Asthma
Conditions
Keywords
fluticasone furoate
Brief summary
A randomised, double-blind, multi-centre study to evaluate the efficacy and safety of two doses of inhaled fluticasone furoate in the treatment of persistent asthma in adults and adolescents currently receiving mid to high strength inhaled corticosteroids.
Detailed description
This will be a multi-centre, randomised, double-blind, parallel-group study. Subjects meeting all the inclusion criteria and none of the exclusion criteria during Visit 1 (screening visit) will enter a four week Run-In period during which they will remain on their baseline ICS medication. In addition, all subjects will be provided with albuterol/salbutamol for relief of asthma symptoms. Subjects failing screening will not be eligible for re-screening. During the Run-In and double-blind treatment periods subjects will maintain an electronic daily diary to record morning and evening Peak Expiratory Flow (PEF), asthma symptom score and rescue albuterol/salbutamol use. Subjects will receive a contact (Phone Contact 1/optional office visit (1b)) during Run-In to reinforce compliance with Run-In medication and diary monitoring. Those subjects who meet the eligibility criteria at the end of the Run-In period will be stratified in an approximately 1:1 ratio according to their baseline FEV1 as a percentage of predicted normal - one stratum for those with FEV1 percent predicted ≥40% to ≤65% and one for those with FEV1 percent predicted \>65% to ≤90%. Once stratified, subjects will be randomised to one of the following treatments and enter into a 24 week double-blind treatment period:1) Fluticasone furoate 100mcg once daily in the evening or 2) Fluticasone furoate 200mcg once daily in the evening. Subjects will then attend 6 on-treatment visits at Visits 3, 4, 5, 6, 7 and 8 (Weeks 2, 4, 8, 12, 18 and 24 respectively). All visits including Visit 1 must be conducted in the evening between 5 PM and 11 PM. Subjects will receive treatment for 24 weeks. Twenty four hour urinary cortisol assessments will be collected at the end of Run-In (Visit 2) and at end of treatment (Visit 8) visits. A follow-up contact will be performed 1-week after completing study medication (Visit 9). Subjects will participate in the study for up to a maximum of 29 weeks (including screening, treatment and follow-up contact). In addition, partially used NDPIs will be collected in a subset of subjects. For subjects who have consented for pharmacogenetics, a blood sample will also be taken for pharmacogenetic analysis.
Interventions
DRUGfluticasone furoate
Inhaled corticosteroid
DRUGalbuterol/salbutamol
Provided as rescue relief of asthma symptoms
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Signed informed consent * Outpatient at least 12 years of age with diagnosis of asthma at least 12 weeks prior to first visit * Both genders; females of child bearing potential must be willing to use appropriate contraception * Pre-bronchodilator FEV1 of 40-90% predicted * Reversibility FEV1 of at least 12% and 200mLs * Current asthma therapy that includes inhaled corticosteroid for at least 4 weeks prior to first visit
Exclusion criteria
* History of life threatening asthma * Respiratory infection or candidiasis * Asthma exacerbation requiring OCS within last 4 weeks or overnight hospital stay within the last 3 months * Concurrent respiratory disease or other disease that would confound study participation of affect subject safety * Allergies to study drugs, study drug excipients, medications related to study drugs * Taking another investigational medication or medication prohibited for use during the study * Previous treatment with FF or FF/VI in a phase II or III study * Night shift workers * Children in care
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Clinic Visit Evening (Pre-bronchodilator and Pre-dose) Forced Expiratory Volume in One Second (FEV1) at the End of the 24-week Treatment Period | Baseline and Week 24 | FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Evening clinic visit FEV1 is defined as the clinic visit (pre-bronchodilator and pre-dose) FEV1 measurement taken at the Week 24 clinic visit. Pre-dose and pre-rescue albuterol/salbutamol trough FEV1 were measured electronically by spirometry in the evening at the Baseline through Week 24 clinic visits. The highest of 3 technically acceptable measurements was recorded. Baseline was the pre-dose value obtained at