Safety and Efficacy Study of Fluticasone Furoate/Vilanterol (FF/VI) Fixed Dose Combination (FDC) Compared to FF Alone in Subjects With Asthma

Study Overview
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Brief Summary
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The goal of asthma treatment is to achieve and maintain asthma control and to reduce the future risk of exacerbations. Inhaled corticosteroids (ICS) are considered as the most effective anti- inflammatory treatment for all severities of persistent asthma. For children >=5 years of age and adolescents whose asthma is uncontrolled, low-dose ICS plus adjunctive therapy with long-acting beta agonist (LABA) is considered as effective. Thus, this study is designed to evaluate the efficacy and safety of FF (ICS component)/VI (LABA component) compared to FF alone for the treatment of asthma, in subjects aged 5 to 17 years old currently uncontrolled on ICS. The study will be conducted over a total duration of approximately 29 weeks: 4 week run-in period, 24-week double-blind treatment period and 1-week follow-up period. Subjects will be randomized to receive FDC of FF/VI or FF administered via ELLIPTA® dry powder inhaler (DPI). The dose of both FF/VI and FF alone will be selected based on the age of subjects. Subjects will receive a short acting beta 2 agonist (SABA) (albuterol /salbutamol) as a rescue medication throughout the study. A total of 870 subjects will be randomized in the study. Of this, 652 subjects will be aged 5 to 11 years (cohort A), and 218 will be aged 12 to 17 years inclusive (cohort B). ELLIPTA is a registered trademark of GlaxoSmithKline (GSK) group of companies.

Official Title
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A Randomised, Double-blind, Parallel Group, Multicentre, Stratified, Study Evaluating the Efficacy and Safety of Once Daily Fluticasone Furoate/Vilanterol Inhalation Powder Compared to Once Daily Fluticasone Furoate Inhalation Powder in the Treatment of Asthma in Participants Aged 5 to 17 Years Old (Inclusive) Currently Uncontrolled on Inhaled Corticosteroids

Conditions
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Asthma

Intervention / Treatment
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* Drug: FF/VI via ELLIPTA DPI
* Drug: FF via ELLIPTA DPI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For all subjects: Between 5 and 17 years of age inclusive, at the time of signing the informed consent. A history of symptoms consistent with a diagnosis of asthma for at least 6 months. Pre-bronchodilator FEV1 >50 percent to <=90 percent predicted normal. A minimum of 2 efforts that are considered acceptable (not necessarily repeatable) are required to be eligible. Lung function reversibility defined as an increase of >=12 percent in FEV1 within 10 to 40 minutes following 2 to 4 inhalations of salbutamol inhalation aerosol (or 1 nebulized treatment with albuterol/salbutamol solution). Use of a spacer is permitted. Uncontrolled asthma, with a childhood asthma control test (cACT)/ACT score <=19. Receiving stable asthma therapy (SABA inhaler plus ICS [total daily dose <=FP 250 micrograms (mcg) or equivalent]) for at least 4 weeks prior to Visit 1 (i.e. screening). Able to replace their current SABA treatment with salbutamol aerosol inhaler at Visit 1 for use as needed for the duration of the study. Salbutamol metered dose inhaler (MDI) will be administered with or without a spacer, to be used as determined by the investigator. The use or non-use of the spacer should be consistent for an individual subject throughout the study. Male or female subjects will be included. Females of reproductive potential must agree to follow 1 of the options listed (which include abstinence) in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication and until at least five terminal half-lives or until any continuing pharmacologic effect has ended, whichever is longer after the last dose of study medication and completion of the follow-up call. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. Written informed consent from at least 1 parent/care giver (legal guardian) and accompanying informed assent from the subject (where the subject is able to provide assent) prior to admission to the study. If applicable, subject must be able and willing to give assent to take part in the study according to the local requirement. The study investigator is accountable for determining a child's capacity to assent to participation in a research study, taking into consideration any standards set by the responsible independent ethics committee (IEC); subject and their legal guardian(s) understand that the study requires them to be treated on an outpatient basis; subject and their legal guardian(s) understand that they must comply with study medication and study assessments including recording of PEF and rescue SABA use, attending scheduled study visits, and being accessible by a telephone call. For subjects eligible for randomization; asthma control: uncontrolled asthma, with a cACT/ACT score <=19. A technically acceptable pre-bronchodilator FEV1 >50 percent to <=90 percent predicted normal at Visit 2. A minimum of 2 efforts that are considered acceptable and repeatable following the over read are required to be eligible. Symptoms and rescue use: demonstrated and reported in a daily diary symptoms of asthma (a score of >=1 on the day-time or night-time asthma symptom scores) and/or daily albuterol/salbutamol on at least 3 of the