Effects of a Orally Inhaled Fluticasone Furoate on Growth Velocity in Prepubertal, Paediatric Subjects With Asthma Over a Year

Study Overview
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Brief Summary
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There is a regulatory requirement to evaluate the extent of reduction (if any) of growth velocity associated with inhaled corticosteroid (ICS) containing products that are to be administered to children, and to this end there is Food and Drug Administration (FDA) regulatory guidance. This is a randomised, single-blind (run-in period)/double-blind (treatment period), parallel group, placebo controlled, multicentre study to assess the effect of once daily (OD) inhaled fluticasone furoate (FF) 50 microgram (mcg) on growth velocity in prepubertal asthmatic children on a background therapy of open-label montelukast. This study will be conducted over a total duration of approximately 76 weeks: 16-week run-in period (single-blind placebo inhaler), 52-week double-blind treatment period (inhaled FF 50 mcg /placebo administered OD in the morning for 52 weeks) and 8-week follow-up period. The purpose of the study is to evaluate the magnitude of effect (with a level of precision) on growth velocity of prepubertal asthmatic paediatric subjects (aged 5 to <9 years) following administration of OD inhaled FF 50 mcg for one year. This study fulfills European Union (EU) and United States (US) regulatory requirements for the evaluation of potential growth suppression in children.

Official Title
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Study HZA114971, A Multicentre Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Effects of a One-Year Regimen of Orally Inhaled Fluticasone Furoate 50 mcg Once Daily on Growth Velocity in Prepubertal, Paediatric Subjects With Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Fluticasone furoate
* Drug: Placebo
* Drug: Montelukast
* Drug: Short Acting Beta 2 Agonist


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects. Age: Males between 5 and <9 years old; Females between 5 and <8 years old. Subjects must be pre-pubertal (Tanner Stage 1). Height centile between 3% and 97% based on local growth charts. Subjects with body weight and body mass index that is between 3rd and 97th centile based on the United State (US) Centres for Disease Control and Prevention (CDC) standard statistics or any local standards outside the US. A documented history of symptoms consistent with a diagnosis of asthma for at least 6 months prior to Visit 1. A pre-bronchodilatory forced expiratory flow in 1 second (FEV1) at Visit 1 (Screening) of between >=60% to <=95% predicted. There should be no short acting beta 2 agonist (SABA) use within 4 hours of this measurement. Able to replace their current SABA treatment with study supplied rescue albuterol/salbutamol provided at Visit 1 for use as needed for the duration of the study. A childhood asthma control test (cACT) score of >19. Subjects should have required at least one course of corticosteroid for their asthma (inhaled or oral) in the past year. There must be no ICS use within 6 weeks of Visit 1 (Screening). There must be no oral corticosteroids use within 12 weeks of Visit 1 (Screening). Using one or more of the following asthma therapies prior to entry into the study: Short acting beta-agonist (SABA) inhaler alone (example given [e.g.] salbutamol) on an as needed basis and/or regular non-ICS controller medications for asthma (e.g. cromones or leukotriene receptor antagonists). - Written informed consent from at least one 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 local requirement. The study investigator is accountable for determining a child's capacity to assent for 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 they must comply with study medication administration regimens and study assessments including recording of symptom scores and rescue albuterol/salbutamol use, attending all study visits, and being accessible by telephone. Exclusion Criteria: Growth Criteria: Any previous or current condition that affects growth, including sleep disorders, endocrine disorders, skeletal dysplasia, Turner and Noonan syndromes, Marfan, Beckwith-Wiedeman and Sotos syndromes, Klinefelter's syndrome, coeliac disease, inflammatory bowel diseases and renal failure or any significant abnormality or medical condition that is identified at the screening medical assessment (including serious psychological disorder) that is likely to interfere with the conduct of the study. Subjects with premature adrenarche. A child who is unable to stand, or who finds standing difficult due to illness or physical disabilities should be excluded. Disease Criteria: Subjects with a history of asthma exacerbation requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days or use of a depot corticosteroid injection within 3 months or those requiring hospitalisation for asthma (within 6 months) prior to screening. Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved within 4 weeks of Visit 1 and 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 candidiasis at Visit 1 (Screening). Any significant abnormality or medical condition identified at the screening medical assessment that in the Investigator's opinion, preclude entry into the study due to risk to the subject or that may interfere with the outcome of the study. General: Prior use of any medication or treatment that might affect growth including, but not limited to: amphetamines, anticonvulsants, biphosphonates, calcitonin, calcitriol, erythropoietin, growth hormone, methylphenidate, phosphate binders, antithyroid drugs (e.g., Methimazole) or thyroid hormone. Use of any of the prohibited medications listed in the study protocol. Hypersensitivity: Known hypersensitivity to corticosteroids, leukotrienes, or any excipients in the ELLIPTA (ELLIPTA is a Glaxosmithkline owned trademark for dry powder inhaler) inhaler and study tablets. Milk Protein Allergy: History of severe milk protein allergy. The subject has 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, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Exposure to more than 4 investigational medicinal products within 12 months prior to the first dosing day. Children who are 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 known or suspected psychiatric disease, intellectual deficiency, substance abuse or other condition (e.g. 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 (e.g. 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.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 9 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 |
| --- | --- |
| Experimental: Fluticasone furoate 50 mcg<br>During run-in period, subjects will receive inhaled placebo for 16 weeks using ELLIPTA inhaler. Followed by treatment period where subjects will receive inhaled FF 50 mcg administered once daily in the morning for 52 weeks using ELLIPTA inhaler. Subjects will also receive open-label montelukast (4 milligrams [mg] for subjects who are 5 years old and 5 mg for subjects who are >= 6 years old) to be administered as one tablet of montelukast each evening for the duration of the study. Each subject will receive a SABA (albuterol/salbutamol [inhalation aerosol or nebuliser]) to be used as needed throughout the entire study period as rescue medication for symptomatic relief of asthma symptoms. | Drug: Fluticasone furoate<br>* Fluticasone furoate will be supplied as 50 mcg per blister dry white powder for inhalation using ELLIPTA inhaler.<br>Drug: Placebo<br>* Placebo will be supplied as dry white powder Lactose for inhalation using ELLIPTA inhaler.<br>Drug: Montelukast<br>* Montelukast will be supplied as 4 mg chewable tablet (5 year old subjects) and as 5 mg chewable tablet (>=6 year old subjects)<br>Drug: Short Acting Beta 2 Agonist<br>* Albuterol/salbutamol will be supplied as inhalation aerosol or nebulizer.<br>|
| Placebo Comparator: Placebo<br>During run-in period, subjects will receive inhaled placebo for 16 weeks using ELLIPTA inhaler. Followed by treatment period where subjects will receive inhaled placebo administered once daily in the morning for 52 weeks using ELLIPTA inhaler. Subjects will also receive open-label montelukast (4 milligrams [mg] for subjects who are 5 years old and 5 mg for subjects who are >=6 years old) to be administered as one tablet of montelukast each evening for the duration of the study. Each subject will receive a SABA (albuterol/salbutamol [inhalation aerosol or nebuliser]) to be used as needed throughout the entire study period as rescue medication for symptomatic relief of asthma symptoms. | Drug: Placebo<br>* Placebo will be supplied as dry white powder Lactose for inhalation using ELLIPTA inhaler.<br>Drug: Montelukast<br>* Montelukast will be supplied as 4 mg chewable tablet (5 year old subjects) and as 5 mg chewable tablet (>=6 year old subjects)<br>Drug: Short Acting Beta 2 Agonist<br>* Albuterol/salbutamol will be supplied as inhalation aerosol or nebulizer.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Growth Velocity (Centimeter Per Year) Over the Double-blind Treatment Period, as Determined by Stadiometry | Three reproducible height measurements were taken using a stadiometer at each visit and were recorded to nearest 1/10th of centimeter. Each set of triplicate measurements was averaged to derive one estimated height per participant per visit. Growth velocity was calculated for each participant over double-blind treatment period (up to 52 weeks [wk]) by fitting a regression line to averaged height measurements at each visit for that participant during period. Slope of this regression line was participant's growth velocity for double-blind treatment period. Treatment policy estimand was assessed, including all on- and post-treatment data. Baseline was included as covariate which was calculated based on stadiometric height measurements recorded at Visits 1(wk -16), 3(wk-8), and 5(wk0), data from at least two of these visits were used to fit a simple linear regression line against time and the slope of the fitted regression line was the participant's Baseline growth velocity. | Up to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Below the Third Percentile of Growth Velocity During Double-blind Treatment Period | Three reproducible height