Asthma
Conditions
Keywords
salmeterol/fluticasone combination, Asthma, bronchial hyperresponsiveness, Children, symptom control
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.
Interventions
DRUGSalmeterol/ fluticasone propionate Diskus® inhaler 50/100 mcg
comparator
DRUGfluticasone propionate 2 x 100 mcg
comparator
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to 12 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Symptom-free Days During the Last 10 Weeks of the Treatment Period | Last 10 weeks of the treatment period (Weeks 16-26) | Asthma symptom-free days are defined as days (24 hour period) with no symptoms, as recorded in the participant's diary. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Percentage Predicted Forced Expiratory Volume in One Second (FEV1) at Week 26 | Baseline and 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. |
| Mean Change From Baseline in Forced Vital Capacity (FVC) at Week 26 | Baseline and 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. |
| Mean Change From Baseline in Midexpiratory Flow (MEF 50) at Week 26 | Baseline and 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. |
| Geometric Means of Nitric Oxide (NO) at Week 26 | Baseline and 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. |
| Percent Change From Baseline in RINT Measurements at Week 26 | Baseline and 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. |
| Number of Asthma Exacerbations Per Treatment Group at Week 26 | 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. |
| Percentage of Symptom-free Days During the Entire Treatment Period | Baseline to Week 26 | Asthma symptom-free days are defined as days (24 hour period) with no symptoms, as recorded in the participant's diary |
| Bronchial Hyperresponsiveness With PD20 AMP in Selected Centres | 26 weeks | Bronchial hyperresponsiveness with PD20 AMP in selected centres was not analyzed, as this outcome measure was removed in a protocol amendment. |
| Daily FEV1 and PEF Via the Electronic Peak Flow/FEV1 Meter (PIKO-1) | 26 weeks | 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. |
| Frequency of Asthma Exacerbations (Discriminated on Severity) | 26 weeks | The frequency of asthma exacerbations (discriminated on severity) was not analyzed because of the low overall frequency. |
| Cumulative Number of Symptom-free Weeks Until the End of Treatment | 26 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. |
| Weekly Percentage of Participants With 'Good Controlled Weeks' and 'Maximal Controlled Weeks' | 26 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. |
| Time to Asthma Control, Defined as the Time to First 'Good Controlled Week' or 'Maximum Controlled Week' | 26 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. |
| Mean Change From Baseline in Provocation Dose (PD20) Causing a 20% Fall in FEV1 at Week 26 | Baseline and 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. |
Countries
Netherlands
Participant flow
Recruitment details
Participants were eligible to enter the run-in period if they had a documented clinical history of asthma with hyperresponsiveness. Only participants who were symptomatic after this period were eligible to be enrolled into the study and were randomized into either the Salmeterol/Fluticasone propionate (FP) 50/100 mcg plus placebo or FP groups.
Pre-assignment details
257 participants started the run-in phase of the study, and 99 of these did not meet the inclusion criteria to be entered into the treatment phase. Only baseline characteristics for the 158 participants meeting the inclusion criteria and randomized to either salmeterol/fluticasone propionate 50/100 mcg BID or fluticasone 200 mcg BID are provided.
Participants by arm
| Arm | Count |
|---|---|
| Salmeterol/FP 50/100 mcg Plus Placebo Salmeterol/FP 50/100 mcg plus placebo BID via DISKUS inhaler | 78 |
| FP 200 mcg FP 200 mcg BID via DISKUS inhaler | 80 |
| Total | 158 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 4-Week Run-In Period | Did not meet entry criteria | 99 | 0 | 0 |
| Overall Treatment Period | Lack of Efficacy | 0 | 1 | 0 |
| Overall Treatment Period | Lost to Follow-up | 0 | 0 | 2 |
| Overall Treatment Period | Protocol Violation | 0 | 0 | 2 |
| Overall Treatment Period | Withdrawal by Subject | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Salmeterol/FP 50/100 mcg Plus Placebo | FP 200 mcg | Total |
|---|---|---|---|
| Age, Continuous | 9.4 years STANDARD_DEVIATION 1.8 | 9.3 years STANDARD_DEVIATION 1.9 | 9.3 years STANDARD_DEVIATION 1.8 |
| Asthma duration | 5.7 years STANDARD_DEVIATION 3.1 | 5.5 years STANDARD_DEVIATION 3 | 5.6 years STANDARD_DEVIATION 3 |
| Race/Ethnicity, Customized African | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized African-American | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian | 73 participants | 75 participants | 148 participants |
| Race/Ethnicity, Customized Mixed | 4 participants | 3 participants | 7 participants |
| Sex: Female, Male Female | 36 Participants | 31 Participants | 67 Participants |
| Sex: Female, Male Male | 42 Participants | 49 Participants | 91 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 40 / 78 | 44 / 80 |
| serious Total, serious adverse events | 2 / 78 | 3 / 80 |
Outcome results
Primary
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.
