Asthma
Conditions
Keywords
GW642444, once daily dosing, asthma, efficacy, safety, FEV1
Brief summary
The study is a multi-center, double-blind, placebo-controlled, cross-over study to evaluate the efficacy and safety of selected doses and dose intervals of the novel long acting beta agonist (LABA), GW642444 in asthmatic subjects ≥18 years of age who are currently receiving inhaled corticosteroid treatment.
Detailed description
The study will be a five-period cross-over study with each 7 day treatment period separated by a 7 day wash-out period. The study will enroll asthmatic subjects ≥18 years of age who are currently receiving inhaled corticosteroid treatment with an FEV1 of between 40-85% of predicted normal and with airway reversibility as demonstrated by an increase in FEV1 of ≥12% and ≥200ml . Efficacy assessments include 24-hour serial lung function testing. Safety assessments include incidence of adverse events and measurement of vital signs.
Interventions
DRUGDose 4 QD
QD once daily
DRUGDose 3 QD
QD once daily
DRUGplacebo
placebo
DRUGDose 2 QD
QD once daily
DRUGDose 1 BD
BD twice daily
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Outpatient * ≥18 years of age at Visit 1 * Male or Eligible Female * Diagnosis of asthma at least 12 weeks prior to Visit 1 * Disease reversibility * Current anti-asthma therapy * Appropriately signed and dated informed consent has been obtained * Able to comply with all the study requirements
Exclusion criteria
* History of Life-Threatening Asthma * No use of systemic corticosteroids for any indication within 8 weeks prior to Visit * No concurrent diseases/abnormalities that would put the safety of the subject at risk through study participation * Drug Allergy to β2 agonist or sympathomimetic drugs, or known or suspected sensitivity to lactose or magnesium stearate * History of severe milk protein allergy * Non-compliance with study medication and other study-related requirements * No use of inhaled tobacco products within the past three months or historical use of 10 pack years or more * Administration of prohibited medications and non-drug therapies and corresponding timeframes as outlined in the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Trough (Pre-bronchodilator and Pre-dose) FEV1 on Day 7 of the Treatment Period | Baseline and Day 7 of the treatment period (up to Study Day 63) | Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 is defined as the mean of the FEV1 values obtained at the last two scheduled time points at the Day 7 clinic visit (i.e., 11 and 12 hours after the morning dose, or 23 and 24 hours after the evening dose). Change from Baseline was calculated as the Day 7 value minus the Baseline value. Analysis was performed using a mixed model analysis of covariance (ANCOVA) with fixed effects of treatment, period, sex, and age. Participants is fitted as a random effect, and the period Baseline measurement is included as part of a bivariate response. The model for the period Baseline value is not affected by treatment group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Weighted Mean 24-hour FEV1 on Day 7 of the Treatment Period | Baseline and Day 7 of the treatment period (up to Study Day 63) | Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. Weighted mean was derived by calculating the average area under curve, and then dividing by the relevant time interval. 24-hour serial measurements of FEV1 were performed on Day 7 of each of the 5 treatment periods (Visits 3, 5, 7, 9, and 11). Measurements were taken at pre-dose; 30 and 60 minutes; and 3, 5, 11, 12, 12.5, 13, 15, 17, 23, and 24 hours post-dose. Visits 3, 5, 7, 9, and 11 were overnight visits. Change from Baseline was calculated as the Day 7 value minus the Baseline value. Analysis was performed using a mixed effects analysis of covariance (ANCOVA) model, with fixed effects for treatment, period, sex, and age. Participant was fitted as a random effect, and the period Baseline FEV1 measurement was included as part of a bivariate response. The model for the period Baseline value is not affected by treatment group. |
Countries
United States
Participant flow
Recruitment details
Participants (par,) who met all inclusion criteria at screening entered a 7-day Run-in Period (RIP). Par. were instructed to administer albuterol inhalation aerosol as needed and to continue their inhaled corticosteroid at a stable dose throughout the study. Par. who met randomization criteria at the end of the RIP entered Treatment Period 1.
Pre-assignment details
The study was a multi-centre, double-blind, placebo-controlled, five-period cross-over study. Following the 7(+7)-day RIP, eligible participants were randomized to 1 of 5 sequences of GW642444 at doses of 6.25 micrograms (µg) once daily (QD), 6.25 µg twice daily, 12.5 µg QD, 25 µg QD, and placebo.
