Evaluate the Safety, Efficacy and Dose Response of GSK573719 in Combination With Fluticasone Furoate in Subjects With Asthma

Study Overview
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Brief Summary
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Brief Summary: The purpose of this study is to characterize the dose response of GSK573719 in combination with Fluticasone furoate 100mcg in patients with asthma. Treatment with inhaled Fluticasone furoate and Fluticasone furoate/Vilanterol are included as an active control. Detailed Description: Long acting muscarinic receptor antagonists (anti-cholinergic bronhcodilator) exert their effects via distinct and complementary bronchodilator mechanisms on large and small airways. Most of the experience with older anti-cholinergics had been with acute use and little is known about their effect in chronic use in asthma. This is a multicenter, randomized, double-blind, crossover study to evaluate 5 doses of inhaled GSK573719 inhaled over 14 days in patients with asthma. Fluticasone furoate (100 mcg) and Fluticasone furoate/Vilanterol (100/59mcg) will be included as an active comparator. Each eligible subject will receive a sequence of 3 of 7 potential treatments for a total of 3 treatment periods per subject. The total duration of subject participation is approximately 14 weeks.

Official Title
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A Multi-center, Randomized, Double-blind, Dose-ranging Study to Evaluate GSK573719 in Combination With Fluticasone Furoate, Fluticasone Furoate Alone, and an Active Control of Fluticasone Furoate/Vilanterol Combination in Subjects With Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: FF/GSK573719
* Drug: FF/GSK573719
* Drug: FF/GSK573719
* Drug: FF/GSK573719
* Drug: FF/GSK573719
* Drug: FF
* Drug: FF/VI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Outpatient 18 years of age or older at Visit 1 Diagnosis of Asthma Male or eligible Female Pre-bronchodilator FEV1 of 40-80% of the predicted normal value at Visit 1 Demonstrated reversibility by ≥12% and ≥200mL of FEV1 within 40 minutes following albuterol at Visit 1 A need for regular controller therapy (i.e., inhaled corticosteroids alone or in combination with a long-acting beta-agonist, or leukotriene modifier etc.,) for a minimum of 8 weeks prior to Visit 1. Exclusion Criteria: History of Life threatening asthma Respiratory infection not resolved Asthma exacerbation Concurrent respiratory disease Current Smokers Other diseases that are uncontrolled disease or disease state that, in the opinion of the investigator, would put the safety of the patient at risk through study participation or would confound the interpretation of the efficacy results if the condition/disease exacerbated during the study A positive Hepatitis B surface antigen or positive Hepatitis C antibody and/or HIV Visual clinical evidence of oropharyngeal candidiasis Drug or milk protein allergies Concomitant medications affecting course of asthma Use of any other investigational medication within 30 days or 5 drug half-lives (whichever is longer) Previous use of GSK573719 Any disease preventing use of anticholinergics Any condition that impairs compliance with study protocol including visit schedule and completion of daily diaries Any subject with a history of alcohol or substance abuse Any affiliation with Investigator's site

