Asthma
Conditions
Keywords
pediatric, ADVAIR, FLOVENT, asthma
Brief summary
The purpose of this study is to assess whether the risk of serious asthma-related events (asthma-related hospitalizations, endotracheal intubations, and deaths) in children 4-11 years old taking inhaled fluticasone propionate/salmeterol combination is the same as those taking inhaled fluticasone propionate alone.
Detailed description
Progress of Enrollment, Updated Annually: This study has been completed and the final clinical study report was submitted to the FDA in May of 2016. This is the final update, as this study is complete.
Interventions
DRUGADVAIR 100/50mcg
fluticasone propionate/salmeterol combination (100/50mcg) twice daily (AM and PM) for 6 months
DRUGADVAIR 250/50mcg
fluticasone propionate/salmeterol combination (250/50mcg) twice daily (AM and PM) for 6 months
DRUGFLOVENT 100mcg
fluticasone propionate (100) twice daily (AM and PM) for 6 months
DRUGFLOVENT 250mcg
fluticasone propionate (250mcg) twice daily (AM and PM) for 6 months
Sponsors
Parexel
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
4 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
1. Consent to participate in the study 2. Age 4-11 years old 3. Male or eligible female - Female subjects should not be enrolled if they are pregnant, lactating or plan to become pregnant during the time of study participation 4. Asthma diagnosis for at least 6 months 5. Ability to answer questions regarding asthma control and use a metered dose inhaler and DISKUS 6. A history of clinical varicella infection or recipient of a varicella vaccine in countries where the product label includes a warning regarding more serious chickenpox infections in patients using corticosteroids. 7. History of at least once occurrence of asthma exacerbation within the prior 12 months 8. Currently being treated for asthma and no change in asthma therapy for the last 4 weeks (Eligible subjects include: subjects with use of short-acting beta-agonist, leukotriene receptor antagonist, theophylline, or cromolyn whose asthma is not well-controlled; subjects on low-dose ICS monotherapy whose asthma is not well-controlled; subjects on low-dose ICS and one or more adjunctive therapy whose asthma is either controlled or not well-controlled asthma; subjects on medium-dose ICS monotherapy whose asthma is either controlled or not well-controlled; and subjects on medium-dose ICS and one or more adjunctive therapy whose asthma is well-controlled)
Exclusion criteria
1. History of life-threatening asthma 2. Unstable asthma 3. Current use of high-dose ICS or ICS/LABA therapy to treat asthma symptoms 4. Concurrent respiratory disease: Current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, allergic bronchopulmonary aspergillosis, cystic fibrosis, bronchopulmonary dysplasia, or other severe respiratory abnormalities other than asthma. 5. Respiratory infection 6. Subjects with only exercise-induced asthma 7. An asthma exacerbation within the last 4 weeks or more than 4 separate exacerbations in the last 12 months 8. Hospitalization for asthma within 4 weeks or more than 2 hospitalizations within the last 12 months 9. Other current evidence of clinically significant uncontrolled disease/conditions of any body or organ system 10. Neurological or psychiatric disease or history of drug or alcohol abuse of a subject or his/her guardian which in the opinion of the investigator could interfere with the subject's proper completion of the protocol requirements 11. Participation in an interventional study or used any investigational drug for any disease state within the last 30 days 12. Any adverse reaction including immediate or delayed hypersensitivity to any beta-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy, or vehicle contained within these medication 13. Severe hypersensitivity to cow's milk proteins 14. Administration of prescription or over the counter medications that would significantly affect the course of asthma, or interact with sympathomimetic amines such as: anti-IgE (omalizumab), anticonvulsants (barbiturates, hydantoins, carbamazepine); polycyclic antidepressants, beta-adrenergic blockers; phenothiazines, monoamine oxidase inhibitors, or diuretics 15. Potent cytochrome P450 3A4 (CYP3A4) inhibitors within the last 4 weeks (e.g., ritonavir, ketoconazole, itraconzole) 16. Affiliation with investigator's site, including a immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator. 17. A Child in Care (CiC) is a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing an Event in the Composite Safety Endpoint of Serious Asthma Outcomes ( Asthma-related Hospitalization, Asthma-related Endotracheal Intubation, or Asthma-related Death) | From Day 1 up to 6 months | Composite endpoint was defined as clinically relevant endpoint that is constructed from combinations of other clinically relevant endpoints of serious asthma outcomes (i.e., asthma-related hospitalization, asthma-related endotracheal intubation, or asthma-related death). Hospitalization was defined as an inpatient stay or a \>=24-hour stay in an observation area in an emergency department or other equivalent facility. Time to first event in the composite endpoint of serious asthma-related outcomes over the 6-month study treatment period was analyzed using a Cox proportional hazards regression model. An estimate of absolute risk difference and its corresponding 95% confidence interval (CI) were also included. The Intent-to-Treat (ITT) Population included all participants randomized to study drug and who took study treatment. |
