Asthma
Conditions
Keywords
ADVAIR, Asthma, safety, FLOVENT
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 adolescents and adults (12 years of age and older) taking inhaled fluticasone propionate/salmeterol combination is the same as those taking inhaled fluticasone propionate alone. ADVAIR™ and FLOVENT™ are trademarks of the GlaxoSmithKline Group of Companies.
Detailed description
Progress of Enrollment, Updated Annually: This study has been completed and the final clinical study report was submitted to the FDA in January 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
DRUGADVAIR 500/50mcg
fluticasone propionate/salmeterol combination (500/50mcg) 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
DRUGFLOVENT 500mcg
fluticasone propionate (500mcg) twice daily (AM and PM) for 6 months
Sponsors
Parexel
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Provided consent to participate in the study * Male or female, 12 years of age and older * Clinical diagnosis of asthma for at least 1 year prior to the randomization * Clinic PEF of greater than or equal to 50% of predicted normal value * Subject must be appropriately using one of the treatments for asthma listed in the protocol * Subject must be able to complete the asthma control questionnaire, daily questions about asthma, and use a DISKUS inhaler * Subject must have history of at least 1 asthma exacerbation including one of the following in the year prior to randomization: * requiring treatment with systemic corticosteroids * an asthma-related hospitalization
Exclusion criteria
* History of life threatening asthma defined for this protocol as asthma episode that required intubation and/or was associated with hypercapnea requiring non-invasive ventilatory support * Concurrent respiratory disease other than asthma * Current evidence of, or ever been told by a physician that they have chronic bronchitis, emphysema, or chronic obstructive pulmonary disease. * Exercise induced asthma (as the only asthma-related diagnosis) not requiring daily asthma control medicine * Presence of a bacterial or viral respiratory infection that is not resolved at randomization * An asthma exacerbation requiring systemic corticosteriods within 4 weeks of randomization or more than 4 separate exacerbations in the 12 months preceding randomization * More than 2 hospitalizations for treatment of asthma in the 12 months preceding randomization * Subject must not meet unstable asthma severity criteria as listed in the protocol * Potent cytochrome P450 3A4 (CYP3A4) inhibitors within the last 4 weeks (e.g., ritonavir, ketoconazole, itraconzole) * Pregnancy, breast-feeding or planned pregnancy during the study * 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 26 weeks | 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. Probability of having event was summarized with Kaplan-Meier estimates.Hazard ratio, confidence interval, and p-value are from a stratified Cox proportional hazard model, using randomization stratum as the stratification factor. The 95% CI provided in the table is actually the 95. |
| Number of Participants Experiencing at Least One Asthma Exacerbation | From Day 1 up to 26 weeks | An asthma exacerbation is defined as a deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least three days or an inpatient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing at Least One Asthma Related Hospitalization , Endotracheal Intubation and Death | From Day 1 up to 26 weeks | Hospitalization was defined as an inpatient stay or a ≥24-hour stay in an observation area in an emergency department or other equivalent facility. |
| Number of Participant Withdrawals From Study Treatment Due to Asthma Exacerbation | From Day 1 up to 26 weeks | An asthma exacerbation is defined as a deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least three days or an inpatient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. |
| Mean Rescue Medication (Albuterol/Salbutamol) Use as Puffs Per 24 Hours | From Day 1 up to 26 weeks | Rescue medication included albuterol/salbutamol used to treat acute asthma were reported as puffs per 24 hours over a period of 6 months. |
Countries
Argentina, Australia, Austria, Belgium, Bulgaria, Canada, Chile, Colombia, Croatia, Czechia, Denmark, Germany, Hungary, Indonesia, Italy, Latvia, Lithuania, Malaysia, Mexico, Peru, Philippines, Poland, Romania, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Taiwan, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Study duration was 29 weeks, comprised of a randomization visit followed by a treatment period of 26 weeks and a 1 week follow-up phone call. Participants were assessed for eligibility at screening up to 15 days prior to randomization.