Ages Eligible for Study
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Minimum Age: 18 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: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Fluticasone Furoate (FF)<br>100mcg, inhaled | Drug: FF<br>* 100<br>|
| Active Comparator: Fluticasone Furoate /Vilanterol (VI)<br>100/25mcg inhaled | Drug: FF/VI<br>* 100/25<br>|
| Experimental: Fluticasone Furoate/GSK573719<br>100/15.6-250mcg inhaled | Drug: FF/GSK573719<br>* 100/15.6<br>Drug: FF/GSK573719<br>* 100/31.25<br>Drug: FF/GSK573719<br>* 100/62.5<br>Drug: FF/GSK573719<br>* 100/125<br>Drug: FF/GSK573719<br>* 100/250<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Model Predicted Change From Baseline Trough Force Expiratory Volume in 1 Second (FEV1) | FEV1 is a lung function measure defined as the maximal amount of air that can be forcefully exhaled in one second. Highest FEV1 from the 3 acceptable spirometric efforts were recorded between 5.00 ante meridiem (AM) and 11.00 AM after withholding albuterol (salbutamol) at all visits for at least 4 hours. Baseline was defined as the pre- dose FEV1 value obtained on Day 1 and trough was defined as FEV1 value obtained 24 hours after morning dosing on Day 14 of each treatment period. Change from baseline value for each participant in each treatment period was the difference between the observed on-treatment value obtained 24 hours after morning dosing on Day 14 and the baseline value for that period. Slope-intercept on log dose model was used to predict trough FEV1 change from baseline for each of the FF+UMEC doses adjusted by FF 100 mcg alone. Mean value for the expected response and associated 95% confidence interval (CI) in change from baseline trough FEV1 is presented. | Baseline (Day 1) and Day 15 of each treatment period | 
| Percentage of Chance That FF 100 mcg Alone Corrected Change From Baseline FEV1 Response Would Exceed a Target Response by Dose of UMEC Combined With FF 100 mcg | FEV1 is a lung function measure defined as the maximal amount of air that can be forcefully exhaled in one second. Highest FEV1 from the 3 acceptable spirometric efforts were recorded between 5.00 AM and 11.00 AM after withholding albuterol (salbutamol) at all visits for at least 4 hours. Baseline was defined as the pre- dose FEV1 value obtained on Day 1 and trough was defined as FEV1 value obtained 24 hours after morning dosing on Day 14 of each treatment period. Change from baseline value for each participant in each treatment period was the difference between the observed on-treatment value obtained 24 hours after morning dosing on Day 14 and the baseline value for that period. Data is presented as percentage chance that FF 100 mcg alone corrected change from baseline trough FEV1 response would exceed a target response of 50 mL, 75 mL, 100 mL and 150 mL by doses of UMEC combined with FF 100 mcg. | Baseline (Day 1) and Day 15 of each treatment period | 
| Mean Change From Baseline in Trough FEV1 on Day 15 of Each of the 3 Treatment Periods | FEV1 is a lung function measure defined as the maximal amount of air that can be forcefully exhaled in one second. The highest FEV1 from the 3 acceptable spirometric efforts were recorded between 5.00 AM and 11.00 AM after withholding albuterol (salbutamol) at all visits for at least 4 hours. Baseline was defined as the pre- dose FEV1 value obtained on Day 1 and trough was defined as the FEV1 value obtained 24 hours after morning dosing on Day 14 of each treatment period. The change from baseline value for each participant in each treatment period was the difference between the observed on-treatment value obtained 24 hours after morning dosing on Day 14 and the baseline value for that period. Analysis was done using a mixed model, including treatment, period, period baseline FEV1, and mean baseline FEV1 as fixed effects and participant as a random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC. | Baseline (Day 1) and Day 15 of each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Daily Morning (Pre-dose and Pre-rescue Bronchodilator) Peak Expiratory Flow (PEF) of Each Treatment Period | PEF is a measure of lung function and measures how fast a person can breathe out. Morning PEF was measured pre-dose and pre- rescue bronchodilator use with an electronic Peak Flow Meter. Participants were issued an electronic diary (eDiary) for daily use throughout the study and instructed on how to complete it. Best of 3 attempts were recorded in eDiary. Mean change from baseline was calculated where, baseline was defined as the measurement from (Week 0), includes Day 1 and six days immediately preceding Day 1 for each treatment period. The change from baseline values for each participant in each treatment period were differences between on-treatment week (last 7 days of each treatment period) values and baseline week. Analysis was done using a mixed model, including treatment, period, period baseline morning PEF and mean baseline morning PEF as fixed effects and participant as a random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC. | Baseline (Week 0) and last 7 days of each treatment period | 
| Mean Change From Baseline in Daily Evening (Pre-dose and Pre-rescue Bronchodilator) PEF of Each Treatment Period | PEF is a measure of lung function and measures how fast a person can breathe out. Evening PEF was measured pre-dose and pre-rescue bronchodilator use with an electronic Peak Flow Meter. Participants were issued an electronic diary (eDiary) for daily use throughout the study and instructed on how to complete it. Best of 3 attempts were recorded in eDiary. Mean change from baseline was calculated where, baseline was defined as the measurement from (Week 0), includes Day 1 and seven days immediately preceding Day 1 for each treatment period. The change from baseline values for each participant in each treatment period were differences between on-treatment week (last 7 days of each treatment period) values and baseline week. Analysis was done using a mixed model, including treatment, period, period baseline evening PEF and mean baseline evening PEF as fixed effects and participant as a random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC. | Baseline (Week 0) and last 7 days of each treatment period | 
| Mean Change From Baseline in Rescue Albuterol/Salbutamol Use of Each Treatment Period. | Short-Acting Beta2-Agonists albuterol/salbutamol was provided to participants as rescue medication, to use in morning and evening. Participants recorded number of puffs of salbutamol MDI used in last 24 hours (sum of night time and day time puffs) daily for relief of symptoms in eDiary. Mean change from baseline was calculated where, baseline was defined as measurement from (Week 0), includes Day 1 and six days immediately preceding Day 1 (for night time puffs) and seven days (for day time puffs) for each treatment period. Change from baseline values for each participant in each treatment period were differences between on-treatment week (last 7 days of each treatment period) values and the baseline week. Analysis was done using a mixed model, including treatment, period, period baseline rescue albuterol use, and mean baseline rescue albuterol use as fixed effects and participant as random effect. A post hoc analysis was performed to confirm nullification of carry over effect of UMEC. | Baseline (Week 0) and last 7 days of each treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fluticasone Furoate, Vilanterol, Adults, GSK573719, Asthma