| Number of Participants With at Least One Asthma Exacerbation Over the 6-month Study Treatment Period | From Day 1 up to 6 months | Number of participants with asthma exacerbation over the 6-month study treatment period are presented. Participants from mITT population with screening childhood asthma control test (C-ACT) scores of 20 or higher, one exacerbation in the previous year, and either low-dose inhaled corticosteroid (ICS) + one or more adjunctive therapy or medium-dose ICS monotherapy or medium-dose ICS and one or more adjunctive therapy as prior asthma therapy were included for this endpoint. Time to first exacerbation analyzed using a cox proportional hazards regression model. The number of asthma exacerbations were compared between treatments using a negative binomial regression model. The modified Intent-to-Treat (mITT) Population consisted of the ITT participants with a different data cut-off for supportive analyses of the primary composite safety endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Asthma-related Hospitalizations Over the 6-month Study Treatment Period | From Day 1 up to 6 months | Hospitalization is defined as a \>=24-hour stay as an inpatient or in an observation ward. The number of participants experiencing asthma-related hospitalizations over the 6-month study treatment period are presented. |
| Number of Participants Withdrawn From Study Treatment Due to Asthma Exacerbation Over the 6-month Study Treatment Period | From Day 1 up to 6 months | An exacerbation is defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days (up to 10 days) or a single depot corticosteroid injection. Number of participants experiencing at least one exacerbation from mITT population were included for this endpoint. The number of participants withdrawn from study treatment due to asthma exacerbation over the 6-month study treatment period are presented. |
| Number of Participants Experiencing Asthma-related Deaths Over the 6-month Study Treatment Period. | From Day 1 up to 6 months | Number of participants experiencing asthma-related death over the 6-month study treatment period are presented. |
| Percentage of Asthma Control Days Over the 6-month Study Treatment Period | From Day 1 up to 6 months | An asthma control day is one on which rescue albuterol/salbutamol use was recorded as 0, no night time awakenings were recorded, no asthma exacerbations were recorded, no work, school, or daycare days were missed by caregiver or participant due to asthma, coughing symptom score was \<=1 and wheezing symptom score was 0. The mean percentages of asthma control days over the months 1-6 (defined as treatment days 2-182) are summarized. Number of participants over treatment days 2-182 from mITT Population were included for this endpoint. |
| Percentage of Rescue-free Days Over the 6-month Study Treatment Period | From Day 1 up to 6 months | Rescue-free days were days without use of rescue albuterol/salbutamol (other than pre-exercise treatment) over the 6-month study treatment period. The mean percentages of rescue-free days over the months 1-6 (defined as treatment days 2-182) are summarized. Number of participants over treatment days 2-182 from mITT Population were included for this endpoint. |
| Number of Participants Experiencing Asthma-related Endotracheal Intubations Over the 6-month Study Treatment Period | From Day 1 up to 6 months | Intubation is defined as endotracheal intubation with ventilation (mechanical or by hand). The number of participants experiencing asthma-related endotracheal intubations over the 6-month study treatment period are presented. |
Countries
Argentina, Australia, Austria, Belgium, Bulgaria, Canada, Chile, Colombia, Croatia, Czechia, Germany, Hungary, Italy, Latvia, Lithuania, Malaysia, Mexico, Peru, Philippines, Poland, Romania, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Taiwan, Thailand, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
A total of 6250 participants were enrolled and randomized to study treatments; total 6208 participants took at least one dose of study drug.
Pre-assignment details
Participants aged between 4 to 11 years having asthma, defined by the regional asthma guidelines for at least 6 months, having history of at least one occurrence of treatment with systemic corticosteroid and with no change in asthma therapy for the last 4 weeks from first visit were enrolled for the study.
