from '0' (implying no symptoms) to 5 (implying severe symptoms). Participants recorded the symptoms in a daily eDiary. The number of days when symptoms were not experienced (symptom-free days) during the last 3 weeks of the 6-week treatment period were counted, and percentage calculated by dividing by 21 and multiplying by 100. Analysis was done using mixed effect ANCOVA model for treatment effects, incorporating fixed effects of baseline, period, age, center, smoking status, and random effects of participant. | Week 4 to Week 6 | 
| Percentage of Symptom-free Nights During the Last 3 Weeks of the 6 Week Treatment Period | Night time asthma symptoms were recorded every morning upon rising, before taking any rescue or study medication and before assessing the PEF. Symptoms were recorded on a 5-point scale ranging from '0' (implying no symptoms) to 4 (implying severe symptoms). Participants recorded the symptoms in a daily eDiary. The number of nights when symptoms were not experienced (symptom-free nights) during the last 3 weeks of the 6-week treatment period were counted, and percentage calculated by dividing by 21 and multiplying by 100. Analysis was done using mixed effect ANCOVA model for treatment effects, incorporating fixed effects of baseline, period, age, center, smoking status, and random effects of participant. | Week 4 to Week 6 | 
| Percentage of Rescue-free Days During the Last 3 Weeks of the 6-week Treatment Period | Albuterol was provided as a rescue medication, and participants were required to record rescue medication use in the morning and in the evening. Participants recorded the number of inhalations of rescue medication in a daily eDiary. The number of days when rescue medication was not used (rescue-free days) during the last 3 weeks of the 6-week treatment period were counted, and percentage calculated by dividing by 21 and multiplying by 100. Analysis was done using mixed effect ANCOVA model for treatment effects, incorporating fixed effects of baseline, period, age, center, smoking status, and random effects of participant. | Week 4 to Week 6 | 
| Percentage of Rescue-free Nights During the Last 3 Weeks of the 6-week Treatment Period | Albuterol was provided as a rescue medication, and participants were required to record rescue medication use in the morning and in the evening. Participants recorded the number of inhalations of rescue medication in a daily eDiary. The number of nights when rescue medication was not used (rescue-free nights) during the last 3 weeks of the 6-week treatment period were counted, and percentage calculated by dividing by 21 and multiplying by 100. Analysis was done using mixed effect ANCOVA model for treatment effects, incorporating fixed effects of baseline, period, age, center, smoking status, and random effects of participant. | Week 4 to Week 6 | 
| Percentage of Nights Without Awakenings Due to Asthma During the Last 3 Weeks of the 6-week Treatment Period | Night time asthma symptoms were recorded every morning upon rising, before taking any rescue or study medication and before assessing the PEF. Symptoms were recorded on a 5-point scale: 0 = no symptoms during the night, 1 = symptoms causing to wake once, 2 = symptoms causing to wake twice or more, 3 = symptoms causing to be awake most of the night, 4 = could not sleep due to severe symptoms. Participants recorded the symptoms in a daily eDiary. The number of nights with no awakenings due to asthma during the last 3 weeks of the 6-week treatment period were counted, and percentage calculated by dividing by 21 and multiplying by 100. Analysis was done using mixed effect ANCOVA model for treatment effects, incorporating fixed effects of baseline, period, age, center, smoking status, and random effects of participant. | Week 4 to Week 6 | 
| Number of Participants Withdrawn Due to Lack of Efficacy During the Last 3 Weeks of the 6-week Treatment Period | Participants were withdrawn if they met any of the following three criteria for 'lack of efficacy': 1) Clinic FEV1 below the FEV1 'Stability Limit' value, 2) During any consecutive 7-day period, the participant experienced PEF fallen below the PEF 'Stability Limit' for more than 3 days, or if >= 12 inhalations per day of albuterol were used for more than 2 days, and 3) Ashtma exacerbation. The number of withdrawals due to lack of efficacy were summarized for each treatment and Fisher's Exact test was used for comparison with placebo add-on. Withdrawals occurring during active washout periods are not included. | Week 4 to Week 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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asthma, GSK2190915