Time frame: Last 10 weeks of the treatment period (Weeks 16-26)
Population: Per protocol (PP) population: participants of the Intent-to-Treat (ITT) Population (participants who had taken at least one dose of study medication) who completed the study without any major protocol violations
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Salmeterol/FP 50/100 mcg Plus Placebo | Percentage of Symptom-free Days During the Last 10 Weeks of the Treatment Period | 50.45 percentage of days | Standard Deviation 33.52 |
| FP 200 mcg | Percentage of Symptom-free Days During the Last 10 Weeks of the Treatment Period | 49.75 percentage of days | Standard Deviation 35.77 |
p-value: 0.6395% CI: [-8.1, 13.4]Repeated Measurements Anal. of Variance
Secondary
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.
Time frame: 26 weeks
Secondary
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.
Time frame: 26 weeks
Secondary
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.
Time frame: 26 weeks
Secondary
Frequency of Asthma Exacerbations (Discriminated on Severity)
The frequency of asthma exacerbations (discriminated on severity) was not analyzed because of the low overall frequency.
Time frame: 26 weeks
Secondary
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.
Time frame: Baseline and Week 26
Population: Per protocol (PP) population: participants of the Intent-to-Treat (ITT) Population (participants who had taken at least one dose of study medication) who completed the study without any major protocol violations and completed two NO measurements (Baseline and Week 26)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Salmeterol/FP 50/100 mcg Plus Placebo | Geometric Means of Nitric Oxide (NO) at Week 26 | 8.6 parts per billion |
| FP 200 mcg | Geometric Means of Nitric Oxide (NO) at Week 26 | 10.0 parts per billion |
Secondary
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.
Time frame: Baseline and Week 26
Population: Per protocol (PP) population: participants of the Intent-to-Treat (ITT) Population (participants who had taken at least one dose of study medication) who completed the study without any major protocol violations. At baseline there were 6 missing data and 4 improper testings that could not be used in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Salmeterol/FP 50/100 mcg Plus Placebo | Mean Change From Baseline in Forced Vital Capacity (FVC) at Week 26 | 2.28 liters | Standard Deviation 0.62 |
| FP 200 mcg | Mean Change From Baseline in Forced Vital Capacity (FVC) at Week 26 | 2.28 liters | Standard Deviation 0.59 |
Secondary
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.
Time frame: Baseline and Week 26
Population: Per protocol (PP) population: participants of the Intent-to-Treat (ITT) Population (participants who had taken at least one dose of study medication) who completed the study without any major protocol violations. For some participants, the data for the MEF 50 measurements are missing, resulting in a smaller number of participants analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Salmeterol/FP 50/100 mcg Plus Placebo | Mean Change From Baseline in Midexpiratory Flow (MEF 50) at Week 26 | 2.28 liters/second | Standard Deviation 0.67 |
| FP 200 mcg | Mean Change From Baseline in Midexpiratory Flow (MEF 50) at Week 26 | 2.19 liters/second | Standard Deviation 0.72 |
Secondary
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.