Participants by arm
| Arm | Count |
|---|---|
| FSC DPI Participants were randomized to either FSC or FP, and the treatment dose was based on participants' asthma control status. There was no intent to compare the dosage levels received, therefore participants were combined for comparison regardless of dosage. In this treatment arm, participants received one of following treatments: FSC 100/50 microgram (µg) or FSC 250/50 µg as one inhalation twice daily (BID) (approximately 12 hours apart) via Dry powder inhaler (DPI) during the 6 month treatment period. Rescue medication (albuterol/salbutamol) via metered dose inhaler (MDI) was permitted during study treatment. | 3,107 |
| FP DPI Participants were randomized to either FSC or FP, and the treatment dose was based on participants' asthma control status. There was no intent to compare the dosage levels received, therefore participants were combined for comparison regardless of dosage. In this treatment arm, participants received one of the following treatments: FP 100 µg or FP 250 µg as one inhalation BID (approximately 12 hours apart) via DPI during the 6 month treatment period. Rescue medication (albuterol/salbutamol) via MDI was permitted during study treatment. | 3,101 |
| Total | 6,208 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 24 | 23 |
| Overall Study | Asthma Exacerbation | 34 | 35 |
| Overall Study | Lack of Efficacy | 5 | 6 |
| Overall Study | Lost to Follow-up | 7 | 7 |
| Overall Study | Protocol Violation | 68 | 53 |
| Overall Study | Withdrawal by Subject | 245 | 226 |
Baseline characteristics
| Characteristic | FSC DPI | Total | FP DPI |
|---|---|---|---|
| Age, Continuous | 7.6 Years STANDARD_DEVIATION 2.21 | 7.6 Years STANDARD_DEVIATION 2.2 | 7.6 Years STANDARD_DEVIATION 2.2 |
| Race/Ethnicity, Customized African American / African Heritage | 539 Participants | 1050 Participants | 511 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 144 Participants | 262 Participants | 118 Participants |
| Race/Ethnicity, Customized Asian - Central / South Asian Heritage | 30 Participants | 67 Participants | 37 Participants |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 96 Participants | 208 Participants | 112 Participants |
| Race/Ethnicity, Customized Asian - South East Asian Heritage | 122 Participants | 230 Participants | 108 Participants |
| Race/Ethnicity, Customized Japanese Heritage | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Missing | 5 Participants | 7 Participants | 2 Participants |
| Race/Ethnicity, Customized Mixed Race | 167 Participants | 347 Participants | 180 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 5 Participants | 6 Participants | 1 Participants |
| Race/Ethnicity, Customized White - Arabic / North African Heritage | 13 Participants | 28 Participants | 15 Participants |
| Race/Ethnicity, Customized White - White / Caucasian / European Heritage | 1985 Participants | 4002 Participants | 2017 Participants |
| Sex: Female, Male Female | 1187 Participants | 2414 Participants | 1227 Participants |
| Sex: Female, Male Male | 1920 Participants | 3794 Participants | 1874 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 31 / 3,107 | 39 / 3,101 |
| serious Total, serious adverse events | 56 / 3,107 | 54 / 3,101 |
Outcome results
Primary
Number of Participants Experiencing an Event in the Composite Safety Endpoint of Serious Asthma Outcomes ( Asthma-related Hospitalization, Asthma-related Endotracheal Intubation, or Asthma-related Death)
Composite endpoint was defined as clinically relevant endpoint that is constructed from combinations of other clinically relevant endpoints of serious asthma outcomes (i.e., asthma-related hospitalization, asthma-related endotracheal intubation, or asthma-related death). Hospitalization was defined as an inpatient stay or a \>=24-hour stay in an observation area in an emergency department or other equivalent facility. Time to first event in the composite endpoint of serious asthma-related outcomes over the 6-month study treatment period was analyzed using a Cox proportional hazards regression model. An estimate of absolute risk difference and its corresponding 95% confidence interval (CI) were also included. The Intent-to-Treat (ITT) Population included all participants randomized to study drug and who took study treatment.
Time frame: From Day 1 up to 6 months
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FSC DPI | Number of Participants Experiencing an Event in the Composite Safety Endpoint of Serious Asthma Outcomes ( Asthma-related Hospitalization, Asthma-related Endotracheal Intubation, or Asthma-related Death) | 27 Participants |
| FP DPI | Number of Participants Experiencing an Event in the Composite Safety Endpoint of Serious Asthma Outcomes ( Asthma-related Hospitalization, Asthma-related Endotracheal Intubation, or Asthma-related Death) | 21 Participants |
p-value: 0.00695% CI: [0.726, 2.272]Regression, Cox
95% CI: [-0.0024, 0.0063]
Primary
Number of Participants With at Least One Asthma Exacerbation Over the 6-month Study Treatment Period
Number of participants with asthma exacerbation over the 6-month study treatment period are presented. Participants from mITT population with screening childhood asthma control test (C-ACT) scores of 20 or higher, one exacerbation in the previous year, and either low-dose inhaled corticosteroid (ICS) + one or more adjunctive therapy or medium-dose ICS monotherapy or medium-dose ICS and one or more adjunctive therapy as prior asthma therapy were included for this endpoint. Time to first exacerbation analyzed using a cox proportional hazards regression model. The number of asthma exacerbations were compared between treatments using a negative binomial regression model. The modified Intent-to-Treat (mITT) Population consisted of the ITT participants with a different data cut-off for supportive analyses of the primary composite safety endpoint.