Participants by arm
| Arm | Count |
|---|---|
| PB, GW642444 6.25 µg QD, 6.25 µg BID, 12.5 µg QD, and 25 µg QD All participants received one of the following five treatments in one of the five Treatment Periods from two DPI dispensed on Day 1of each of the five 7-day treatment periods: Placebo (PB), GW642444 6.25 µg once daily (QD) in the evening, GW642444 6.25 µg twice daily (BID), GW642444 12.5 µg QD in the evening, and GW642444 25 µg QD in the evening. Participants received their first evening medication dose in the clinic on Day 1 of each of the five treatment periods. The treatments were administered in the morning (AM) and in the evening (PM), approximately 12 hours apart. All participants took blinded treatment (active or placebo) every 12 hours, and therefore followed a 12-hour dosing interval. The five treatment periods were separated by a 7-day washout period. | 75 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| 7-day Treatment Period 1 | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 |
| 7-day Treatment Period 3 | Lack of Efficacy | 0 | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | PB, GW642444 6.25 µg QD, 6.25 µg BID, 12.5 µg QD, and 25 µg QD |
|---|---|
| Age, Continuous | 38.9 Years STANDARD_DEVIATION 14.37 |
| Gender Female | 47 Participants |
| Gender Male | 28 Participants |
| Race/Ethnicity, Customized African American/African Heritage | 23 participants |
| Race/Ethnicity, Customized Asian-Central/South Asian Heritage | 1 participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 51 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 74 | 0 / 73 | 3 / 74 | 0 / 73 | 3 / 73 |
| serious Total, serious adverse events | 0 / 74 | 0 / 73 | 0 / 74 | 0 / 73 | 0 / 73 |
Outcome results
Primary
Change From Baseline in Trough (Pre-bronchodilator and Pre-dose) FEV1 on Day 7 of the Treatment Period
Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 is defined as the mean of the FEV1 values obtained at the last two scheduled time points at the Day 7 clinic visit (i.e., 11 and 12 hours after the morning dose, or 23 and 24 hours after the evening dose). Change from Baseline was calculated as the Day 7 value minus the Baseline value. Analysis was performed using a mixed model analysis of covariance (ANCOVA) with fixed effects of treatment, period, sex, and age. Participants is fitted as a random effect, and the period Baseline measurement is included as part of a bivariate response. The model for the period Baseline value is not affected by treatment group.
Time frame: Baseline and Day 7 of the treatment period (up to Study Day 63)
Population: Intent-to Treat (ITT) Population: all participants randomized to treatment who received at least one dose of trial medication. Randomized participants were assumed to have received trial medication unless definitive evidence to the contrary existed. Only participants available at the indicated time point were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Trough (Pre-bronchodilator and Pre-dose) FEV1 on Day 7 of the Treatment Period | 0.059 Liters | Standard Error 0.0221 |
| GW642444 6.25 µg QD | Change From Baseline in Trough (Pre-bronchodilator and Pre-dose) FEV1 on Day 7 of the Treatment Period | 0.153 Liters | Standard Error 0.0222 |
| GW642444 6.25 µg BID | Change From Baseline in Trough (Pre-bronchodilator and Pre-dose) FEV1 on Day 7 of the Treatment Period | 0.198 Liters | Standard Error 0.0221 |
| GW642444 12.5 µg QD | Change From Baseline in Trough (Pre-bronchodilator and Pre-dose) FEV1 on Day 7 of the Treatment Period | 0.161 Liters | Standard Error 0.0221 |
| GW642444 25 µg QD | Change From Baseline in Trough (Pre-bronchodilator and Pre-dose) FEV1 on Day 7 of the Treatment Period | 0.184 Liters | Standard Error 0.0221 |
p-value: <0.00195% CI: [0.049, 0.14]ANCOVA
p-value: <0.00195% CI: [0.095, 0.185]ANCOVA
p-value: <0.00195% CI: [0.057, 0.147]ANCOVA
p-value: <0.00195% CI: [0.08, 0.17]ANCOVA
Secondary
Change From Baseline in Weighted Mean 24-hour FEV1 on Day 7 of the Treatment Period
Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. Weighted mean was derived by calculating the average area under curve, and then dividing by the relevant time interval. 24-hour serial measurements of FEV1 were performed on Day 7 of each of the 5 treatment periods (Visits 3, 5, 7, 9, and 11). Measurements were taken at pre-dose; 30 and 60 minutes; and 3, 5, 11, 12, 12.5, 13, 15, 17, 23, and 24 hours post-dose. Visits 3, 5, 7, 9, and 11 were overnight visits. Change from Baseline was calculated as the Day 7 value minus the Baseline value. Analysis was performed using a mixed effects analysis of covariance (ANCOVA) model, with fixed effects for treatment, period, sex, and age. Participant was fitted as a random effect, and the period Baseline FEV1 measurement was included as part of a bivariate response. The model for the period Baseline value is not affected by treatment group.
Time frame: Baseline and Day 7 of the treatment period (up to Study Day 63)
Population: ITT Population. Only those participants available at the indicated time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Weighted Mean 24-hour FEV1 on Day 7 of the Treatment Period | 0.028 Liters | Standard Error 0.0195 |
| GW642444 6.25 µg QD | Change From Baseline in Weighted Mean 24-hour FEV1 on Day 7 of the Treatment Period | 0.181 Liters | Standard Error 0.0195 |
| GW642444 6.25 µg BID | Change From Baseline in Weighted Mean 24-hour FEV1 on Day 7 of the Treatment Period | 0.194 Liters | Standard Error 0.0195 |
| GW642444 12.5 µg QD | Change From Baseline in Weighted Mean 24-hour FEV1 on Day 7 of the Treatment Period | 0.196 Liters | Standard Error 0.0195 |
| GW642444 25 µg QD | Change From Baseline in Weighted Mean 24-hour FEV1 on Day 7 of the Treatment Period | 0.213 Liters | Standard Error 0.0195 |