Asthma
Conditions
Keywords
mild asthma, allergen challenge, early asthmatic response
Brief summary
We propose to use an inhaled allergen challenge model to explore the individual contributions of the components of a novel long-acting beta agonist (LABA)/ inhaled corticosteroid (ICS) combination product on protection from allergic triggers in asthma.
Interventions
DRUGFluticasone Furoate
FF
DRUGFF/Vilanterol (VI; GW642444M)
FF/VI
DRUGPlacebo
Placebo Inhaler
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Body mass index within the range 18.5-35.0 kilograms/metre2 (kg/m2). * Females of non-child bearing potential. * Documented history of bronchial asthma, first diagnosed at least 6 months prior to the screening visit and currently being treated only with intermittent short-acting beta -agonist therapy by inhalation * Pre-bronchodilator FEV1 \>70% of predicted at screening * Subjects who are current non-smokers * Methacholine challenge PC20 \< 8 mg/mL at screening * Screening allergen challenge demonstrates that the subject experiences an early asthmatic response
Exclusion criteria
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities * Subject is hypertensive at screening * Respiratory tract infection and/or exacerbation of asthma within 4 weeks prior to the first dose of study medication. * History of life-threatening asthma * Symptomatic with hay fever at screening or predicted to have symptomatic hayfever * Unable to abstain from short acting beta agonists * Unable to abstain from antihistamines * Unable to abstain from other medications including non-steroidal anti-inflammatory drugs (NSAIDs), anti-depressant drugs, anti-asthma anti-rhinitis or hay fever medication * The subject has participated in a study with a new molecular entity during the previous 3 months or has participated in 4 or more clinical studies in the previous 12 months * undergoing allergen desensitisation therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Weighted Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Between 0-2 Hours, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each Treatment Period | Baseline and Day 29 of each treatment period (up to Study Day 197) | FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants (par.) were exposed to an allergen (administered by inhalation) 22-23 hours after dosing on Day 28. FEV1 was measured 5 minutes (min), 10 min, 15 min, 20 min, 30 min, and 45 min and 1 hour, 1.5 hours, and 2 hours post-allergen challenge on Day 29. Immediately prior to the exposure of allergen and starting at 2 minutes after inhalation of saline, 3 single measurements of FEV1 were recorded at 1-minute intervals, and the best was taken as the post-saline value. The FEV1 weighted mean was derived by calculating the area under the curve, and then dividing the value by the relevant time interval. Weighted mean change from Baseline is calculated as the weighted mean FEV1 value on Day 29 minus the Baseline value. The Baseline FEV1 value was the post-saline value on Day 29. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Percent Decrease From Baseline in FEV1 Between 0 2 Hour, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each Treatment Period | Baseline and Day 29 of each treatment period (up to Study Day 197) | FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants were exposed to an allergen 22-23 hours after dosing on Day 28. Immediately prior to the exposure of allergen and starting at 2 minutes (min) after inhalation of saline, 3 single measurements of FEV1were recorded at 1-min intervals, and the best was taken as the post-saline value. The maximum change (i.e., drop in FEV1) from post-saline Baseline (BL) is defined by ordering all of the change from BL values for the 5 min, 10 min, 15 min, 20 min, 30 min, and 45 min and the 1 hour, 1.5 hours, and 2 hours post-allergen challenge and selecting the largest change (i.e., drop in FEV1) from the BL value. If there were no negative change values, indicating a worse FEV1 value as compared to the BL value, the smallest change in FEV1, indicating an improvement from the BL value, was selected. The BL FEV1 value was the post-saline value on Day 29. |
| Minimum FEV1 Absolute Change From Baseline Between 0-2 Hour, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each Treatment Period | Baseline and Day 29 of each treatment period (up to Study Day 197) | FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants were exposed to an allergen 22-23 hours after dosing on Day 28. Immediately prior to the exposure of allergen and starting at 2 minutes after inhalation of saline, 3 single measurements of FEV1were recorded at 1-minute intervals, and the best was taken as the post-saline value. The minimum FEV1 over 0-2 hours post-allergen challenge (PAC) (minimum early asthmatic response) was the minimum value of all of the PAC time points up to and including 2 hours PAC (i.e., minimum over 5 minutes (min), 10 min, 15 min, 20 min, 30 min, and 45 min and 1 hour, 1.5 hours, and 2 hours). Change from Baseline was calculated using the post-saline FEV1 on Day 29 as Baseline. Minimum FEV1 absolute change from Baseline between 0-2 hour, following the 22-23 hour post-treatment allergen challenge was calculated as the minimum change value on Day 29 minus the Baseline value |
| Number of Participants With Treatment-emergent Adverse Events (AEs) | From the start of study medication until Follow-up/Early Withdrawal (up to 197 days) | The number of participants with treatment-emergent AEs was measured. A treatment-emergent adverse event is defined as any event not present prior to the initiation of the treatments, or any event already present that worsens in either intensity of frequency following exposure to the treatments. |
Countries
Germany, New Zealand, United Kingdom
Participant flow
Recruitment details
Participants were screened within 42 days of the first dose, conducted over 2 days (not consecutive days). During this time, a methacholine challenge and an allergen challenge test were performed. Participants meeting all inclusion criteria and none of the exclusion criteria were randomized to 3 study treatment periods, each lasting 28 days.