Pre-assignment details
Eligible adolescent and adult participants with asthma were stratified based on current asthma medication and a Asthma Control Questionnaire (ACQ-6) score and randomized 1:1 to double-blind study treatment. A total of 11751 were enrolled; however, 72 were randomized but did not receive study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Fluticasone Propionate/Salmeterol Combination (FSC) Participants received one of following treatments: FSC 100/50 microgram (µg) or FSC 250/50 µg or FSC 500/50 µg as one inhalation twice daily (BID) via Dry powder inhaler (DPI) for 26 weeks. Rescue medication (albuterol/salbutamol) via metered dose inhaler (MDI) was permitted during study treatment. Participants were instructed to stop using their current asthma medication. | 5,834 |
| Fluticasone Propionate (FP) Participants received one of following treatments: FP 100 µg or FP 250 µg or FP 500 µg as one inhalation (BID) via (DPI) for 26 weeks. Rescue medication (albuterol/salbutamol) via metered dose inhaler (MDI) was permitted during study treatment. Participants were instructed to stop using their current asthma medication. | 5,845 |
| Total | 11,679 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 6 |
| Overall Study | Withdrawal by Subject | 8 | 8 |
Baseline characteristics
| Characteristic | Fluticasone Propionate (FP) | Total | Fluticasone Propionate/Salmeterol Combination (FSC) |
|---|---|---|---|
| Age, Continuous | 43.4 Years STANDARD_DEVIATION 17.28 | 43.4 Years STANDARD_DEVIATION 17.36 | 43.4 Years STANDARD_DEVIATION 17.45 |
| Race/Ethnicity, Customized African American/African Heritage | 856 Participants | 1726 Participants | 870 Participants |
| Race/Ethnicity, Customized American Indian/Alaska native | 116 Participants | 225 Participants | 109 Participants |
| Race/Ethnicity, Customized Asian-Central/South Asian Heritage | 45 Participants | 81 Participants | 36 Participants |
| Race/Ethnicity, Customized Asian-East Asian Heritage | 88 Participants | 182 Participants | 94 Participants |
| Race/Ethnicity, Customized Asian-South East Asian Heritage | 224 Participants | 458 Participants | 234 Participants |
| Race/Ethnicity, Customized Japanese Heritage | 3 Participants | 7 Participants | 4 Participants |
| Race/Ethnicity, Customized Missing | 3 Participants | 6 Participants | 3 Participants |
| Race/Ethnicity, Customized Multiple | 91 Participants | 193 Participants | 102 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 10 Participants | 18 Participants | 8 Participants |
| Race/Ethnicity, Customized White-Arabic/North African Heritage | 21 Participants | 43 Participants | 22 Participants |
| Race/Ethnicity, Customized White-White/Caucasian/European Heritage | 4388 Participants | 8740 Participants | 4352 Participants |
| Sex: Female, Male Female | 3898 Participants | 7749 Participants | 3851 Participants |
| Sex: Female, Male Male | 1947 Participants | 3930 Participants | 1983 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 46 / 5,834 | 75 / 5,845 |
| serious Total, serious adverse events | 134 / 5,834 | 125 / 5,845 |
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. Probability of having event was summarized with Kaplan-Meier estimates.Hazard ratio, confidence interval, and p-value are from a stratified Cox proportional hazard model, using randomization stratum as the stratification factor. The 95% CI provided in the table is actually the 95.
Time frame: From Day 1 up to 26 weeks
Population: Intent to treat (ITT) Population comprised of all participants randomized to study drug and who took study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluticasone Propionate/Salmeterol Combination (FSC) | 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) | 34 Participants |
| Fluticasone Propionate (FP) | 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) | 33 Participants |
p-value: 0.00395% CI: [0.638, 1.662]Regression, Cox
Primary
Number of Participants Experiencing at Least One Asthma Exacerbation
An asthma exacerbation is defined as a deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least three days or an inpatient hospitalization or emergency department visit due to asthma that required systemic corticosteroids.
