24-week Trial Comparing GSK573719/GW642444 With GSK573719 and With Tiotropium in Chronic Obstructive Pulmonary Disease

Pulmonary Disease, Chronic Obstructive Clinical Trial

Official title:

A Multi-center Trial Comparing the Efficacy and Safety of GSK573719/GW642444 With GSK573719 and With Tiotropium Over 24 Weeks in Subjects With COPD

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01316913
• Other study ID #: 113374
• Status: Completed
• Phase: Phase 3
• First received: March 15, 2011
• Last updated: November 19, 2015
• Start date: March 2011
• Est. completion date: April 2012

Study information

• Verified date: August 2015
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This is a Phase III multicenter, randomized, double-blind, double-dummy, parallel-group study to evaluate the efficacy and safety of two doses of GSK573719/GW642444 Inhalation Powder, GSK573719 Inhalation Powder via a Novel Dry Powder Inhaler and tiotropium via HandiHaler when administered once-daily over a 24-week treatment period in subjects with chronic obstructive pulmonary disease (COPD). Subjects who meet eligibility criteria at Screening (Visit 1) will complete a 7 to10 day run-in period followed by a randomization visit (Visit 2) then a 24-week treatment period. There will be a total of 9 clinic study visits. A follow-up phone contact for adverse event assessment will be conducted approximately one week after the last study visit (Visit 9 or Early Withdrawal). The total duration of subject participation in the study will be approximately 26 weeks. The primary measure of efficacy is clinic visit trough (pre-bronchodilator and pre-dose) forced expiratory volume in one second (FEV1) on Treatment Day 169. Safety will be assessed by adverse events, 12-lead ECGs, vital signs, and clinical laboratory tests.

Description:

This is a 24-week, Phase III multicenter, randomized, double-blind, double-dummy, parallel-group study. Eligible subjects will be randomized to GSK573719/GW642444 125/25mcg, GSK573719/GW642444 62.5/25mcg, GSK573719 125mcg, or tiotropium treatment groups in a 1:1:1:1 ratio. Treatments will be administered once-daily in the morning by inhalation using a Novel Dry Powder Inhaler (Novel DPI) and HandiHaler. There will be a total of 9 study clinic visits conducted on an outpatient basis. Subjects who meet the eligibility criteria at Screening (Visit 1) will complete a 7 to 10 day run-in period followed by a 24-week treatment period. Clinic visits will be at Screening, Randomization (Day 1), Day 2, after 4, 8, 12, 16, and 24-weeks of treatment, and 1 day after the Week 24 Visit (also referred as Treatment Day 169). A follow-up contact for adverse assessment will be conducted by telephone approximately 7 days after Visit 9 or the Early Withdrawal Visit. The total duration of subject participation, including follow-up will be approximately 26 weeks. All subjects will be provided with albuterol/salbutamol for use on an "as-needed" basis throughout the run-in and study treatment periods. At screening, pre-bronchodilator spirometry testing will be followed by post-albuterol/salbutamol spirometry testing. Post-albuterol/salbutamol FEV1 and FEV1/forced vital capacity (FVC) values will be used to determine subject eligibility. To further characterize bronchodilator responsiveness, post-ipratropium testing will be conducted following completion of post-albuterol/salbutamol spirometry. Spirometry will be conducted at each post-randomization clinic visit. Six hour post-dose serial spirometry will be conducted at Visits 2, 6, and 8. Trough spirometry will be obtained 23 and 24 hours after the previous day's dose of blinded study medication at Visits 3 to 9. All subjects will be provided with an electronic diary (eDiary) for completion daily in the morning and the evening throughout the run-in and treatment periods. Subjects will use the eDiary to record peak expiratory flow (PEF) each morning, dyspnea scores using the Shortness of Breath with Daily Activities instrument (SOBDA), daily use of supplemental albuterol/salbutamol as either puffs/day from a metered-dose inhaler (MDI) and/or nebules used per day, and any healthcare contacts related to COPD. Additional assessments of dyspnea will be obtained using the Baseline and Transition Dyspnea Index (BDI/TDI) which is an interviewer based instrument. At Visit 2, the severity of dyspnea at baseline will be assessed using the BDI. At subsequent visits (Visits 4, 6, and 8) change from baseline will be assessed using the TDI. General health status will be evaluated using the subject-completed EQ-5D questionnaire at Visits 2, 4, 6, and 8. Disease specific health status will be evaluated using the subject-completed St. George's Respiratory Questionnaire (SGRQ) at Visits 2, 4, 6, and 8, and the subject-completed COPD Assessment Test (CAT) at Visits 2, 6, and 8. The occurrence of adverse events will be evaluated throughout the study beginning at Visit 2. SAEs will be collected over the same time period as for AEs. However, any SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication, will be recorded from the time a subject consents to participate in the study up to and including any follow up contact. Additional safety assessments of vital signs (blood pressure and pulse rate), 12-lead ECGs and standard clinical laboratory tests (hematology and chemistry) will be obtained at selected clinic visits.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 872
• Est. completion date: April 2012
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