Visit 2. Change from Baseline was calculated as the Week 24 value minus the Baseline value. Analysis was performed using analysis of covariance (ANCOVA) with covariates of Baseline, region, sex, age, and treatment. The last observation carried forward (LOCF) method was used to impute missing data, in which the last non-missing, pre-dose, post-Baseline on-treatment measurement at scheduled clinic visits was used to impute the missing value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Percentage of Rescue-free 24-hour (hr) Periods Over the 24-week Treatment Period | From Baseline up to Week 24 | The number of inhalations of rescue bronchodilator, albuterol/salbutamol inhalation aerosol, used during the day and night was recorded by the participants in a daily electronic diary (eDiary). A 24-hour period in which a participant's responses to both the morning and evening assessments indicated no use of rescue medication was considered to be rescue free. A 24-hour period was considered as missing if both day time and night time values were missing or if one of the day time or night time values were missing and the other value indicated no use of rescue medication. The Baseline value is the average of the values over the last 7 days of the daily eDiary prior to the randomization of the participant. Change from Baseline was calculated as the averaged value during the 24-week Treatment Period minus the Baseline value. Analysis was performed using ANCOVA with covariates of Baseline, region, sex, age, and treatment. |
| Change From Baseline in Daily Evening (PM) Peak Expiratory Flow (PEF) Averaged Over the 24-week Treatment Period | From Baseline up to Week 24 | PEF is a measure of lung function and is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF was measured by the participants using a hand-held electronic peak flow meter each morning and evening prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. Change from Baseline (defined as the average of the values of the last 7 days prior to randomization of the participants) was calculated as the value of the averaged daily trough PM PEF over the 24-week Treatment Period minus the Baseline value. Analysis was performed using ANCOVA with covariates of Baseline, region, sex, age, and treatment. |
| Change From Baseline in Daily Morning (AM) PEF Averaged Over the 24-week Treatment Period | From Baseline up to Week 24 | PEF is a measure of lung function and is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF was measured by the participants using a hand-held electronic peak flow meter each morning and evening prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. Change from Baseline (defined as the average of the values of the last 7 days prior to randomization of the participants) was calculated as the value of the averaged daily AM PEF over the 24-week Treatment Period minus the Baseline value. Analysis was performed using ANCOVA with covariates of Baseline, region, sex, age, and treatment. |
| Change From Baseline in the Percentage of Symptom-free 24-hour (hr) Periods Over the 24-week Treatment Period | From Baseline up to Week 24 | Asthma symptoms were recorded in a daily eDairy by the participants every day in the morning and evening before taking any rescue or study medication and before the peak expiratory flow measurement. A 24-hour period in which a participant's responses to both the morning and evening assessments indicated no symptoms was considered to be symptom free. A 24-hour period was considered as missing if both the day time and night time data were missing or if one was symptom-free but the other was missing. The Baseline value was the average of the values of the last 7 days of the daily eDiary prior to the randomization of the participant. Change from Baseline was calculated as the averaged value during the 24-week Treatment Period minus the Baseline value. Analysis was performed using ANCOVA with covariates of Baseline, region, sex, age, and treatment. |
Countries
Argentina, Chile, France, Mexico, Russia, United States
Participant flow
Pre-assignment details
Participants meeting eligibility criteria at the Screening visit entered a 4-week Run-in Period for Baseline safety evaluations and to obtain measures of asthma status. Participants were then randomized to a 24-week Treatment Period. A total of 500 participants were screened; 239 were randomized, and 238 received \>=1 dose of study treatment.