Time frame: From Day 1 up to 6 months
Population: mITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FSC DPI | Number of Participants With at Least One Asthma Exacerbation Over the 6-month Study Treatment Period | 265 Participants |
| FP DPI | Number of Participants With at Least One Asthma Exacerbation Over the 6-month Study Treatment Period | 309 Participants |
95% CI: [0.729, 1.012]
Secondary
Number of Participants Experiencing Asthma-related Deaths Over the 6-month Study Treatment Period.
Number of participants experiencing asthma-related death over the 6-month study treatment period are presented.
Time frame: From Day 1 up to 6 months
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FSC DPI | Number of Participants Experiencing Asthma-related Deaths Over the 6-month Study Treatment Period. | 0 Participants |
| FP DPI | Number of Participants Experiencing Asthma-related Deaths Over the 6-month Study Treatment Period. | 0 Participants |
Secondary
Number of Participants Experiencing Asthma-related Endotracheal Intubations Over the 6-month Study Treatment Period
Intubation is defined as endotracheal intubation with ventilation (mechanical or by hand). The number of participants experiencing asthma-related endotracheal intubations over the 6-month study treatment period are presented.
Time frame: From Day 1 up to 6 months
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FSC DPI | Number of Participants Experiencing Asthma-related Endotracheal Intubations Over the 6-month Study Treatment Period | 0 Participants |
| FP DPI | Number of Participants Experiencing Asthma-related Endotracheal Intubations Over the 6-month Study Treatment Period | 0 Participants |
Secondary
Number of Participants Experiencing Asthma-related Hospitalizations Over the 6-month Study Treatment Period
Hospitalization is defined as a \>=24-hour stay as an inpatient or in an observation ward. The number of participants experiencing asthma-related hospitalizations over the 6-month study treatment period are presented.
Time frame: From Day 1 up to 6 months
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FSC DPI | Number of Participants Experiencing Asthma-related Hospitalizations Over the 6-month Study Treatment Period | 27 Participants |
| FP DPI | Number of Participants Experiencing Asthma-related Hospitalizations Over the 6-month Study Treatment Period | 21 Participants |
Secondary
Number of Participants Withdrawn From Study Treatment Due to Asthma Exacerbation Over the 6-month Study 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 (up to 10 days) or a single depot corticosteroid injection. Number of participants experiencing at least one exacerbation from mITT population were included for this endpoint. The number of participants withdrawn from study treatment due to asthma exacerbation over the 6-month study treatment period are presented.
Time frame: From Day 1 up to 6 months
Population: mITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FSC DPI | Number of Participants Withdrawn From Study Treatment Due to Asthma Exacerbation Over the 6-month Study Treatment Period | 33 Participants |
| FP DPI | Number of Participants Withdrawn From Study Treatment Due to Asthma Exacerbation Over the 6-month Study Treatment Period | 35 Participants |
Secondary
Percentage of Asthma Control Days Over the 6-month Study Treatment Period
An asthma control day is one on which rescue albuterol/salbutamol use was recorded as 0, no night time awakenings were recorded, no asthma exacerbations were recorded, no work, school, or daycare days were missed by caregiver or participant due to asthma, coughing symptom score was \<=1 and wheezing symptom score was 0. The mean percentages of asthma control days over the months 1-6 (defined as treatment days 2-182) are summarized. Number of participants over treatment days 2-182 from mITT Population were included for this endpoint.
Time frame: From Day 1 up to 6 months
Population: mITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FSC DPI | Percentage of Asthma Control Days Over the 6-month Study Treatment Period | 74.8 Percentage of asthma control days | Standard Error 0.57 |
| FP DPI | Percentage of Asthma Control Days Over the 6-month Study Treatment Period | 73.4 Percentage of asthma control days | Standard Error 0.58 |
Secondary
Percentage of Rescue-free Days Over the 6-month Study Treatment Period
Rescue-free days were days without use of rescue albuterol/salbutamol (other than pre-exercise treatment) over the 6-month study treatment period. The mean percentages of rescue-free days over the months 1-6 (defined as treatment days 2-182) are summarized. Number of participants over treatment days 2-182 from mITT Population were included for this endpoint.
Time frame: From Day 1 up to 6 months
Population: mITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FSC DPI | Percentage of Rescue-free Days Over the 6-month Study Treatment Period | 83.0 Percentage of rescue-free days | Standard Error 0.5 |
| FP DPI | Percentage of Rescue-free Days Over the 6-month Study Treatment Period | 81.9 Percentage of rescue-free days | Standard Error 0.52 |