Treatment Of Symptomatic Asthma In Children

Study Overview
=================
Brief Summary
-----------------
This study is being conducted to investigate whether in childhood salmeterol/ fluticasone propionate 50/100 bd delivered via the Diskus® inhaler and fluticasone propionate 200 mcg bd delivered via the Diskus® inhaler are non- inferior in terms of symptom control. Additionally we aim to show that salmeterol/ fluticasone propionate 50/100 bd is at least as good in terms of lung function improvement and bronchial hyperreactivity and enables a steroid-sparing management of asthma in children.

Detailed Description
-----------------
A multicentre, randomised, double blind, parallel group study to compare the efficacy and safety of Salmeterol/Fluticasone propionate combination product (Seretide®) 50/100mcg with Fluticasone propionate (Flixotide®) 200mcg, both delivered twice daily via the DISKUS inhaler, in the treatment of children aged 6-12 years with symptomatic asthma.

Official Title
-----------------
A Multicentre, Randomised, Double-blind, Parallel Group Study to Compare the Efficacy and Safety of Salmeterol/Fluticasone Propionate Combination Product (Seretide®) 50/100 mcg With Fluticasone Propionate (Flixotide® ) 200 mcg, Both Delivered Twice Daily Via the DISKUS Inhaler, in the Treatment of Children Aged 6-12 Years With Symptomatic Asthma

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Drug: Salmeterol/ fluticasone propionate Diskus® inhaler 50/100 mcg
* Drug: fluticasone propionate 2 x 100 mcg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Male or female subjects aged 6-12 years (inclusive) A female is eligible to enter and participate in the study if she is: of non-child-bearing potential; OR of child-bearing potential, but not lactating and pregnant. She declares that it is not probable that she will become pregnant during the study (a pregnancy test can be performed at the investigators discretion) Subjects with a documented history of asthma for at least 6 months Subjects with a documented history of BHR within 12 months prior to inclusion or BHR on visit 1 (PD20 methacholine < 150 mcg or an equivalence for histamine) Subjects who have received BDP, budesonide up to 100-200 mcg bd or fluticasone propionate at a dose of up to 125 mcg bd for at least 4 weeks before the start of the run-in period. Subjects who are able to use a electronic peakflow /FEV1 meter (PIKO-1) Subjects who have a normal length SD score between -2SD and +2SD Subjects who are able to use a Diskus inhaler Subjects who are able to perform reproducible lung function tests at visit 1 (variation FEV1 < 5% between the two best measurements) Subjects and their guardians, who have given written informed consent to participate in the study Subjects or their parent/ guardian who are able to understand and complete a DRC. The DRC may be completed by a parent/guardian if the subject is unable to do this him/ herself Subjects able to use Ventolin on an 'as required for symptoms' basis Exclusion criteria: Subjects who have been hospitalised for their asthma within 4 weeks of visit 1 Subjects who had an acute upper respiratory tract infection within 2 weeks or a lower respiratory tract infection within 4 weeks prior to visit 1 Subjects who received oral, parental or depot corticosteroids within 4 weeks prior to visit 1 Subjects who have a known respiratory disorder other than asthma and/or systemic/thoracic abnormalities which influence normal lung function Subjects with a disorder that affects growth (e.g. Turner's syndrome) Subjects who have received any investigational drugs within 4 weeks of visit 1 Subjects with a known or suspected hypersensitivity to inhaled steroids, β2-agonists or lactose Subjects who use any medication that significantly inhibit the cytochrome P450 subfamily enzyme CYP3A4, including ritonavir and ketoconazole Subjects who concurrently participate in another clinical study Subjects who have previously been randomised in this trial