Participants by arm
| Arm | Count |
|---|---|
| FF 100 µg OD Participants received fluticasone furoate (FF) 100 micrograms (µg) inhalation powder via a Dry Powder Inhaler (DPI) once daily (OD) in the evening for 24 weeks. In addition, all participants were provided with albuterol/salbutamol aerosol to be used as rescue medication as needed. | 119 |
| FF 200 µg OD Participants received FF 200 µg via a DPI OD in the evening for 24 weeks. In addition, all participants were provided with albuterol/salbutamol aerosol to be used as rescue medication as needed. | 119 |
| Total | 238 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Lack of Efficacy | 2 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Met Protocol-defined Stopping Criteria | 0 | 1 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Protocol Violation | 2 | 3 |
| Overall Study | Study Site Closed/Terminated | 7 | 3 |
| Overall Study | Withdrawal by Subject | 4 | 3 |
Baseline characteristics
| Characteristic | FF 100 µg OD | FF 200 µg OD | Total |
|---|---|---|---|
| Age, Continuous | 46.6 Years STANDARD_DEVIATION 15.41 | 45.1 Years STANDARD_DEVIATION 15.78 | 45.9 Years STANDARD_DEVIATION 15.58 |
| Gender Female | 81 Participants | 79 Participants | 160 Participants |
| Gender Male | 38 Participants | 40 Participants | 78 Participants |
| Race/Ethnicity, Customized African American/African Heritage (HER) | 5 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native & White | 11 Participants | 12 Participants | 23 Participants |
| Race/Ethnicity, Customized Central/South Asian HER | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Japanese/East Asian HER /South East Asian HER | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 101 Participants | 100 Participants | 201 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 52 / 119 | 49 / 119 |
| serious Total, serious adverse events | 3 / 119 | 4 / 119 |
Outcome results
Primary
Change From Baseline in Clinic Visit Evening (Pre-bronchodilator and Pre-dose) Forced Expiratory Volume in One Second (FEV1) at the End of the 24-week Treatment Period
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Evening clinic visit FEV1 is defined as the clinic visit (pre-bronchodilator and pre-dose) FEV1 measurement taken at the Week 24 clinic visit. Pre-dose and pre-rescue albuterol/salbutamol trough FEV1 were measured electronically by spirometry in the evening at the Baseline through Week 24 clinic visits. The highest of 3 technically acceptable measurements was recorded. Baseline was the pre-dose value obtained at Visit 2. Change from Baseline was calculated as the Week 24 value minus the Baseline value. Analysis was performed using analysis of covariance (ANCOVA) with covariates of Baseline, region, sex, age, and treatment. The last observation carried forward (LOCF) method was used to impute missing data, in which the last non-missing, pre-dose, post-Baseline on-treatment measurement at scheduled clinic visits was used to impute the missing value.
Time frame: Baseline and Week 24
Population: Intent-to-Treat (ITT) Population: all participants (par.) randomized to treatment who received \>=1 dose of study medication, except for the par. of one investigator (excluded after good clinical practice \[GCP\] issues identified during a site audit). Only those par. with non-missing covariates and post-Baseline FEV1 data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF 100 µg OD | Change From Baseline in Clinic Visit Evening (Pre-bronchodilator and Pre-dose) Forced Expiratory Volume in One Second (FEV1) at the End of the 24-week Treatment Period | 0.208 Liters | Standard Error 0.0417 |
| FF 200 µg OD | Change From Baseline in Clinic Visit Evening (Pre-bronchodilator and Pre-dose) Forced Expiratory Volume in One Second (FEV1) at the End of the 24-week Treatment Period | 0.284 Liters | Standard Error 0.0411 |
95% CI: [-0.039, 0.192]
Secondary
Change From Baseline in Daily Evening (PM) Peak Expiratory Flow (PEF) Averaged Over the 24-week Treatment Period
PEF is a measure of lung function and is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF was measured by the participants using a hand-held electronic peak flow meter each morning and evening prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. Change from Baseline (defined as the average of the values of the last 7 days prior to randomization of the participants) was calculated as the value of the averaged daily trough PM PEF over the 24-week Treatment Period minus the Baseline value. Analysis was performed using ANCOVA with covariates of Baseline, region, sex, age, and treatment.