Time frame: From Day 1 up to 26 weeks
Population: Modified intent to treat (mITT) Population comprised of participants included in the ITT population that correspond to each participant's period of exposure to study drug plus seven days after the last date of study drug treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluticasone Propionate/Salmeterol Combination (FSC) | Number of Participants Experiencing at Least One Asthma Exacerbation | 480 Participants |
| Fluticasone Propionate (FP) | Number of Participants Experiencing at Least One Asthma Exacerbation | 597 Participants |
Comparison: The hazard ratio computed is essentially the relative risk of having the event in the treatment group relative to the control group, adjusted for time to the event.p-value: 0.20395% CI: [0.63, 1.103]Regression, Cox
Comparison: The hazard ratio computed is essentially the relative risk of having the event in the treatment group relative to the control group, adjusted for time to the event.p-value: 0.18895% CI: [0.645, 1.09]Regression, Cox
Comparison: The hazard ratio computed is essentially the relative risk of having the event in the treatment group relative to the control group, adjusted for time to the event.p-value: 0.00295% CI: [0.645, 0.905]Regression, Cox
Comparison: The hazard ratio computed is essentially the relative risk of having the event in the treatment group relative to the control group, adjusted for time to the event.p-value: 0.07195% CI: [0.451, 1.034]Regression, Cox
Comparison: The hazard ratio computed is essentially the relative risk of having the event in the treatment group relative to the control group, adjusted for time to the event.p-value: 0.37395% CI: [0.659, 1.17]Regression, Cox
Comparison: The hazard ratio computed is essentially the relative risk of having the event in the treatment group relative to the control group, adjusted for time to the event.p-value: 0.27195% CI: [0.665, 1.122]Regression, Cox
Comparison: The hazard ratio computed is essentially the relative risk of having the event in the treatment group relative to the control group, adjusted for time to the event.p-value: 0.00195% CI: [0.637, 0.895]Regression, Cox
Comparison: The hazard ratio computed is essentially the relative risk of having the event in the treatment group relative to the control group, adjusted for time to the event.p-value: 0.07595% CI: [0.454, 1.04]Regression, Cox
Secondary
Mean Rescue Medication (Albuterol/Salbutamol) Use as Puffs Per 24 Hours
Rescue medication included albuterol/salbutamol used to treat acute asthma were reported as puffs per 24 hours over a period of 6 months.
Time frame: From Day 1 up to 26 weeks
Population: mITT Population. Only those participants available at specified timepoint were analysed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fluticasone Propionate/Salmeterol Combination (FSC) | Mean Rescue Medication (Albuterol/Salbutamol) Use as Puffs Per 24 Hours | 0.90 Number of Puffs | Standard Error 0.018 |
| Fluticasone Propionate (FP) | Mean Rescue Medication (Albuterol/Salbutamol) Use as Puffs Per 24 Hours | 1.09 Number of Puffs | Standard Error 0.02 |
p-value: <0.00195% CI: [-0.385, -0.141]Regression, Cox
p-value: 0.00395% CI: [-0.369, -0.076]Regression, Cox
p-value: <0.00195% CI: [-0.238, -0.106]Regression, Cox
p-value: 0.25195% CI: [-0.216, 0.056]Regression, Cox
Secondary
Number of Participants Experiencing at Least One Asthma Related Hospitalization , Endotracheal Intubation and 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 frame: From Day 1 up to 26 weeks
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fluticasone Propionate/Salmeterol Combination (FSC) | Number of Participants Experiencing at Least One Asthma Related Hospitalization , Endotracheal Intubation and Death | Hospitalization | 34 Participants |
| Fluticasone Propionate/Salmeterol Combination (FSC) | Number of Participants Experiencing at Least One Asthma Related Hospitalization , Endotracheal Intubation and Death | Endotracheal intubation | 0 Participants |
| Fluticasone Propionate/Salmeterol Combination (FSC) | Number of Participants Experiencing at Least One Asthma Related Hospitalization , Endotracheal Intubation and Death | Death | 0 Participants |
| Fluticasone Propionate (FP) | Number of Participants Experiencing at Least One Asthma Related Hospitalization , Endotracheal Intubation and Death | Hospitalization | 33 Participants |
| Fluticasone Propionate (FP) | Number of Participants Experiencing at Least One Asthma Related Hospitalization , Endotracheal Intubation and Death | Endotracheal intubation | 2 Participants |
| Fluticasone Propionate (FP) | Number of Participants Experiencing at Least One Asthma Related Hospitalization , Endotracheal Intubation and Death | Death | 0 Participants |
Secondary
Number of Participant Withdrawals From Study Treatment Due to Asthma Exacerbation
An asthma exacerbation is defined as a deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least three days or an inpatient hospitalization or emergency department visit due to asthma that required systemic corticosteroids.
Time frame: From Day 1 up to 26 weeks
Population: mITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluticasone Propionate/Salmeterol Combination (FSC) | Number of Participant Withdrawals From Study Treatment Due to Asthma Exacerbation | 66 Participants |
| Fluticasone Propionate (FP) | Number of Participant Withdrawals From Study Treatment Due to Asthma Exacerbation | 84 Participants |
p-value: 0.12395% CI: [0.562, 1.071]Regression, Cox