• outpatient

• signed and dated written informed consent

• 40 years of age or older

• male and female subjects

• COPD diagnosis

• at least 10 pack-year smoking history

• post-albuterol/salbutamol FEV1/FVC ratio of <0.70 and post-albuterol/salbutamol FEV1 of less than or equal to 70% predicted normal values

• score of greater than or equal to 2 on the Modified Medical Resarch Council Dyspnea Scale (mMRC)

Exclusion Criteria:

• women who are pregnant or lactating or are planning on becoming pregnant during the study

• current diagnosis of asthma

• other respiratory disorders other than COPD

• other diseases/abnormalities that are uncontrolled including cancer not in remission for at least 5 years

• chest x-ray or CT scan with clinically significant abnormalities not believed to be due to COPD

• hypersensitivity to anticholinergics, beta-agonists, lactose/milk protein or magnesium stearate or medical conditions associated with inhaled anticholinergics

• hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1

• lung volume reduction surgery within 12 months prior to Visit 1

• abnormal and clinically significant ECG at Visit 1

• significantly abnormal finding from laboratory tests at Visit 1

• unable to withhold albuterol/salbutamol at least 4 hours prior to spirometry at each visit

• use of depot corticosteroids within 12 weeks of Visit 1

• use of oral or parenteral corticosteroids, antibiotics for lower respiratory tract infection, or cytochrome P450 3A4 inhibitors, within 6 weeks of Visit 1

• use of long-acting beta-agonist (LABA)/inhaled corticosteroid (ICS) product if LABA/ICS therapy is discontinued withing 30 days of Visit 1

• use of ICS at a dose of >1000mcg/day of fluticasone propionate or equivalent within 30 days of Visit 1

• initiation or discontinuation of ICS within 30 days of Visit 1

• use of tiotropium or roflumilast within 14 days of Visit 1

• use of theophyllines, oral leukotriene inhibitors, long-acting oral beta-agonists, or inhaled long-acting beta-agonists within 48 hours of Visit 1

• short-acting oral beta-agonists within 12 hours of Visit 1

• use of LABA/ICS combination products only if discontinuing LABA therapy and switching to ICS monotherapy within 48 hours of Visit 1 for the LABA component

• use of sodium cromoglycate or nedocromil sodium within 24 hours of Visit 1

• use of inhaled short-acting beta-agonists, inhaled short-acting anticholinergics, or inhaled short-acting anticholinergic/short-acting beta-agonist combination products within 4 hours of Visit 1

• use of any other investigational medication within 30 days or 5 drug half-lives (whichever is longer)

• long-term oxygen therapy prescribed for >12 hours per day

• regular use of nebulized short-acting bronchodilators

• participation in acute phase of pulmonary rehabilitation program

• known or suspected history of alcohol or drug abse within 2 years prior to Visit 1

• anyone affiliated with the investigator site (e.g., investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member)