Time frame: Baseline and Week 26
Population: Per protocol (PP) population: participants of the Intent-to-Treat (ITT) Population (participants who had taken at least one dose of study medication) who completed the study without any major protocol violations. At baseline there were 6 missing data and 4 improper testings that could not be used in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Salmeterol/FP 50/100 mcg Plus Placebo | Mean Change From Baseline in Percentage Predicted Forced Expiratory Volume in One Second (FEV1) at Week 26 | 102.5 percent predicted change | Standard Deviation 14.2 |
| FP 200 mcg | Mean Change From Baseline in Percentage Predicted Forced Expiratory Volume in One Second (FEV1) at Week 26 | 103.0 percent predicted change | Standard Deviation 15.3 |
Secondary
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.
Time frame: Baseline and Week 26
Population: Per protocol (PP) population: participants of the Intent-to-Treat (ITT) Population (participants who had taken at least one dose of study medication) who completed the study without any major protocol violations. From this population, only participants who had measurements at both baseline and Week 26 have been used for analysis.
| Arm | Measure | Value (LOG_MEAN) |
|---|---|---|
| Salmeterol/FP 50/100 mcg Plus Placebo | Mean Change From Baseline in Provocation Dose (PD20) Causing a 20% Fall in FEV1 at Week 26 | 2.7 ratio |
| FP 200 mcg | Mean Change From Baseline in Provocation Dose (PD20) Causing a 20% Fall in FEV1 at Week 26 | 1.5 ratio |
Secondary
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.
Time frame: Week 26
Population: Intent-to-Treat (ITT) Population (participants who had taken at least one dose of study medication)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Salmeterol/FP 50/100 mcg Plus Placebo | Number of Asthma Exacerbations Per Treatment Group at Week 26 | 10 number of exacerbations |
| FP 200 mcg | Number of Asthma Exacerbations Per Treatment Group at Week 26 | 7 number of exacerbations |
Secondary
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
Time frame: Baseline to Week 26
Population: Per protocol (PP) population: participants of the Intent-to-Treat (ITT) Population (participants who had taken at least one dose of study medication) who completed the study without any major protocol violations
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Salmeterol/FP 50/100 mcg Plus Placebo | Percentage of Symptom-free Days During the Entire Treatment Period | 6-16 weeks | 44.60 percentage of days | Standard Deviation 34.67 |
| Salmeterol/FP 50/100 mcg Plus Placebo | Percentage of Symptom-free Days During the Entire Treatment Period | Baseline | 22.78 percentage of days | Standard Deviation 25.3 |
| Salmeterol/FP 50/100 mcg Plus Placebo | Percentage of Symptom-free Days During the Entire Treatment Period | 16-26 weeks | 50.45 percentage of days | Standard Deviation 33.52 |
| Salmeterol/FP 50/100 mcg Plus Placebo | Percentage of Symptom-free Days During the Entire Treatment Period | 0-6 weeks | 31.58 percentage of days | Standard Deviation 31.34 |
| FP 200 mcg | Percentage of Symptom-free Days During the Entire Treatment Period | 16-26 weeks | 49.75 percentage of days | Standard Deviation 35.77 |
| FP 200 mcg | Percentage of Symptom-free Days During the Entire Treatment Period | 0-6 weeks | 31.50 percentage of days | Standard Deviation 29.73 |
| FP 200 mcg | Percentage of Symptom-free Days During the Entire Treatment Period | Baseline | 23.06 percentage of days | Standard Deviation 25.23 |
| FP 200 mcg | Percentage of Symptom-free Days During the Entire Treatment Period | 6-16 weeks | 45.24 percentage of days | Standard Deviation 34.58 |
Secondary
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.
Time frame: Baseline and Week 26
Population: PP Population: Intent-to-Treat (ITT) Population participants who completed the study without any major protocol violations and completed two NO measurements (Baseline and Week 26). For some participants, the data for the RINT measurement are missing, either at Baseline or at Week 26. As a result, fewer subjects have been included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Salmeterol/FP 50/100 mcg Plus Placebo | Percent Change From Baseline in RINT Measurements at Week 26 | -9.1 percent |
| FP 200 mcg | Percent Change From Baseline in RINT Measurements at Week 26 | -9.9 percent |
Secondary
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.
Time frame: 26 weeks
Secondary
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.
Time frame: 26 weeks