Pre-assignment details
This study was a multi-center, randomized, double-blind, placebo controlled, three-period crossover study in mild asthmatic male and female participants. Following the Run-in period, participants were randomized to 1 of 6 treatment sequences of placebo, FF 100 micrograms (µg) once daily (OD), and FF/VI 100/25 µg OD.
Participants by arm
| Arm | Count |
|---|---|
| Placebo, FF 100 µg OD, FF/VI 100/25 µg OD in 1 of 6 Sequences All participants received one of the following three treatments in one of three treatment periods once daily (OD) in the evening from the Dry Powder Inhaler (DPI) for 28 days: Placebo, Fluticasone Furoate (FF) 100 microgram (µg) dry inhalation powder, and FF/Vilanterol (FF/VI) 100/25 µg dry inhalation powder. Participants were randomized to receive treatment in one of the six following sequences: (1) Placebo, FF 100 µg, FF/VI 100/25 µg; (2) Placebo, FF/VI 100/25 µg, FF 100 µg; (3) FF 100 µg, FF/VI 100/25 µg, Placebo; (4) FF 100 µg, Placebo, FF/VI 100/25 µg; (5) FF/VI 100/25 µg, Placebo, FF 100 µg; (6) FF/VI 100/25 µg, FF 100 µg, Placebo. The three treatment periods were separated by a washout period of at least 21 days (from the Day 28 dose) and a maximum of 35 days. | 52 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment Period 2 | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
| Washout Period 1 | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo, FF 100 µg OD, FF/VI 100/25 µg OD in 1 of 6 Sequences |
|---|---|
| Age, Continuous | 35.4 Years STANDARD_DEVIATION 8.63 |
| Gender Female | 18 Participants |
| Gender Male | 34 Participants |
| Race/Ethnicity, Customized African American/African Heritage | 2 participants |
| Race/Ethnicity, Customized Asian - South East Asian Heritage | 1 participants |
| Race/Ethnicity, Customized Mixed Race | 1 participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 48 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 51 | 18 / 51 | 11 / 51 |
| serious Total, serious adverse events | 0 / 51 | 0 / 51 | 0 / 51 |
Outcome results
Primary
Weighted Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Between 0-2 Hours, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each 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. Participants (par.) were exposed to an allergen (administered by inhalation) 22-23 hours after dosing on Day 28. FEV1 was measured 5 minutes (min), 10 min, 15 min, 20 min, 30 min, and 45 min and 1 hour, 1.5 hours, and 2 hours post-allergen challenge on Day 29. Immediately prior to the exposure of allergen and starting at 2 minutes after inhalation of saline, 3 single measurements of FEV1 were recorded at 1-minute intervals, and the best was taken as the post-saline value. The FEV1 weighted mean was derived by calculating the area under the curve, and then dividing the value by the relevant time interval. Weighted mean change from Baseline is calculated as the weighted mean FEV1 value on Day 29 minus the Baseline value. The Baseline FEV1 value was the post-saline value on Day 29.