• previous exposure to GSK573719, GSK573719/GW642444 combination, GW642444 (vilanterol), or fluticasone furoate/GW642444 combination

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Disease
• Lung Diseases
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• GSK573719/GW642444 125/25
125/25 mcg once-daily
• GSK573719/GW642444 62.5/25
62.5/25 mcg once-daily
• GSK573719
125 mcg once-daily
• tiotropium bromide
18 mcg once-daily

Locations

Country	Name	City	State
Argentina	GSK Investigational Site	Buenos Aires
Argentina	GSK Investigational Site	Buenos Aires
Argentina	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	GSK Investigational Site	Ciudad Autónoma de Buenos Aires
Argentina	GSK Investigational Site	Mendoza
Australia	GSK Investigational Site	Adelaide	South Australia
Australia	GSK Investigational Site	Cairns	Queensland
Australia	GSK Investigational Site	Carina Heights	Queensland
Australia	GSK Investigational Site	Concord	New South Wales
Australia	GSK Investigational Site	Daw Park	South Australia
Australia	GSK Investigational Site	Frankston	Victoria
Australia	GSK Investigational Site	Kippa Ring	Queensland
Australia	GSK Investigational Site	Nedlands	Western Australia
Australia	GSK Investigational Site	Parkville	Victoria
Canada	GSK Investigational Site	Bay Roberts	Newfoundland and Labrador
Canada	GSK Investigational Site	Gatineau	Quebec
Canada	GSK Investigational Site	Mississauga	Ontario
Canada	GSK Investigational Site	Quebec
Canada	GSK Investigational Site	St-Romulad	Quebec
Canada	GSK Investigational Site	Sudbury	Ontario
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Truro	Nova Scotia
Canada	GSK Investigational Site	Winnipeg	Manitoba
Canada	GSK Investigational Site	Winnipeg	Manitoba
Chile	GSK Investigational Site	Puerto Montt	Región De Los Lagos
Chile	GSK Investigational Site	Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Santiago
Chile	GSK Investigational Site	Talca	Región Metro De Santiago
Germany	GSK Investigational Site	Aschaffenburg	Bayern
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Dueren	Nordrhein-Westfalen
Germany	GSK Investigational Site	Essen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Essen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Kassel	Hessen
Germany	GSK Investigational Site	Koblenz	Rheinland-Pfalz
Germany	GSK Investigational Site	Leipzig	Sachsen
Germany	GSK Investigational Site	Mainz	Rheinland-Pfalz
Germany	GSK Investigational Site	Oranienburg	Brandenburg
Germany	GSK Investigational Site	Ruedersdorf	Brandenburg
Germany	GSK Investigational Site	Schwedt	Brandenburg
Germany	GSK Investigational Site	Schwetzingen	Baden-Wuerttemberg
Germany	GSK Investigational Site	Wolfenbuettel	Niedersachsen
Korea, Republic of	GSK Investigational Site	Bucheon-si,
Korea, Republic of	GSK Investigational Site	Cheongju, Chungcheongbuk-do
Korea, Republic of	GSK Investigational Site	Daegu
Korea, Republic of	GSK Investigational Site	Incheon
Korea, Republic of	GSK Investigational Site	Incheon
Korea, Republic of	GSK Investigational Site	Kangwon-do
Korea, Republic of	GSK Investigational Site	Seongnam-si, Gyeonggi-do
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Suwon, Kyonggi-do
Mexico	GSK Investigational Site	Durango
Mexico	GSK Investigational Site	Mexico
Mexico	GSK Investigational Site	Monterrey	Nuevo León
Mexico	GSK Investigational Site	Zapopan	Jalisco
Romania	GSK Investigational Site	Constanta
Romania	GSK Investigational Site	Ploiesti
Romania	GSK Investigational Site	Targoviste
South Africa	GSK Investigational Site	Bloemfontein
South Africa	GSK Investigational Site	Boksburg North
South Africa	GSK Investigational Site	Die Wilgers
South Africa	GSK Investigational Site	Durban
South Africa	GSK Investigational Site	Gatesville
South Africa	GSK Investigational Site	Groenkloof
South Africa	GSK Investigational Site	Pretoria
South Africa	GSK Investigational Site	Thabazimbi
United States	GSK Investigational Site	Beaver	Pennsylvania
United States	GSK Investigational Site	Charlotte	North Carolina
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Clearwater	Florida
