Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
long-acting beta2-receptor agonist, Safety and tolerability, pharmacodynamics, pharmacokinetics, long-acting muscarinic receptor antagonist, COPD
Brief summary
The study will evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of the combination of inhaled GSK573719 and GW64244 compared to placebo, in subjects with COPD.
Detailed description
This is a multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and tolerability of the combination of GSK573719 (500mcg) Inhalation Powder and GW642444 (25mcg) Inhalation Powder administered once-daily via a novel dry powder inhaler (Novel DPI) over 28 days in subjects with COPD
Interventions
DRUG500mcg/25mcg once daily
GSK573719/GW642444
Inactive, excipients only
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A signed and dated written informed consent prior to study participation * Males or females of non-childbearing potential * 40 or more years of age * COPD diagnosis * 10 pack-years history or greater of cigarette smoking * Post-bronchodilator FEV1/FVC ratio of 0.70 or less * Post-bronchodilator FEV1 of 80% or less of predicted normal
Exclusion criteria
* Current diagnosis of asthma * Other significant respiratory disorders besides COPD, including alpha-1 deficiency * Previous lung resection surgery * Significant abnormalities in chest x-ray presentation * Use of oral steroids, antibiotics or hospitalization for a COPD exacerbation within 3 motnhs prior screening * Any significant disease that would put subject at risk through study participation * BMI greater than 35 * Pacemaker * Significantly abnormal ECG, Holter, or clinical lab finding (including Hepatitis B or C) * Cancer * Allergy or hypersensitivity to anticholinergics or inhaler excipients * Diseases that would contra-indicate the use of anticholinergics * Use of oral corticosteroids within 6 weeks of screening * Use of long-acting beta-agonists within 48 hours of screening * Use of tiotropium within 14 days of screening * Use of theophyllines or anti-leukotrienes within 48 hours of screening * Use of short-acting bronchodilators within 4 hours of screening * Use of investigational medicines within 30 days of screening * Use of high dose inhaled corticosteroids * Use of long-term oxygen therapy, CPAP or NIPPV * Previous use of GSK573719 or GW642444
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Weighted Mean Pulse Rate Over 0 to 6 Hours Post-dose at Day 28 | Baseline and Day 28 | Pulse rate is defined as the number of heartbeats in a minute. The weighted mean pulse rate was derived by calculating the area under the pulse rate/time curve (AUC), and then dividing the value by the time interval over which the AUC was calculated. The weighted mean pulse rate was calculated using the 0 to 6 hours post dose measurements at Day 28, which included pre-dose, and post-dose 15 minutes, 45 minutes, 1.5 hours, 3 hours and 6 hours. Baseline pulse rate is the most recent result taken on or before pre-dose Day 1. Change from Baseline is the weighted mean pulse rate at Day 28 minus the Baseline value. Analysis was performed using a repeated measures model with covariates of Baseline pulse rate, sex, age, smoking status, treatment and day and day by treatment and day by Baseline interactions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Weighted Mean Pulse Rate Over 0 to 6 Hours Post-dose at Day 1 and Day 14 | Baseline, Day 1, and Day 14 | Pulse rate is defined as the number of heartbeats in a minute. The weighted mean pulse rate was derived by calculating the area under the pulse rate/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The weighted mean pulse rate was calculated using the 0 to 6 hours post dose measurements on Day 1 and Day 14, which included pre-dose, and post-dose 15 minutes, 45 minutes, 1.5 hours, 3 hours and 6 hours. Baseline pulse rate is the most recent result taken on or before pre-dose Day 1. Change from Baseline is the weighted mean pulse rate at Day 1 or Day 14 minus the Baseline value. Analysis was performed using a repeated measures model with covariates of Baseline pulse rate, sex, age, smoking status, treatment and day and day by treatment and day by Baseline interactions. |
