Evaluate the Safety, Efficacy and Dose Response of GSK573719 in Combination With Fluticasone Furoate in Subjects With Asthma (ILA115938)

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

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.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: FF; Drug: FF/VI; Drug: FF/GSK573719; Drug: FF/GSK573719; Drug: FF/GSK573719; Drug: FF/GSK573719; Drug: FF/GSK573719

• Study Type: Interventional
• Enrollment (Actual): 421
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1424BSF
    • GSK Investigational Site
  • Ciudad Autonoma de Buenos Aires, Argentina, C1425BEN
    • GSK Investigational Site
  • Ciudad Autónoma de Buenos Aires, Argentina, C1426ABP
    • GSK Investigational Site
  • Mendoza, Argentina, M5500CCG
    • GSK Investigational Site
  • San Miguel de Tucumán, Argentina, 4000
    • GSK Investigational Site
  • Tucumán, Argentina, T4000DGF
    • GSK Investigational Site
• Chile
  • Santiago, Chile, 8380453
    • GSK Investigational Site
  • Región Metro De Santiago
    • Puente Alto - Santiago, Región Metro De Santiago, Chile, 8207257
      • GSK Investigational Site
    • Santiago, Región Metro De Santiago, Chile, 7500551
      • GSK Investigational Site
    • Santiago, Región Metro De Santiago, Chile, 7500800
      • GSK Investigational Site
    • Santiago, Región Metro De Santiago, Chile, 8880465
      • GSK Investigational Site
    • Talca, Región Metro De Santiago, Chile, 3460001
      • GSK Investigational Site
  • Valparaíso
    • Valparaiso, Valparaíso, Chile, 2341131
      • GSK Investigational Site
• Russian Federation
  • Barnaul, Russian Federation, 656038
    • GSK Investigational Site
  • Kazan, Russian Federation, 420015
    • GSK Investigational Site
  • Klin, Russian Federation, 141600
    • GSK Investigational Site
  • Moscow, Russian Federation, 115 280
    • GSK Investigational Site
  • Moscow, Russian Federation, 123367
    • GSK Investigational Site
  • Saint-Petersburg, Russian Federation, 194354
    • GSK Investigational Site
  • St. Petersburg, Russian Federation, 194356
    • GSK Investigational Site
  • Tomsk, Russian Federation, 634001
    • GSK Investigational Site
  • Tomsk, Russian Federation, 634055
    • GSK Investigational Site
  • Ufa, Russian Federation, 450071
    • GSK Investigational Site
  • Yaroslavl, Russian Federation, 150003
    • GSK Investigational Site
• Thailand
  • Bangkok, Thailand, 10400
    • GSK Investigational Site
  • Bangkok, Thailand, 10330
    • GSK Investigational Site
  • Khon Kaen, Thailand, 40002
    • GSK Investigational Site
  • Nonthaburi, Thailand, 11000
    • GSK Investigational Site
• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • GSK Investigational Site
  • Oregon
    • Medford, Oregon, United States, 97504
      • GSK Investigational Site
  • South Carolina
    • Orangeburg, South Carolina, United States, 29118
      • GSK Investigational Site
    • Spartanburg, South Carolina, United States, 29303
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Lee LA, Yang S, Kerwin E, Trivedi R, Edwards LD, Pascoe S. The effect of fluticasone furoate/umeclidinium in adult patients with asthma: a randomized, dose-ranging study. Respir Med. 2015 Jan;109(1):54-62. doi: 10.1016/j.rmed.2014.09.012. Epub 2014 Oct 2.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start (Actual): April 3, 2012
• Primary Completion (Actual): February 4, 2013
• Study Completion (Actual): February 4, 2013

Study Registration Dates

• First Submitted: April 5, 2012
• First Submitted That Met QC Criteria: April 5, 2012
• First Posted (Estimate): April 9, 2012

Study Record Updates

• Last Update Posted (Actual): October 6, 2017
• Last Update Submitted That Met QC Criteria: September 7, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: Asthma; Adults; GSK573719; Fluticasone Furoate; Vilanterol
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma
• Other Study ID Numbers: 115938

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Study Protocol
   Information identifier: 115938
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Statistical Analysis Plan
   Information identifier: 115938
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Clinical Study Report
   Information identifier: 115938
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Individual Participant Data Set
   Information identifier: 115938
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Informed Consent Form
   Information identifier: 115938
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Dataset Specification
   Information identifier: 115938
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Annotated Case Report Form
   Information identifier: 115938
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register