United States	GSK Investigational Site	Easley	South Carolina
United States	GSK Investigational Site	Elizabeth City	North Carolina
United States	GSK Investigational Site	Huntington Beach	California
United States	GSK Investigational Site	Jasper	Alabama
United States	GSK Investigational Site	Lafayette	Louisiana
United States	GSK Investigational Site	Lawrenceville	Georgia
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Madisonville	Kentucky
United States	GSK Investigational Site	Medford	Oregon
United States	GSK Investigational Site	Mobile	Alabama
United States	GSK Investigational Site	Morgantown	West Virginia
United States	GSK Investigational Site	New Orleans	Louisiana
United States	GSK Investigational Site	Ormond Beach	Florida
United States	GSK Investigational Site	Spartanburg	South Carolina
United States	GSK Investigational Site	St. Louis	Missouri
United States	GSK Investigational Site	Topeka	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Canada,  Chile,  Germany,  Korea, Republic of,  Mexico,  Romania,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change From Baseline (BL) in the Mean Shortness of Breath With Daily Activities (SOBDA) Score for Week 24	The newly developed SOBDA questionnaire assesses dyspnea or shortness of breath (SOB) with daily activities. The SOBDA questionnaire is made up of 13 items completed by the participant (par.) each evening prior to bedtime, when the par. is instructed to reflect on the current day's activities. The daily score is computed as the mean of the scores on the 13 items (>=7 items must have non-missing responses for this to be calculated). The par. is assigned a weekly mean SOBDA score ranging from 1 to 4 (greater scores indicate more severe breathlessness with daily activities) based on the mean of 7 days of data (>=4 of 7 days must be completed for a weekly mean to be calculated). Change from BL is the mean weekly SOBDA score minus BL. Analysis was performed using MMRM with covariates of treatment, BL (mean score in the week prior to treatment), smoking status, center group, week, week by BL and week by treatment interactions. This MMRM analysis only included Weeks 4, 8, 12, and 24.	Baseline and Week 24	No
Primary	Change From Baseline in Clinic Visit Trough Forced Expiratory Volume in One Second (FEV1) at Day 169	FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 measurements were taken electronically by spirometry on Days 2, 28, 56, 84, 112, 168, and 169. Baseline is defined as the mean of the assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1. Trough FEV1 is defined as the mean of the FEV1 values obtained at 23 and 24 hours after the previous morning's dosing (i.e., trough FEV1 on Day 169 is the mean of the FEV1 values obtained 23 and 24 hours after the morning dosing on Day 168). Change from Baseline at a particular visit was calculated as the trough FEV1 at that visit minus Baseline. Analysis was performed using a repeated measures model with covariates of treatment, Baseline, smoking status, center group, day, and day by Baseline and day by treatment interactions. ITT=Intent-to-Treat.	Baseline and Day 169	No
Secondary	Change From Baseline (BL) in Weighted Mean (WM) 0-6 Hour FEV1 Obtained Post-dose at Day 168	FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The WM FEV1 was derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The WM was calculated at Days 1, 84, and Day 168 using the 0-6-hour post-dose FEV1 measurements collected on that day, which included pre-dose (Day 1: 30 minutes [min] and 5 min prior to dosing; other serial visits: 23 and 24 hours after the previous morning dose) and post-dose at 15 minutes, 30 minutes, 1 hour, 3 hours, and 6 hours. Change from BL at a particular visit was calculated as WM at that visit minus BL. Analysis was performed using a repeated measures model with covariates of treatment, BL (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), smoking status, center group, day, and day by BL and day by treatment interactions.	Baseline and Day 168	No