A Dose-ranging Study of Fluticasone Furoate (FF)

Study Overview
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Brief Summary
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This is a Phase IIb, multi-centre, stratified, randomised, double-blind, double-dummy, parallel-group, placebo and active controlled study in children aged 5-11 years with persistent uncontrolled asthma. Subjects meeting all of the inclusion criteria and none of the exclusion criteria at the screening visit (Visit 1) will enter a four week run-in period during which time they will continue their current medications. Visit 2 will occur two weeks into the run-in period to allow a review of compliance with daily diary and run-in medication. At Visit 3 (end of run-in/randomization visit), subjects meeting the eligibility criteria who remain uncontrolled despite baseline therapy will be stratified based on pre screening inhaled corticosteroid (ICS) use. Once stratified, subjects will be randomised to the treatment phase of the study where they will receive one of five treatments for 12 weeks. Approx 1200 subjects ages 5 to 11 will be screened to achieve 575 randomized for a total of 115 randomized/evaluable subjects per treatment arm. Subjects will attend on-treatment visits at 2, 4, 8 and 12 weeks (Visits 4, 5, 6 and 7 respectively). A follow-up contact will be performed one week after completing study medication. All subjects must attempt spirometry measurements at Visits 1 and 3. For all subjects, a timed 24-hour urine collection for urinary cortisol and creatinine excretion will be performed prior to randomization at Visit 2 and within 7 days prior to Visit 7. All subjects must perform PEF daily between visits 1 and 7. The primary endpoint will be change from baseline in pre-dose (i.e. dosing trough) PM PEF from patient hand held electronic daily diary at Endpoint (Endpoint is defined as the mean over the last 7 days of treatment). Safety assessments include adverse events, oropharyngeal examinations, clinical chemistry, urinary cortisol, and vital signs.

Official Title
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A Dose-ranging Study of Fluticasone Furoate (FF) Inhalation Powder in Children Aged 5-11 Years With Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Fluticasone Furoate
* Drug: Fluticasone Propionate
* Drug: Placebo


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 therapy of short acting beta-agonist (SABA) alone, LTM, or ICS (total daily dose <FP 200mcg or equivalent)Exclusion : 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1<br>Fluticasone Furoate 100mcg inhalation powder once daily in the evening ICS powder | Drug: Fluticasone Furoate<br>* current asthma medicine<br>|
| Active Comparator: Arm 2<br>Fluticasone Furoate 50mcg inhalation powder once daily in the evening ICS powder | Drug: Fluticasone Furoate<br>* current asthma medicine<br>|
| Active Comparator: Arm 3<br>Fluticasone Furoate 25mcg inhalation powder once daily in the evening ics powder | Drug: Fluticasone Furoate<br>* current asthma medicine<br>|
| Active Comparator: Arm 4<br>Fluticasone Propionate 100mcg inhalation powder twice daily ICS powder | Drug: Fluticasone Propionate<br>* Fluticasone propionate<br>|
| Placebo Comparator: Arm 5<br>Placebo inhalation powder once daily in the evening Placebo powder | Drug: Placebo<br>* placebo<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 Morning (AM) Peak Expiratory Flow (PEF) From Participant Electronic Daily Diary Averaged Over the 12-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. The best of three measurements was recorded. Change from Baseline was calculated as the value of the averaged daily AM PEF over the 12-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 Period. Statistical analysis was performed using an analysis of covariance (ANCOVA) model with covariates of Baseline AM PEF, actual pre-screening inhaled corticosteroid (ICS) use, region, sex, age, and treatment. Particpants analyzed included those who have PEF data for at least 2 non-missing days in the Baseline week prior to randomisation and at least 2 non-missing days after randomisation. | Baseline; Week 1 up to Week 12 | 

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 12-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 was calculated as the Week 12 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, actual pre-screening ICS use, 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. Only those participants available at the specified time points were analyzed. | Baseline, Week 12 | 
| Change From Baseline in the Percentage of Rescue-free 24-hour Periods During the 12-week Treatment Period | The number of inhalations of rescue albuterol/salbutamol 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 (hr) 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. The Baseline rescue-free value was defined as the percentage of rescue-free 24-hr periods from the last 7 days of the Run-in Period. Change from Baseline was calculated as the average value during the 12-week Treatment Period minus the value at Baseline. Analysis was performed using ANCOVA with covariates of Baseline, region, sex, actual pre-screening ICS use, age, and treatment. | Baseline; Week 1 up to Week 12 | 
| Change From Baseline in Daily Evening (PM) PEF Averaged Over the 12-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. Change from Baseline was calculated as the value of the averaged daily PM PEF over the 12-week Treatment Period (at Week 12) minus the Baseline value. The Baseline PEF value is defined as the average of the last 7 days of the Run-in Period. Statistical analysis was performed using ANCOVA model with covariates of Baseline, actual pre-screening ICS use, region, sex, age, and treatment. Particpants analyzed included those who have PEF data for at least 2 non-missing days in the Baseline week prior to randomisation and at least 2 non-missing days after randomisation. | Baseline; Week 1 up to Week 12 | 
| Change From Baseline in PM PEF Over the Last 7 Days of the Treatment Period (Week 12) | 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 in PM PEF was calculated as the value over the last 7 days of the Treatment Period minus the Baseline value. The Baseline PEF value is defined as the average of the last 7 days of the Run-in Period. Statistical analysis was performed using ANCOVA model with covariates of Baseline, actual pre-screening ICS use, region, sex, age, and treatment. The LOCF method was used to impute missing data, in which the last non-missing post-Baseline on-treatment measurement was used to impute the missing measurements. | Baseline; Week 12 | 
| Change From Baseline in AM PEF Over the Last 7 Days of the Treatment Period (Week 12) | 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 in AM PEF was calculated as the value over the last 7 days of the Treatment Period minus the Baseline value. The Baseline PEF value is defined as the average of the last 7 days of the Run-in Period. Statistical analysis was performed using ANCOVA model with covariates of Baseline, pre-screening ICS use, region, sex, age, and treatment. The LOCF method was used to impute missing data, in which the last non-missing post-Baseline on-treatment measurement was used to impute the missing measurements. | Baseline; Week 12 | 
| Change From Baseline in the Percentage of Symptom-free 24-hour Periods During the 12-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 percentage of symptom free 24-hr periods in the last 7 days of the run-in period. Change from Baseline was calculated as the averaged value during the 12-week Treatment Period minus the Baseline value. The analysis was performed using an ANCOVA model with covariates of Baseline, region, sex, actual pre-screening ICS use, age, and treatment group. | Baseline; Week 1 up to Week 12 | 
| Number of Withdrawals Due to Lack of Efficacy Throughout the 12-week Treatment Period | The number of participants whose primary reason for withdrawal from the study was due to lack of efficacy is presented together with p-values for the treatment comparisons. | Up to Week 12 |