| Change From Baseline in Maximum and Minimum Pulse Rate 0 to 6 Hours Post-dose on Days 1, 14, and 28 | Baseline, Day 1, Day 14 and Day 28 | Pulse rate is defined as the number of heartbeats in a minute (m). A maximum post-Baseline pulse rate was derived as the maximum value recorded at Days 1, 14 and 28. A minimum post-Baseline pulse rate was derived as the minimum value recorded at Days 1, 14 and 28. The maximum and minimum pulse rates were calculated using the 0 to 6 hours (h) post dose measurements on Days 1, 14 and 28, which included pre-dose, and post-dose 15 m, 45 m, 1.5 h, 3 h and 6 h. Maximum and minimum post-Baseline rate were calculated using the nominal 0-6 h post-dose records, and only records collected during the actual 0-7 h post-dose interval were used. Baseline pulse rate is the most recent result taken on or before pre-dose Day 1. Change from Baseline is the maximum or minimum pulse rate minus the Baseline value. Analysis performed using a repeated measures model with covariates of Baseline pulse rate, sex, age, smoking status, treatment and day and day by treatment and day by Baseline interactions. |
Countries
United States
Participant flow
Pre-assignment details
Participants (par.) who met eligibility criteria at Screening (Visit 1) completed a 5- to 8-day Run-in period and were then randomized to a 4-week treatment period. A total of 77 par. were screened; 52 par. were randomized and 51 par. received at least one dose of study drug (one par. was randomized in error but did not receive study drug).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received matching placebo QD via a DPI in the morning for 4 weeks. | 9 |
| UMEC/VI 500/25 µg QD Participants received UMEC/VI 500/25 µg QD via a DPI in the morning for 4 weeks. | 42 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Lack of Efficacy | 0 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | UMEC/VI 500/25 µg QD | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 59.2 Years STANDARD_DEVIATION 9.48 | 59.1 Years STANDARD_DEVIATION 9.43 | 58.7 Years STANDARD_DEVIATION 9.77 |
| Race/Ethnicity, Customized African American/African Heritage | 6 Participants | 7 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 36 Participants | 44 Participants | 8 Participants |
| Sex: Female, Male Female | 18 Participants | 20 Participants | 2 Participants |
| Sex: Female, Male Male | 24 Participants | 31 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 9 | 1 / 42 |
| serious Total, serious adverse events | 0 / 9 | 0 / 42 |
Outcome results
Primary
Change From Baseline in Weighted Mean Pulse Rate Over 0 to 6 Hours Post-dose at Day 28
Pulse rate is defined as the number of heartbeats in a minute. The weighted mean pulse rate was derived by calculating the area under the pulse rate/time curve (AUC), and then dividing the value by the time interval over which the AUC was calculated. The weighted mean pulse rate was calculated using the 0 to 6 hours post dose measurements at Day 28, which included pre-dose, and post-dose 15 minutes, 45 minutes, 1.5 hours, 3 hours and 6 hours. Baseline pulse rate is the most recent result taken on or before pre-dose Day 1. Change from Baseline is the weighted mean pulse rate at Day 28 minus the Baseline value. Analysis was performed using a repeated measures model with covariates of Baseline pulse rate, sex, age, smoking status, treatment and day and day by treatment and day by Baseline interactions.
Time frame: Baseline and Day 28
Population: Intent-to-Treat (ITT) Population: all participants randomized to treatment who received \>= 1 dose of randomized study medication. All participants with \>=1 post-BL assessment and non-missing covariate data are included in the analysis. The number of participants represents participants who provided data at Day 28.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Weighted Mean Pulse Rate Over 0 to 6 Hours Post-dose at Day 28 | 1.4 Beats per minutes (bpm) | Standard Error 2.2 |
| UMEC/VI 500/25 µg QD | Change From Baseline in Weighted Mean Pulse Rate Over 0 to 6 Hours Post-dose at Day 28 | 0.9 Beats per minutes (bpm) | Standard Error 1.05 |
95% CI: [-5.5, 4.5]
Secondary
Change From Baseline in Maximum and Minimum Pulse Rate 0 to 6 Hours Post-dose on Days 1, 14, and 28
Pulse rate is defined as the number of heartbeats in a minute (m). A maximum post-Baseline pulse rate was derived as the maximum value recorded at Days 1, 14 and 28. A minimum post-Baseline pulse rate was derived as the minimum value recorded at Days 1, 14 and 28. The maximum and minimum pulse rates were calculated using the 0 to 6 hours (h) post dose measurements on Days 1, 14 and 28, which included pre-dose, and post-dose 15 m, 45 m, 1.5 h, 3 h and 6 h. Maximum and minimum post-Baseline rate were calculated using the nominal 0-6 h post-dose records, and only records collected during the actual 0-7 h post-dose interval were used. Baseline pulse rate is the most recent result taken on or before pre-dose Day 1. Change from Baseline is the maximum or minimum pulse rate minus the Baseline value. Analysis performed using a repeated measures model with covariates of Baseline pulse rate, sex, age, smoking status, treatment and day and day by treatment and day by Baseline interactions.
