Trial Outcomes & Findings for Efficacy and Safety Study in Subjects With Asthma (NCT NCT00980200)

Last Updated: 2017-01-30

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

75 participants

Primary outcome timeframe

Baseline and Day 7 of the treatment period (up to Study Day 63)

Results posted on

2017-01-30

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Sequence 1: 6.25 µg BID, Pbo, 12.5 µg QD, 25 µg QD, 6.25 µg QD Participants received GW642444 6.25 micrograms (µg) twice a day (BID), placebo (pbo), GW642444 12.5 µg once a day (QD) in the evening, GW642444 25 µg QD in the evening, and GW642444 6.25 µg QD in the evening in Treatment Periods 1, 2, 3, 4, and 5 respectively. Participants received all treatments from a Dry Powder Inhaler (DPI) for 7 days. The treatments were administered 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 washout period of at least 7 days.	Sequence 2: Pbo, 6.25 µg BID, 6.25 µg QD, 12.5 µg QD, 25 µg QD Participants received placebo, GW642444 6.25 µg BID, GW642444 6.25 µg QD in the evening, GW642444 12.5 µg QD in the evening, and GW642444 25 µg QD in the evening and in Treatment Periods 1, 2, 3, 4, and 5 respectively. Participants received all treatments from a DPI for 7 days. The treatments were administered 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 washout period of at least 7 days.	Sequence 3: 6.25 µg QD, 25 µg QD, Pbo, 6.25 µg BID, 12.5 µg QD Participants received GW642444 6.25 µg QD in the evening, GW642444 25 µg QD in the evening, placebo, GW642444 6.25 µg BID, and GW642444 12.5 µg QD in the evening in Treatment Periods 1, 2, 3, 4, and 5 respectively. Participants received all treatments from a DPI for 7 days. The treatments were administered 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 washout period of at least 7 days.	Sequence 4: 12.5 µg QD, 6.25 µg QD, 25 µg QD, Pbo, 6.25 µg BID Participants received GW642444 12.5 µg QD in the evening, GW642444 6.25 µg QD in the evening, GW642444 25 µg QD in the evening, placebo, and GW642444 6.25 µg BID and in Treatment Periods 1, 2, 3, 4, and 5 respectively. Participants received all treatments from a DPI for 7 days. The treatments were administered 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 washout period of at least 7 days.	Sequence 5: 25 µg QD, 12.5 µg QD, 6.25 µg BID, 6.25 µg QD, Pbo Participants received GW642444 25 µg QD in the evening, GW642444 12.5 µg QD in the evening, GW642444 6.25 µg BID, GW642444 6.25 µg QD in the evening, and placebo in Treatment Periods 1, 2, 3, 4, and 5 respectively. Participants received all treatments from a DPI for 7 days. The treatments were administered 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 washout period of at least 7 days.
7-day Treatment Period 1 STARTED	15	14	15	16	15
7-day Treatment Period 1 COMPLETED	15	13	15	16	15
7-day Treatment Period 1 NOT COMPLETED	0	1	0	0	0
7-day Washout Period 1 STARTED	15	13	15	16	15
7-day Washout Period 1 COMPLETED	15	13	15	16	15
7-day Washout Period 1 NOT COMPLETED	0	0	0	0	0
7-day Treatment Period 2 STARTED	15	13	15	16	15
7-day Treatment Period 2 COMPLETED	15	13	15	16	15
7-day Treatment Period 2 NOT COMPLETED	0	0	0	0	0
7-day Washout Period 2 STARTED	15	13	15	16	15
7-day Washout Period 2 COMPLETED	15	13	15	16	15
7-day Washout Period 2 NOT COMPLETED	0	0	0	0	0
7-day Treatment Period 3 STARTED	15	13	15	16	15
7-day Treatment Period 3 COMPLETED	15	12	15	16	14
7-day Treatment Period 3 NOT COMPLETED	0	1	0	0	1
7-day Washout Period 3 STARTED	15	12	15	16	14
7-day Washout Period 3 COMPLETED	15	12	15	16	14
7-day Washout Period 3 NOT COMPLETED	0	0	0	0	0
7-day Treatment Period 4 STARTED	15	12	15	16	14
7-day Treatment Period 4 COMPLETED	15	12	15	16	14
7-day Treatment Period 4 NOT COMPLETED	0	0	0	0	0
7-day Washout Period 4 STARTED	15	12	15	16	14
7-day Washout Period 4 COMPLETED	15	12	15	16	14
7-day Washout Period 4 NOT COMPLETED	0	0	0	0	0
7-day Treatment Period 5 STARTED	15	12	15	16	14
7-day Treatment Period 5 COMPLETED	15	12	15	16	14
7-day Treatment Period 5 NOT COMPLETED	0	0	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Sequence 1: 6.25 µg BID, Pbo, 12.5 µg QD, 25 µg QD, 6.25 µg QD Participants received GW642444 6.25 micrograms (µg) twice a day (BID), placebo (pbo), GW642444 12.5 µg once a day (QD) in the evening, GW642444 25 µg QD in the evening, and GW642444 6.25 µg QD in the evening in Treatment Periods 1, 2, 3, 4, and 5 respectively. Participants received all treatments from a Dry Powder Inhaler (DPI) for 7 days. The treatments were administered 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 washout period of at least 7 days.	Sequence 2: Pbo, 6.25 µg BID, 6.25 µg QD, 12.5 µg QD, 25 µg QD Participants received placebo, GW642444 6.25 µg BID, GW642444 6.25 µg QD in the evening, GW642444 12.5 µg QD in the evening, and GW642444 25 µg QD in the evening and in Treatment Periods 1, 2, 3, 4, and 5 respectively. Participants received all treatments from a DPI for 7 days. The treatments were administered 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 washout period of at least 7 days.	Sequence 3: 6.25 µg QD, 25 µg QD, Pbo, 6.25 µg BID, 12.5 µg QD Participants received GW642444 6.25 µg QD in the evening, GW642444 25 µg QD in the evening, placebo, GW642444 6.25 µg BID, and GW642444 12.5 µg QD in the evening in Treatment Periods 1, 2, 3, 4, and 5 respectively. Participants received all treatments from a DPI for 7 days. The treatments were administered 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 washout period of at least 7 days.	Sequence 4: 12.5 µg QD, 6.25 µg QD, 25 µg QD, Pbo, 6.25 µg BID Participants received GW642444 12.5 µg QD in the evening, GW642444 6.25 µg QD in the evening, GW642444 25 µg QD in the evening, placebo, and GW642444 6.25 µg BID and in Treatment Periods 1, 2, 3, 4, and 5 respectively. Participants received all treatments from a DPI for 7 days. The treatments were administered 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 washout period of at least 7 days.	Sequence 5: 25 µg QD, 12.5 µg QD, 6.25 µg BID, 6.25 µg QD, Pbo Participants received GW642444 25 µg QD in the evening, GW642444 12.5 µg QD in the evening, GW642444 6.25 µg BID, GW642444 6.25 µg QD in the evening, and placebo in Treatment Periods 1, 2, 3, 4, and 5 respectively. Participants received all treatments from a DPI for 7 days. The treatments were administered 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 washout period of at least 7 days.
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