last 7 consecutive days of the run-in period (not including the date of randomization). Compliance with run-in medication: compliance is defined as use of run-in medication on at least 4 of the last 7 consecutive days of the run-in period (not including the date of randomization) recorded in the electronic subject diary. Compliance with completion of the daily diary reporting: defined as completion of all questions on 4 out of the last 7 days during the run-in period (not including the date of randomization). Exclusion Criteria: For all subjects: History of life threatening asthma defined as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic seizures. Any asthma exacerbation requiring the use of oral steroids within 6 weeks of Visit 1, systemic or depot corticosteroids within 12 weeks of Visit 1, or ER attendance within 3 months of Visit 1 or hospitalization within 6 months of Visit 1. A culture documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that has not resolved within 4 weeks of Visit 1 and which led to a change in asthma management or, in the opinion of the investigator, is expected to affect the subject's asthma status or the subject's ability to participate in the study. Clinical visual evidence of oropharyngeal candidiasis. Fasting blood glucose at screening >100 milligrams/deciliter (mg/dL) (5.6 moles per liter [mol/L]). Obesity (Body Mass Index [BMI] above the 97th centile based on the centers for disease control and prevention [CDC] charts). Any significant abnormality or medical condition identified at the screening medical assessment (including serious psychological disorder) that in the investigator's opinion, preclude entry into the study due to risk to the subject or that may interfere with the conduct and/or outcome of the study. QTc >450 milliseconds (msec) or QTc >480 msec in subjects with bundle branch block or any other clinically significant abnormality in the screening 12-lead ECG. Use of any prohibited medications. Present use of any tobacco products. Drug allergies: any adverse reaction including immediate or delayed hypersensitivity to any beta 2-agonists, sympathomimetic drug or any intranasal, inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of the ELLIPTA Inhaler (i.e. lactose or magnesium stearate). Milk Protein Allergy: history of severe milk protein allergy. Participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, five half-lives or twice the duration of the biological effect of the study treatment (whichever is longer). Exposure to more than 4 investigational medicinal products within 12 months prior to the first dosing day. An affiliation with the investigator site: the parents/guardians or child is an immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator. The parent or guardian has a history of psychiatric disease, intellectual deficiency, substance abuse or other condition (example, inability to read, comprehend or write) which may affect: validity of consent to participate in the study; adequate supervision of the subject during the study; compliance of subject with study medication and study procedures (example, completion of daily diary, attending scheduled clinic visits); subject safety and well-being. Children in care: children who are wards of the government or state are not eligible for participation in this study. For subjects eligible for randomization; Changes in asthma medication that occur after screening. Occurrence of a culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear during the run-in period that led to a change in asthma management or, in the opinion of the investigator, is expected to affect the subject's asthma status or the subject's ability to participate in the study. Evidence of an exacerbation, defined as a: deterioration of asthma requiring the use of oral corticosteroids for at least 3 days, or a depot corticosteroid injection, or an in-patient hospitalization due to asthma that required systemic corticosteroids between screening and randomization. Clinical visual evidence of oropharyngeal candidiasis at the randomization Visit. Unable to use the ELLIPTA inhaler correctly.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 17 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
Interventional Model Description: Subjects will be randomized to receive FDC of FF/VI inhalation powder compared to FF inhalation powder, once daily in cohort A and cohort B.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Subjects receiving FF/VI in cohort A<br>Subjects will be randomized in 1:1 ratio to receive a FDC of FF/VI with a dose of 50/25 mcg administered once daily in the morning via ELLIPTA DPI. | Drug: FF/VI via ELLIPTA DPI<br>* ELLIPTA DPI inhaler will contain two individual blister strips; the first strip will contain FF(50 or 100 mcg) and second strip will contain VI (25 mcg).<br>|
| Active Comparator: Subjects receiving FF in cohort A<br>Subjects will be randomized in 1:1 ratio to receive FF with a dose of 50 mcg administered once daily in the morning via ELLIPTA DPI. | Drug: FF via ELLIPTA DPI<br>* ELLIPTA DPI inhaler will contain a single blister strip of FF (50 or 100 mcg).<br>|
| Experimental: Subjects receiving FF/VI in cohort B<br>Subjects will be randomized in 1:1 ratio to receive a FDC of FF/VI with a dose of 100/25 mcg administered once daily in the morning via ELLIPTA DPI. | Drug: FF/VI via ELLIPTA DPI<br>* ELLIPTA DPI inhaler will contain two individual blister strips; the first strip will contain FF(50 or 100 mcg) and second strip will contain VI (25 mcg).<br>|