Time frame: Baseline, Day 1, Day 14 and Day 28
Population: ITT Population. The overall number of participants presented is the number who provided at least one post-Baseline assessment of 0-6 hours maximum or minimum pulse rate. Those participants who provided data at the indicated time point are represented by n=X, X in the category titles.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Maximum and Minimum Pulse Rate 0 to 6 Hours Post-dose on Days 1, 14, and 28 | Maximum pulse rate, Day 1, n=9, 42 | 4.5 Beats per minutes | Standard Error 2.53 |
| Placebo | Change From Baseline in Maximum and Minimum Pulse Rate 0 to 6 Hours Post-dose on Days 1, 14, and 28 | Maximum pulse rate, Day 14, n=9, 40 | 4.9 Beats per minutes | Standard Error 2.93 |
| Placebo | Change From Baseline in Maximum and Minimum Pulse Rate 0 to 6 Hours Post-dose on Days 1, 14, and 28 | Maximum pulse rate, Day 28, n=9, 35 | 7.4 Beats per minutes | Standard Error 2.45 |
| Placebo | Change From Baseline in Maximum and Minimum Pulse Rate 0 to 6 Hours Post-dose on Days 1, 14, and 28 | Minimum pulse rate, Day 1, n=9, 42 | -7.0 Beats per minutes | Standard Error 2.1 |
| Placebo | Change From Baseline in Maximum and Minimum Pulse Rate 0 to 6 Hours Post-dose on Days 1, 14, and 28 | Minimum pulse rate, Day 14, n=9, 40 | -7.2 Beats per minutes | Standard Error 2.78 |
| Placebo | Change From Baseline in Maximum and Minimum Pulse Rate 0 to 6 Hours Post-dose on Days 1, 14, and 28 | Minimum pulse rate, Day 28, n=9, 35 | -6.8 Beats per minutes | Standard Error 2.37 |
| UMEC/VI 500/25 µg QD | Change From Baseline in Maximum and Minimum Pulse Rate 0 to 6 Hours Post-dose on Days 1, 14, and 28 | Minimum pulse rate, Day 14, n=9, 40 | -3.2 Beats per minutes | Standard Error 1.28 |
| UMEC/VI 500/25 µg QD | Change From Baseline in Maximum and Minimum Pulse Rate 0 to 6 Hours Post-dose on Days 1, 14, and 28 | Maximum pulse rate, Day 1, n=9, 42 | 6.4 Beats per minutes | Standard Error 1.15 |
| UMEC/VI 500/25 µg QD | Change From Baseline in Maximum and Minimum Pulse Rate 0 to 6 Hours Post-dose on Days 1, 14, and 28 | Minimum pulse rate, Day 1, n=9, 42 | -6.7 Beats per minutes | Standard Error 0.95 |
| UMEC/VI 500/25 µg QD | Change From Baseline in Maximum and Minimum Pulse Rate 0 to 6 Hours Post-dose on Days 1, 14, and 28 | Maximum pulse rate, Day 14, n=9, 40 | 9.7 Beats per minutes | Standard Error 1.37 |
| UMEC/VI 500/25 µg QD | Change From Baseline in Maximum and Minimum Pulse Rate 0 to 6 Hours Post-dose on Days 1, 14, and 28 | Minimum pulse rate, Day 28, n=9, 35 | -5.1 Beats per minutes | Standard Error 1.15 |
| UMEC/VI 500/25 µg QD | Change From Baseline in Maximum and Minimum Pulse Rate 0 to 6 Hours Post-dose on Days 1, 14, and 28 | Maximum pulse rate, Day 28, n=9, 35 | 6.1 Beats per minutes | Standard Error 1.19 |
Secondary
Change From Baseline in Weighted Mean Pulse Rate Over 0 to 6 Hours Post-dose at Day 1 and Day 14
Pulse rate is defined as the number of heartbeats in a minute. The weighted mean pulse rate was derived by calculating the area under the pulse rate/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The weighted mean pulse rate was calculated using the 0 to 6 hours post dose measurements on Day 1 and Day 14, which included pre-dose, and post-dose 15 minutes, 45 minutes, 1.5 hours, 3 hours and 6 hours. Baseline pulse rate is the most recent result taken on or before pre-dose Day 1. Change from Baseline is the weighted mean pulse rate at Day 1 or Day 14 minus the Baseline value. Analysis was performed using a repeated measures model with covariates of Baseline pulse rate, sex, age, smoking status, treatment and day and day by treatment and day by Baseline interactions.
Time frame: Baseline, Day 1, and Day 14
Population: ITT Population. All participants with \>=1 post-BL assessment are included in the analysis. Different participants may have been analyzed at different time points (represented by n=X, X in the category titles), so the overall number of participants analyzed reflects everyone in the ITT Population with data avaialable at \>=1 time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Weighted Mean Pulse Rate Over 0 to 6 Hours Post-dose at Day 1 and Day 14 | Day 1, n=9, 42 | -1.2 Beats per minutes | Standard Error 2.04 |
| Placebo | Change From Baseline in Weighted Mean Pulse Rate Over 0 to 6 Hours Post-dose at Day 1 and Day 14 | Day 14, n=9, 39 | -1.7 Beats per minutes | Standard Error 2.7 |
| UMEC/VI 500/25 µg QD | Change From Baseline in Weighted Mean Pulse Rate Over 0 to 6 Hours Post-dose at Day 1 and Day 14 | Day 1, n=9, 42 | -0.6 Beats per minutes | Standard Error 0.92 |
| UMEC/VI 500/25 µg QD | Change From Baseline in Weighted Mean Pulse Rate Over 0 to 6 Hours Post-dose at Day 1 and Day 14 | Day 14, n=9, 39 | 3.1 Beats per minutes | Standard Error 1.26 |