Dose-ranging Study of Vilanterol (VI) Inhalation Powder in Children

Study Overview
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Brief Summary
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This is a Phase IIb, multi-centre, randomised, double-blind, parallel-group, placebo-controlled study in children aged 5-11 years with persistent uncontrolled asthma. Subjects entering the run-in period will stop their current asthma medication and be given open label fluticasone propionate (FP) 100mcg twice daily via DISKUS/ACCUHALER and salbutamol/albuterol as required to use throughout the run-in and double-blind treatment period. At Visit 3 subjects meeting the randomization eligibility criteria will receive vilanterol (6.25mcg, 12.5mcg, or 25mcg,) or placebo via the Novel Dry Powder Inhaler (NDPI) once daily for 4 weeks in addition to open-label fluticasone propionate twice daily throughout the treatment period. Primary endpoints consist of change from baseline in clinic visit trough (pre-bronchodilator and pre-dose) PEF at the end of the 28-day treatment period in all subjects. Safety assessments include adverse events, oropharyngeal examinations, clinical chemistry, 12-lead ECG, and vital signs. Blood samples will be taken from all subjects for pharmacokinetic analysis to determine plasma concentrations of vilanterol at specific time intervals relative to the dose of study drug.

Official Title
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A Dose-ranging Study of Vilanterol (VI) Inhalation Powder in Children Aged 5-11 Years With Asthma on a Background of Inhaled Corticosteroid Therapy

Conditions
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Asthma

Intervention / Treatment
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* Drug: Fluticasone propionate 100mcg
* Drug: Placebo
* Drug: Vilanterol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent from at least one parent/ legal guardian to take part in the study.: Diagnosis of asthma pre-bronchodilator PEF between ≥50% to ≤90% of their best post-bronchodilator value Receiving stable asthma therapy of short acting beta-agonist (SABA) plus ICS (total daily dose FP 200mcg or equivalent) Exclusion Criteria: history of life-threatening asthma history of asthma exacerbation for asthma within 6 months prior to screening. Culture-documented or suspected bacterial or viral infection significant abnormality or medical condition Present use of any tobacco products