measurements were taken using stadiometer at each visit&were recorded to nearest 1/10th of a centimeter.Each set of triplicate measurements was averaged to derive one estimated height per participant per visit.Growth velocity(GV)was calculated for each participant over double-blind treatment(up to 52 weeks)period by fitting regression line to height measurements recorded for that participant during period.Each participant's double-blind(DB) treatment period GV was calculated based on all on &off treatment height data &was programmatically compared to data values from Standards from Birth to Maturity for Height,Weight,Height Velocity, established in British Children(1965)&further updated for North American children(1985)using 3rd percentile value of age closest to participant's age at end of endpoint(i.e.either end of participant's DB treatment period [Visit18 Wk 52]/withdrawal from study[Early Withdrawal Visit]).Percentage values presented is rounded off. | Up to 52 weeks | 
| Percentage of Participants With Change in Growth Velocity Quartiles From Baseline to Endpoint | Growth velocity(GV) quartile(defined as 1st quartile(1Q)=1st-25th percentile,2Q=26th-50th percentile,3Q=51st-75th percentile,4Q=76th-100th percentile) was determined at Baseline&endpoint.Endpoint was defined as slope of simple linear regression of average stadiometric height recorded at week 28& upto wk52.Baseline growth velocity was calculated as slope from simple linear regression of average stadiometric height recorded at wk-16,-8&0.Baseline GV was programmatically compared to reference for standard height data using participant's estimated age at wk0& age in reference data closest to actual age of participant to determine Baseline GV quartile.Endpoint GV was programmatically compared to reference data using participant's age at endpoint & age in reference data that was closest to actual age of participant to determine endpoint GV quartile. Any increase/decrease indicates any increase/decrease in quartiles with reference to Baseline. Percentage values presented is rounded off. | Baseline and Endpoint (Week 28[Visit 12] up to and including Week 52 [Visit 18]) | 
| Growth Velocity Over the First 12 Weeks of Double-blind Treatment Period | Growth velocity was calculated for each participant over double blind period by fitting regression line to height measurements recorded for that participant during period.Slope of this regression line was participant's growth velocity for double-blind treatment period.In order to be included in this analysis,participant must have data from Visit8(Wk 12) stadiometric height assessment.Baseline was included as covariate which was calculated based on stadiometric height measurements recorded at Visits 1(wk -16),3(wk-8),& 5(wk0),data from at least two of these visits were used to fit simple linear regression line against time&slope of fitted regression line was participant's Baseline growth velocity.All available height data collected during double-blind treatment period upto Visit8(Wk12) while participant was on randomized double-blind treatment was considered.ANCOVA model was used to estimate mean treatment difference in growth velocity over 1st 12weeks of double-blind treatment period. | Up to 12 weeks (Visit 8) of double-blind treatment period | 
| Change in Height Standard Deviation Scores (SDS) From Baseline to Endpoint | Each participant's SDS for each of three required stadiometric height measurements was calculated as:(observed height measurement-standard median height for age at Visit [week-16]) divided by (/) ([standard 95th height percentile for age at visit-standard 5th height percentile for age at visit]/[2*1.645]).Standard median, 95th percentile, & 5th percentile values were obtained from standard tables (Guidance for Industry Orally Inhaled & Intranasal Corticosteroid). SDS for each height stadiometric measurement at each visit was calculated using percentiles from standard tables & averaged for each participant before being summarized by treatment group. A reduction in SDS over time indicates growth deceleration & an increase in SDS over time means growth acceleration.Baseline was defined as height SD score at Visit 5 (week 0). Endpoint was defined as height SD score at Visit 18 (week52) (on- & off-treatment data). Change from Baseline was calculated as Endpoint value minus Baseline value. | Baseline (Week 0 [Visit 5]) and up to Endpoint (Week 52 [Visit 18]) | 
| Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose which results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations as per investigator's judgement. | Up to 76 weeks | 
| Number of Participants With On-treatment Asthma Exacerbations Over Double-blind Treatment Period | An exacerbation is defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days or a single depot corticosteroid injection, or an in-patient hospitalization or emergency department (ED) visit due to asthma that required systemic corticosteroids. Number of participants with on-treatment asthma exacerbations during double-blind treatment period is presented. | Up to 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Growth Velocity, Prepubertal, Asthma, Paediatric