Efficacy and Safety Study in Subjects With Asthma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	PB, GW642444 6.25 µg QD, 6.25 µg BID, 12.5 µg QD, and 25 µg QD n=75 Participants 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.
Age, Continuous	38.9 Years STANDARD_DEVIATION 14.37 • n=93 Participants
Gender Female	47 Participants n=93 Participants
Gender Male	28 Participants n=93 Participants
Race/Ethnicity, Customized African American/African Heritage	23 participants n=93 Participants
Race/Ethnicity, Customized Asian-Central/South Asian Heritage	1 participants n=93 Participants
Race/Ethnicity, Customized White - White/Caucasian/European Heritage	51 participants n=93 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=74 Participants Participants received 2 placebo actuations per day during one of the five 7-day Treatment Periods. Participants received treatment in the morning (AM) and evening (PM), approximately 12 hours apart, from two seperate DPIs starting with their first dose on the evening of Day 1. Each treatment period was followed by a 7-day washout period.	GW642444 6.25 µg QD n=73 Participants Participants received 2 actuations per day (AM and PM) during one of the five 7-day Treatment Periods from two seperate DPIs starting with their first dose on the evening of Day 1. Participants received one actuation of GW642444 6.25 µg and another actuation of placebo. The treatments were administered approximately 12 hours apart. All participants took blinded treatment (active or placebo) every 12 hours, and therefore followed a 12-hour dosing interval. Each treatment period was followed by a 7-day washout period.	GW642444 6.25 µg BID n=74 Participants Participants received 2 actuations per day for during one of the five 7-day Treatment Periods from two separate DPIs starting with their first dose on the evening of Day 1. Participants received one actuation of GW642444 6.25 µg in the morning and a second actuation in the evening. The treatments were administered approximately 12 hours apart. All participants took blinded treatment every 12 hours, and therefore followed a 12-hour dosing interval. Each treatment period was followed by a 7-day washout period.	GW642444 12.5 µg QD n=73 Participants Participants received 2 actuations per day (AM and PM) during one of the five 7-day Treatment Periods from two seperate DPIs starting with their first dose on the evening of Day 1. Participants received one actuation of GW642444 12.5 µg and another actuation of placebo. The treatments were administered approximately 12 hours apart. All participants took blinded treatment (active or placebo) every 12 hours, and therefore followed a 12-hour dosing interval. Each treatment period was followed by a 7-day washout period.	GW642444 25 µg QD n=73 Participants Participants received 2 actuations per day (AM and PM) during one of the five 7-day Treatment Periods from two seperate DPIs starting with their first dose on the evening of Day 1. Participants received one actuation of GW642444 25 µg and another actuation of placebo. The treatments were administered approximately 12 hours apart. All participants took blinded treatment (active or placebo) every 12 hours, and therefore followed a 12-hour dosing interval. Each treatment period was followed by a 7-day washout period.
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	0.153 Liters Standard Error 0.0222	0.198 Liters Standard Error 0.0221	0.161 Liters Standard Error 0.0221	0.184 Liters Standard Error 0.0221

SECONDARY outcome

Timeframe: 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.

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.