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 11 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1<br>Vilanterol 25mcg inhalation powder inhaled once daily in the PM via the new powder inhaler | Drug: Fluticasone propionate 100mcg<br>* all subjects recieve open-label Flovent twice daily duirng the run in and treatment period<br>Drug: Vilanterol<br>* subjects will recieve 4 weeks via NDPI during treament period<br>|
| Active Comparator: Arm 2<br>Vilanterol 12.5mcg inhalation powder inhaled once daily in the PM via the new powder inhaler | Drug: Fluticasone propionate 100mcg<br>* all subjects recieve open-label Flovent twice daily duirng the run in and treatment period<br>Drug: Vilanterol<br>* subjects will recieve 4 weeks via NDPI during treament period<br>|
| Active Comparator: Arm 3<br>Vilanterol 6.25mcg inhalation powder inhaled once daily in the PM via the new powder inhaler | Drug: Fluticasone propionate 100mcg<br>* all subjects recieve open-label Flovent twice daily duirng the run in and treatment period<br>Drug: Vilanterol<br>* subjects will recieve 4 weeks via NDPI during treament period<br>|
| Placebo Comparator: Arm 4<br>Placebo inhalation powder inhaled once daily in the PM via the new powder inhaler | Drug: Fluticasone propionate 100mcg<br>* all subjects recieve open-label Flovent twice daily duirng the run in and treatment period<br>Drug: Placebo<br>* Placebo inhalation powder during treatment period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Daily Pre-dose Evening (PM) Peak Expiratory Flow (PEF) From Participant Electronic Daily Diary Averaged Over the 4-week Treatment Period | PEF is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF was measured by the participants using a hand-held electronic peak flow meter each evening prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use each morning. The best of three measurements was recorded. Change from Baseline was calculated as the value of the averaged daily PM PEF over the 4-week Treatment Period minus the Baseline value. The Baseline PEF value is defined as the average of the last 7 days of the Run-in Phase. The analysis was performed using an analysis of covariance (ANCOVA) model with covariates of Baseline, region, sex, age, and treatment. Only those participants contributing data per the daily eDiary were analyzed. | Baseline; Week 1 up to Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Evening Clinic Visit Trough (Pre-bronchodilator and Pre-dose) Forced Expiratory Volume in One Second (FEV1) at the End of the 4-week Treatment Period in Children Who Could Perform the Maneuver | Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 is defined as a pre-dose FEV1 measurement taken at a clinic visit while still on treatment. Change from Baseline in trough FEV1 at the end of the 4-week Treatment Period was defined using the pre-dose FEV1 measurement taken at the Week 4 clinic visit. Change from Baseline was calculated as the Week 4 trough FEV1 value minus the Baseline value. The Baseline FEV1 value is defined as the value at Visit 3 (randomization). The analysis was performed using an ANCOVA model with covariates of Baseline trough FEV1, region, sex, age, and treatment. The last observation carried forward (LOCF) method was used to impute missing data, in which the last non-missing post-Baseline on-treatment measurement at scheduled clinic visits was used to impute the missing measurements. | Baseline; Week 4 | 
| Change From Baseline in the Percentage of Rescue-free 24-hour Periods During the 4-week Treatment Period | The number of inhalations of rescue albuterol/salbutamol inhalation aerosol (medication used to relieve symptoms immediately) used during the day and night) was recorded by the participants in a daily diary. A 24-hour period in which a participant's responses to both the morning and evening assessments indicated no use of rescue medication was considered as rescue free. Participants who were rescue free for 24-hour periods during the 4-week Treatment Period were assessed. The Baseline value was derived from the last 7 days of the daily diary prior to the randomization of the participant. Change from Baseline is calculated as the average value during the 4-week Treatment Period minus the value at Baseline. The Baseline value is defined as the value at Visit 3 (randomization). Analysis was performed using ANCOVA with covariates of Baseline, region, sex, age, and treatment. | Baseline; Week 1 up to Week 4 | 
| Change From Baseline in Daily Morning (AM) PEF Averaged Over the 4-week Treatment Period | PEF is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF was measured by the participants using a hand-held electronic peak flow meter each morning prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. Change from Baseline was calculated as the value of the averaged daily AM PEF over the 4-week Treatment Period (at Week 4) minus the Baseline value. The Baseline value is defined as the value at Visit 3 (randomization). The analysis was performed using an ANCOVA model with covariates of Baseline, region, sex, age, and treatment group. | Baseline; Week 1 up to Week 4 | 
| Change From Baseline in Evening (PM) PEF Over the Last 7 Days of the Treatment Period (Week 4) | PEF is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF was measured by the participants using a hand-held electronic peak flow meter each evening prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. Change from Baseline is calculated as the value over the last 7 days of the Treatment Period minus the Baseline value. The Baseline value is defined as the value at Visit 3 (randomization). The analysis was performed using an ANCOVA model with covariates of Baseline, region, sex, age, and treatment group. The LOCF method was used to impute missing data, in which the last non-missing post-Baseline on-treatment measurement at scheduled clinic visits was used to impute the missing measurements. | Baseline; Week 4 | 
| Change From Baseline in AM PEF Over the Last 7 Days of the Treatment Period (Week 4) | PEF is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF was measured by the participants using a hand-held electronic peak flow meter each morning prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. Change from Baseline is calculated as the value of the averaged daily AM PEF over the 4-week Treatment Period (at Week 4) minus the Baseline value. The Baseline value is defined as the value at Visit 3 (randomization). The analysis was performed using an ANCOVA model with covariates of Baseline, region, sex, age, and treatment group. | Baseline; Week 4 | 
| Change From Baseline in the Percentage of Symptom-free 24-hour Periods During the 4-week Treatment Period | Asthma symptoms were recorded in a daily eDairy by the participants every day in the morning and evening before taking any rescue or study medication and before the PEF measurement. A 24-hour (hr) period in which a participant's responses to both the morning and evening assessments indicated no symptoms was considered to be symptom free. The Baseline symptom-free value is defined as the value at Visit 3 (randomization). Change from Baseline was calculated as the averaged value during the 4-week Treatment Period minus the Baseline value. The analysis was performed using an ANCOVA model with covariates of Baseline, region, sex, age, and treatment group. | Baseline; Week 1 up to Week 4 |