| Active Comparator: Subjects receiving FF in cohort B<br>Subjects will be randomized in 1:1 ratio to receive FF with a dose of 100 mcg administered once daily in the morning via ELLIPTA DPI. | Drug: FF via ELLIPTA DPI<br>* ELLIPTA DPI inhaler will contain a single blister strip of FF (50 or 100 mcg).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Weighted Mean of Forced Expiratory Volume in 1 Second (FEV1) (0-4 Hours) at Week 12 in 5-17 Year Old Population | Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second using a standardized calibrated spirometer. Weighted mean FEV1 was derived using the post-dose assessments (after 30 minutes and 1, 2, 3, 4 hours) with their actual times and using the pre-dose assessment as the 0 hour measurement. | Week 12 | 
| Change From Baseline in Mean Pre-dose Morning Peak Expiratory Flow (AM PEF) in 5-11 Year Old Population | PEF was defined as the maximum speed of expiration of a participant. PEF was measured 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 were recorded in the electronic patient diary. The mean morning PEF was calculated for each participant as an averaged mean over weeks 1-12 of the treatment period. Baseline was defined as the average of measurements with a non-missing value from Day -6 to Day 1 of pre-dose. | Baseline and Week 1-12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Pre-dose AM PEF Period in 5-17 Year Old Population | PEF was defined as the maximum speed of expiration of a participant. PEF was measured 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 were recorded in the daily diary. The mean morning PEF was calculated for each participant as an averaged mean over weeks 1-12 of the treatment period. Baseline was defined as the average of measurements with a non-missing value from Day -6 to Day 1 of pre-dose. | Baseline and Week 1-12 | 
| Absolute Weighted Mean of FEV1 (0-4 Hours) at Week 12 in 5-11 Year Old Population | Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second using a standardized calibrated spirometer. Weighted mean FEV1 was derived using the post-dose assessments (after 30 minutes and 1, 2, 3, 4 hours) with their actual times and using the pre-dose assessment as the 0 hour measurement. | Week 12 | 
| Change From Baseline in the Percentage of Rescue-free 24-hour Periods Over Weeks 1-12 of the Treatment Period in 5-17 Year Old Population | The number of inhalations of rescue albuterol/salbutamol aerosol used during the day and night were recorded in a daily electronic diary. Percentages of rescue-free 24-hour periods was calculated based on the number of 24-hour periods on which a participant recorded no use of albuterol/salbutamol divided by the length of the time period being assessed (with non-missing values of rescue medication recorded, respectively). A 24-hour period in which the response of participants to both the morning and evening assessments indicated no use of rescue medication was considered as rescue free. Baseline was calculated from the evening (Day -7 to Day -1) and morning (Day -6 to Day 1) measurements. Change from Baseline was calculated as the averaged value during the 12-week treatment period minus the Baseline value. | Baseline and Week 1-12 | 
| Change From Baseline in the Percentage of Symptom-free 24-hour Periods Over Weeks 1-12 of the Treatment Period in 5-17 Year Old Population | The symptom-free days were recorded in a daily electronic diary every day in the morning and evening before taking any rescue or study medication and before the PEF measurement. Percentages of symptom-free 24-hour periods was calculated based on the number of 24-hour periods on which a participant recorded no symptoms divided by the length of the time period being assessed (with non-missing values of rescue medication recorded, respectively). A 24-hour period in which the response of participants to both the morning and evening assessments indicated no symptoms was considered as symptom free. Baseline was calculated from evening (Day -7 to Day -1) and morning (Day -6 to Day 1) measurements. Change from Baseline was calculated as the averaged value during the 12-week treatment period minus the Baseline value. | Baseline and Week 1-12 | 
| Change From Baseline in Morning (AM) FEV1 at Week 12 in 5-17 Year Old Population | Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. Morning FEV1 was measured using the pre-dose serial spirometry assessment at the Week 12. Baseline was defined as the pre-dose assessment with a non missing value on Visit 2 (Day -5). | Baseline and Week 12 | 
| Change From Baseline in Asthma Control Questionnaire (ACQ-5) Score at Week 24 in 5-17 Year Old Population | Asthma control as measured by improvements in ACQ-5, a five-item questionnaire with response options for each question rated from 0 to 6 scale. A score of 0 indicates well controlled asthma and a score of 6 indicates extremely poorly controlled asthma. Individual questions (concerning nocturnal awakening, waking in the morning, activity limitation, shortness of breath and wheeze) are equally weighted and the ACQ-5 score is calculated as the mean of these 5 item responses. A lower mean score indicates greater asthma control and higher mean score indicates lesser asthma control. Baseline was defined as the pre-dose assessment with a non-missing value on Visit 3 (Day 1). | Baseline and Week 24 | 