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Salmeterol/ fluticasone propionate Diskus® inhaler 50/100 mcg<br>Salmeterol/ fluticasone propionate Diskus® inhaler 50/100 mcg | Drug: Salmeterol/ fluticasone propionate Diskus® inhaler 50/100 mcg<br>* comparator<br>|
| Other: fluticasone propionate 2 x 100 mcg<br>fluticasone propionate 2 x 100 mcg | Drug: fluticasone propionate 2 x 100 mcg<br>* comparator<br>* Other names: Salmeterol/ fluticasone propionate Diskus® inhaler 50/100 mcg;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Symptom-free Days During the Last 10 Weeks of the Treatment Period | Asthma symptom-free days are defined as days (24 hour period) with no symptoms, as recorded in the participant's diary. | Last 10 weeks of the treatment period (Weeks 16-26) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Symptom-free Days During the Entire Treatment Period | Asthma symptom-free days are defined as days (24 hour period) with no symptoms, as recorded in the participant's diary | Baseline to Week 26 | 
| Mean Change From Baseline in Percentage Predicted Forced Expiratory Volume in One Second (FEV1) at Week 26 | Change from Baseline was calculated as the Week 26 value minus the Baseline value. The percentage predicted FEV1 is defined as the volume of air that can be forced out in one second after taking a deep breath and is corrected for the FEV1 value corresponding with the same age. | Baseline and Week 26 | 
| Mean Change From Baseline in Forced Vital Capacity (FVC) at Week 26 | Change from Baseline was calculated as the Week 26 value minus the Baseline value. Forced vital capacity is defined as the maximum volume of air that can be forcibly expired from the lungs and is calculated by use of spirometry. The spirometry test is performed by using a device called a spirometer, which measures the amount of air one can blow out maximally. Generally, the participant is asked to take the deepest breath they can, and then exhale into the sensor as hard as possible, for as long as possible. The test is normally repeated three times to ensure reproducibility. | Baseline and Week 26 | 
| Mean Change From Baseline in Midexpiratory Flow (MEF 50) at Week 26 | Change from Baseline was calculated as the Week 26 value minus the Baseline value. MEF 50 is defined as maximum expiratory flow rate at 50% of vital capacity. Vital capacity is the maximum amount of air that a person can expel from the lungs after first filling the lungs to their maximum extent. Midexpiratory flow was calculated by use of spirometry. The test is normally repeated at least three times in order to ensure reproducibility. | Baseline and Week 26 | 
| Geometric Means of Nitric Oxide (NO) at Week 26 | Geometric mean values of NO at week 26 were compared using ANCOVA with adjustment for baseline value of NO, age, gender and center. Analysis of covariance (ANCOVA) is a general linear model with one continuous outcome variable (quantitative) and one or more factor variables. | Baseline and Week 26 | 
| Percent Change From Baseline in RINT Measurements at Week 26 | Change from Baseline was calculated as the Week 26 value minus the Baseline value. Interrupter respiratory resistance (RINT) measurements were calculated by a combined analysis for relation between change from baseline and occurrence of the endpoint. RINT is a technique that is used for evaluating lung function in poorly collaborating patients (e.g., small children). The measurement is performed during tidal breathing (normal breathing) instead of during maximal expiration, as is done by a spirometry test. | Baseline and Week 26 | 
| Number of Asthma Exacerbations Per Treatment Group at Week 26 | An exacerbation is defined as a worsening of the asthma complaints (commonly referred to as an asthma attack) and is reported by the participant experiencing the event. An exacerbation was verified by the use of asthma rescue medication. | Week 26 | 
| Mean Change From Baseline in Provocation Dose (PD20) Causing a 20% Fall in FEV1 at Week 26 | PD20 was calculated by using increasing dosages of methacholine. The dosage that caused a 20% fall in FEV1 was used for analysis. The presented data are ratios (month 6/Baseline) of geometric mean PD20 values. | Baseline and Week 26 | 
| Bronchial Hyperresponsiveness With PD20 AMP in Selected Centres | Bronchial hyperresponsiveness with PD20 AMP in selected centres was not analyzed, as this outcome measure was removed in a protocol amendment. | 26 weeks | 
| Daily FEV1 and PEF Via the Electronic Peak Flow/FEV1 Meter (PIKO-1) | Daily FEV1 and PEF via the electronic pea kflow/FEV1 meter (PIKO-1) was not assessed because data from the peak flow meters could not be used for analysis. | 26 weeks | 
| Frequency of Asthma Exacerbations (Discriminated on Severity) | The frequency of asthma exacerbations (discriminated on severity) was not analyzed because of the low overall frequency. | 26 weeks | 
| Cumulative Number of Symptom-free Weeks Until the End of Treatment | This outcome measure was not analyzed due to different insights after protocol finalization; it has become clear that the definition of good and maximal controlled weeks is not very distinctive and can therefore actually not be used. | 26 weeks | 
| Weekly Percentage of Participants With 'Good Controlled Weeks' and 'Maximal Controlled Weeks' | This outcome measure was not analyzed due to different insights after protocol finalization; it has become clear that the definition of good and maximal controlled weeks is not very distinctive and can therefore actually not be used. | 26 weeks | 
| Time to Asthma Control, Defined as the Time to First 'Good Controlled Week' or 'Maximum Controlled Week' | This outcome measure was not analyzed due to different insights after protocol finalization; it has become clear that the definition of good and maximal controlled weeks is not very distinctive and can therefore actually not be used. | 26 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
salmeterol/fluticasone combination, Asthma, bronchial hyperresponsiveness, Children, symptom control