Time frame: From Baseline up to Week 24
Population: ITT Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF 100 µg OD | Change From Baseline in Daily Evening (PM) Peak Expiratory Flow (PEF) Averaged Over the 24-week Treatment Period | 5.9 Liters/minute (L/min) | Standard Error 3.26 |
| FF 200 µg OD | Change From Baseline in Daily Evening (PM) Peak Expiratory Flow (PEF) Averaged Over the 24-week Treatment Period | 7.2 Liters/minute (L/min) | Standard Error 3.25 |
Secondary
Change From Baseline in Daily Morning (AM) PEF Averaged Over the 24-week Treatment Period
PEF is a measure of lung function and is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF was measured by the participants using a hand-held electronic peak flow meter each morning and evening prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. Change from Baseline (defined as the average of the values of the last 7 days prior to randomization of the participants) was calculated as the value of the averaged daily AM PEF over the 24-week Treatment Period minus the Baseline value. Analysis was performed using ANCOVA with covariates of Baseline, region, sex, age, and treatment.
Time frame: From Baseline up to Week 24
Population: ITT Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF 100 µg OD | Change From Baseline in Daily Morning (AM) PEF Averaged Over the 24-week Treatment Period | 13.4 L/min | Standard Error 3.22 |
| FF 200 µg OD | Change From Baseline in Daily Morning (AM) PEF Averaged Over the 24-week Treatment Period | 13.2 L/min | Standard Error 3.2 |
Secondary
Change From Baseline in the Percentage of Rescue-free 24-hour (hr) Periods Over the 24-week Treatment Period
The number of inhalations of rescue bronchodilator, albuterol/salbutamol inhalation aerosol, used during the day and night was recorded by the participants in a daily electronic diary (eDiary). A 24-hour period in which a participant's responses to both the morning and evening assessments indicated no use of rescue medication was considered to be rescue free. A 24-hour period was considered as missing if both day time and night time values were missing or if one of the day time or night time values were missing and the other value indicated no use of rescue medication. The Baseline value is the average of the values over the last 7 days of the daily eDiary prior to the randomization of the participant. Change from Baseline was calculated as the averaged value during the 24-week Treatment Period minus the Baseline value. Analysis was performed using ANCOVA with covariates of Baseline, region, sex, age, and treatment.
Time frame: From Baseline up to Week 24
Population: ITT Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF 100 µg OD | Change From Baseline in the Percentage of Rescue-free 24-hour (hr) Periods Over the 24-week Treatment Period | 21.3 Percentage of rescue-free 24-hr periods | Standard Error 3.05 |
| FF 200 µg OD | Change From Baseline in the Percentage of Rescue-free 24-hour (hr) Periods Over the 24-week Treatment Period | 23.1 Percentage of rescue-free 24-hr periods | Standard Error 3.03 |
Secondary
Change From Baseline in the Percentage of Symptom-free 24-hour (hr) Periods Over the 24-week Treatment Period
Asthma symptoms were recorded in a daily eDairy by the participants every day in the morning and evening before taking any rescue or study medication and before the peak expiratory flow measurement. A 24-hour period in which a participant's responses to both the morning and evening assessments indicated no symptoms was considered to be symptom free. A 24-hour period was considered as missing if both the day time and night time data were missing or if one was symptom-free but the other was missing. The Baseline value was the average of the values of the last 7 days of the daily eDiary prior to the randomization of the participant. Change from Baseline was calculated as the averaged value during the 24-week Treatment Period minus the Baseline value. Analysis was performed using ANCOVA with covariates of Baseline, region, sex, age, and treatment.
Time frame: From Baseline up to Week 24
Population: ITT Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF 100 µg OD | Change From Baseline in the Percentage of Symptom-free 24-hour (hr) Periods Over the 24-week Treatment Period | 17.5 Percentage of symptom-free 24-hr periods | Standard Error 2.8 |
| FF 200 µg OD | Change From Baseline in the Percentage of Symptom-free 24-hour (hr) Periods Over the 24-week Treatment Period | 19.6 Percentage of symptom-free 24-hr periods | Standard Error 2.79 |