Time frame: Baseline and Day 29 of each treatment period (up to Study Day 197)
Population: Intent-to-Treat (ITT) Population: par. randomized to treatment who received \>=1 dose of study drug. Only those par. available at the specified time points were analyzed. Analysis was performed using mixed model analysis of covariance (ANCOVA) with fixed effects of treatment, period, par.-level Baseline, period level Baseline, country, sex, and age.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Weighted Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Between 0-2 Hours, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each Treatment Period | -0.372 Liters | Standard Error 0.0557 |
| FF 100 µg OD | Weighted Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Between 0-2 Hours, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each Treatment Period | -0.210 Liters | Standard Error 0.0549 |
| FF/VI 100/25 µg OD | Weighted Mean Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Between 0-2 Hours, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each Treatment Period | -0.227 Liters | Standard Error 0.055 |
95% CI: [0.087, 0.237]
95% CI: [0.069, 0.222]
95% CI: [-0.091, 0.057]
Secondary
Maximum Percent Decrease From Baseline in FEV1 Between 0 2 Hour, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each 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. Participants were exposed to an allergen 22-23 hours after dosing on Day 28. Immediately prior to the exposure of allergen and starting at 2 minutes (min) after inhalation of saline, 3 single measurements of FEV1were recorded at 1-min intervals, and the best was taken as the post-saline value. The maximum change (i.e., drop in FEV1) from post-saline Baseline (BL) is defined by ordering all of the change from BL values for the 5 min, 10 min, 15 min, 20 min, 30 min, and 45 min and the 1 hour, 1.5 hours, and 2 hours post-allergen challenge and selecting the largest change (i.e., drop in FEV1) from the BL value. If there were no negative change values, indicating a worse FEV1 value as compared to the BL value, the smallest change in FEV1, indicating an improvement from the BL value, was selected. The BL FEV1 value was the post-saline value on Day 29.
Time frame: Baseline and Day 29 of each treatment period (up to Study Day 197)
Population: ITT Population. Only those participants available at the specified time points were analyzed. Analysis was performed using mixed model analysis of covariance (ANCOVA) with fixed effects of treatment, period, participant-level BL, period level BL, country, sex, and age. Change from BL was calculated as the value on Day 29 minus the BL value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Maximum Percent Decrease From Baseline in FEV1 Between 0 2 Hour, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each Treatment Period | -24.991 Percent change | Standard Error 2.0736 |
| FF 100 µg OD | Maximum Percent Decrease From Baseline in FEV1 Between 0 2 Hour, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each Treatment Period | -14.040 Percent change | Standard Error 2.0435 |
| FF/VI 100/25 µg OD | Maximum Percent Decrease From Baseline in FEV1 Between 0 2 Hour, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each Treatment Period | -13.206 Percent change | Standard Error 2.0491 |
Secondary
Minimum FEV1 Absolute Change From Baseline Between 0-2 Hour, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each 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. Participants were exposed to an allergen 22-23 hours after dosing on Day 28. Immediately prior to the exposure of allergen and starting at 2 minutes after inhalation of saline, 3 single measurements of FEV1were recorded at 1-minute intervals, and the best was taken as the post-saline value. The minimum FEV1 over 0-2 hours post-allergen challenge (PAC) (minimum early asthmatic response) was the minimum value of all of the PAC time points up to and including 2 hours PAC (i.e., minimum over 5 minutes (min), 10 min, 15 min, 20 min, 30 min, and 45 min and 1 hour, 1.5 hours, and 2 hours). Change from Baseline was calculated using the post-saline FEV1 on Day 29 as Baseline. Minimum FEV1 absolute change from Baseline between 0-2 hour, following the 22-23 hour post-treatment allergen challenge was calculated as the minimum change value on Day 29 minus the Baseline value
Time frame: Baseline and Day 29 of each treatment period (up to Study Day 197)
Population: ITT Population. Only those participants available at the specified time points were analyzed. Analysis was performed using mixed model ANCOVA with fixed effects of treatment, period, participant-level Baseline, period level Baseline, country, sex, and age.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Minimum FEV1 Absolute Change From Baseline Between 0-2 Hour, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each Treatment Period | -0.809 Liters | Standard Error 0.0775 |
| FF 100 µg OD | Minimum FEV1 Absolute Change From Baseline Between 0-2 Hour, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each Treatment Period | -0.479 Liters | Standard Error 0.0765 |
| FF/VI 100/25 µg OD | Minimum FEV1 Absolute Change From Baseline Between 0-2 Hour, Following the 22-23 Hour Post-treatment Allergen Challenge on Day 29 of Each Treatment Period | -0.478 Liters | Standard Error 0.0767 |
Secondary
Number of Participants With Treatment-emergent Adverse Events (AEs)
The number of participants with treatment-emergent AEs was measured. A treatment-emergent adverse event is defined as any event not present prior to the initiation of the treatments, or any event already present that worsens in either intensity of frequency following exposure to the treatments.
Time frame: From the start of study medication until Follow-up/Early Withdrawal (up to 197 days)
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Treatment-emergent Adverse Events (AEs) | 20 participants |
| FF 100 µg OD | Number of Participants With Treatment-emergent Adverse Events (AEs) | 22 participants |
| FF/VI 100/25 µg OD | Number of Participants With Treatment-emergent Adverse Events (AEs) | 18 participants |