| Change From Baseline in the Percentage of Rescue-free 24-hour Periods Over Weeks 1-12 of the Treatment Period in 5-11 Year Old Population | The number of inhalations of rescue albuterol/salbutamol aerosol used during the day and night were recorded in a daily electronic diary. Percentages of rescue-free 24-hour periods was calculated based on the number of 24-hour periods on which a participant recorded no use of albuterol/salbutamol divided by the length of the time period being assessed (with non-missing values of rescue medication recorded, respectively). A 24-hour period in which the response of participants to both the morning and evening assessments indicated no use of rescue medication was considered as rescue free. Baseline was calculated from the evening (Day -7 to Day -1) and morning (Day -6 to Day 1) measurements. Change from Baseline was calculated as the averaged value during the 12-week treatment period minus the Baseline value. | Baseline and Week 1-12 | 
| Change From Baseline in the Percentage of Symptom-free 24-hour Periods Over Weeks 1-12 of the Treatment Period in 5-11 Year Old Population | The symptom-free days were recorded in a daily electronic diary every day in the morning and evening before taking any rescue or study medication and before the PEF measurement. Percentages of symptom-free 24-hour periods was calculated based on the number of 24-hour periods on which a participant recorded no symptoms divided by the length of the time period being assessed (with non-missing values of rescue medication recorded, respectively). A 24-hour period in which the response of participants to both the morning and evening assessments indicated no symptoms was considered as symptom free. Baseline was calculated from evening (Day -7 to Day -1) and morning (Day -6 to Day 1) measurements. Change from Baseline was calculated as the averaged value during the 12-week treatment period minus the Baseline value. | Baseline and Week 1-12 | 
| Change From Baseline in Morning (AM) FEV1 at Week 12 in 5-11 Year Old Population | Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. Morning FEV1 was measured using the pre-dose serial spirometry assessment at the Week 12. Baseline was defined as the pre-dose assessment with a non-missing value on Visit 2 (Day -5). | Baseline and Week 12 | 
| Change From Baseline ACQ-5 Score at Week 24 in 5-11 Year Old Population | Asthma control as measured by improvements in ACQ-5, a five-item questionnaire with response options for each question rated from 0 to 6 scale. A score of 0 indicates well controlled asthma and a score of 6 indicates extremely poorly controlled asthma. Individual questions (concerning nocturnal awakening, waking in the morning, activity limitation, shortness of breath and wheeze) are equally weighted and the ACQ-5 score is calculated as the mean of these 5 item responses. A lower mean score indicates greater asthma control and higher mean score indicates lesser asthma control. Baseline was defined as the pre-dose assessment with a non-missing value on Visit 3 (Day 1). | Baseline and Week 24 | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in 5-17 Year Old Population | An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect and important medical events may jeopardize the participant or may require medical or surgical intervention/SOC to prevent one of the other outcomes mentioned before. | Up to week 25 | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings in 5-17 Year Old Population | A single 12-lead ECG was obtained using an ECG machine that automatically calculates the heartrate and measures PR, QRS, QT, and QT interval corrected (QTc). | Week 24 | 
| Change From Baseline in Fasting Glucose in 5-17 Year Old Population | Blood samples were collected for evaluation of fasting blood glucose pre and post-treatment. Baseline was defined as Visit 1 (Screening). | Baseline and Week 24 | 
| Number of Participants With Any Incidence of Asthma Exacerbation Over the 24-week Treatment Period in 5-17 Year Old Population | Asthma exacerbation was defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension or injection) for at least three days or a single depot corticosteroid injection or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. | Up to week 24 | 
| Number of Participants With AEs and SAEs in 5-11 Year Old Population | An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect and important medical events may jeopardize the participant or may require medical or surgical intervention/Standard of care (SOC) to prevent one of the other outcomes mentioned before. | Up to week 25 | 
| Number of Participants With Abnormal ECG Findings in 5-11 Year Old Population | A single 12-lead ECG was obtained using an ECG machine that automatically calculates the heartrate and measures PR, QRS, QT, and QTc. | Week 24 | 
| Change From Baseline in Fasting Glucose in 5-11 Year Old Population | Blood samples were collected for evaluation of fasting blood glucose pre and post-treatment. Baseline was defined as Visit 1 (Screening). | Baseline and Week 24 | 
| Number of Participants With Any Incidence of Asthma Exacerbation Over the 24-week Treatment Period in 5-11 Year Old Population | Asthma exacerbation was defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension or injection) for at least three days or a single depot corticosteroid injection or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. | Up to week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fluticasone furoate, Efficacy, Vilanterol, Asthma, Safety, GW642444, GW685698