A 24-week Evaluation of GSK573719/Vilanterol (62.5/25mcg) and Components in COPD

Pulmonary Disease, Chronic Obstructive Clinical Trial

— DB2113373  

Official title:

A 24-Week, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of GSK573719/GW642444 Inhalation Powder and the Individual Components Delivered Once-Daily Via a Novel Dry Powder Inhaler in Subjects With Chronic Obstructive Pulmonary Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01313650
• Other study ID #: 113373
• Secondary ID: 2010-023349-32
• Status: Completed
• Phase: Phase 3
• Start date: March 1, 2011
• Est. completion date: April 5, 2012

Study information

• Verified date: August 2018
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a phase III multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of GSK573719/GW642444 Inhalation Powder, GSK573719 Inhalation Powder, GW642444 Inhalation Powder and Placebo when administered once-daily via a Novel Dry Powder Inhaler over a 24-week treatment period in subjects with COPD. Subjects who meet eligibility criteria at Screening (Visit 1) will complete a 7 to14 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 27 weeks. A subset of subjects at selected sites will also perform 24-hour serial spirometry and Holter monitoring during the study and provide serial blood samples for pharmacokinetic analysis. Sparse pharmacokinetic sampling for population pharmacokinetic analyses will be obtained from non-subset subjects. The primary measure of efficacy is clinic visit trough (pre-bronchodilator and pre-dose) FEV1 on Treatment Day 169. Safety will be assessed by adverse events, 12-lead ECGs, vital signs, clinical laboratory tests, and 24 hour Holter monitoring (subset only).

Description:

This is a 24-week, phase III multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

Eligible subjects will be randomized to GSK573719/GW642444 125/25mcg, GSK573719 125mcg, GW642444 25mcg, and placebo treatment groups in a 3:3:3:2 ratio such that of the planned 1463 total number of randomized subjects approximately 399 subjects will be randomized to each active treatment group and 266 subjects will be randomized to placebo. All treatments will be administered once-daily in the morning by inhalation using a Novel Dry Powder Inhaler (Novel DPI).

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 14 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 27 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/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, 4, 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 evening throughout the run-in and treatment periods. Subjects will use the eDiary to record 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. Disease specific health status will be evaluated using the subject-completed St. George's Respiratory Questionnaire (SGRQ). The SGRQ will be completed at Visits 2, 4, 6, and 8. Administration of the SGRQ and BDI/TDI should be done prior to spirometry testing.

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. Blood samples for population pharmacokinetic analyses will be obtained.

At selected study sites, a subset of approximately 198 subjects will perform 24-hour serial spirometry during the study for evaluation of lung function over the dosing period. In conjunction with the serial spirometry, this subset of subjects will also perform 24 hour Holter monitoring and provide blood samples for PK analysis.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1538
• Est. completion date: April 5, 2012
• Est. primary completion date: April 1, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

• Diagnosis of COPD

• 10 pack-year or greater history of cigarette smoking

• Post-bronchodilator FEV1/FVC of <0.7

• Predicted FEV1 of 70% of normal or less

• Modified Medical Research Council (mMRC) dyspnea score of 2 or greater

Exclusion Criteria:

• Women who are pregnant, lactating, or planning to become pregnant

• Respiratory disorders other than COPD, including a current diagnosis of asthma

• Clinically significant non-respiratory diseases or abnormalities that are not adequate controlled

• Significant allergy or hypersensitivity to anticholinergics, beta-agonist, or the excipients of magnesium stereate or lactose used in the inhaler delivery device

• Hospitalization for COPD or pneumonia within 12 weeks prior to screening

• Lung volume reduction surgery within 12 weeks prior to screening

• Abnormal and clinically significant ECG findings at screening

• Clinically significant laboratory findings at screening

• Use of systemic corticosteroids, antibiotics for respiratory tract infections, strong cytochrome P450 3A4 inhibitors, high dose inhaled steroids (>1000mcg fluticasone propionate or equivalent), PDE4 inhibitors, tiotropium, oral beta2-agoinists, short- and long-acting inhaled beta2-agonists, ipratropium, inhaled sodium cromoglycate or nedocromil sodium, or investigational medicines for defined time periods prior to the screening visit

• Use of long-term oxygen therapy (12 hours or greater per day)

• Regular use of nebulized treatment with short-acting bronchodilators

• Participation in the acute phase of a pulmonary rehabilitation program

• A know or suspected history of alcohol or drug abuse

• Affiliation with the investigational site

• Previous use of GSK573719 or GW642444 alone or in combination, including the combination of fluticasone furoate and GW64244

Related Conditions & MeSH terms

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

Intervention

Drug:
• 62.5/25mcg
GSK573719/GW64244
• 62.5mcg
GSK573719
• 25mcg
GW642444
• Placebo
Placebo

Locations

Country	Name	City	State
Bulgaria	GSK Investigational Site	Dimitrovgrad
Bulgaria	GSK Investigational Site	Pleven
Bulgaria	GSK Investigational Site	Plovdiv
Bulgaria	GSK Investigational Site	Ruse
Bulgaria	GSK Investigational Site	Sofia
Bulgaria	GSK Investigational Site	Sofia
Bulgaria	GSK Investigational Site	Sofia
Bulgaria	GSK Investigational Site	Sofia
Bulgaria	GSK Investigational Site	Troyan
Bulgaria	GSK Investigational Site	Varna
Canada	GSK Investigational Site	Burlington	Ontario
Canada	GSK Investigational Site	Calgary	Alberta
Canada	GSK Investigational Site	Grimsby	Ontario
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Pointe-Claire	Quebec
Canada	GSK Investigational Site	Quebec
Canada	GSK Investigational Site	Quebec
Canada	GSK Investigational Site	Sarnia	Ontario
Canada	GSK Investigational Site	St-Charles-Borromée	Quebec
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Toronto	Ontario
Canada	GSK Investigational Site	Trois Rivières	Quebec
Canada	GSK Investigational Site	Winnipeg	Manitoba
Chile	GSK Investigational Site	Puente Alto - Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Rancagua	Reg Del Libert Bern Ohiggins
Chile	GSK Investigational Site	Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Santiago	Región Metro De Santiago
Chile	GSK Investigational Site	Talcahuano
Chile	GSK Investigational Site	Valparaiso	Valparaíso
Chile	GSK Investigational Site	Viña del Mar
Czechia	GSK Investigational Site	Cesky Krumlov
Czechia	GSK Investigational Site	Kralupy nad Vltavou
Czechia	GSK Investigational Site	Kyjov
Czechia	GSK Investigational Site	Lovosice
Czechia	GSK Investigational Site	Novy Jicin
Czechia	GSK Investigational Site	Olomouc
Czechia	GSK Investigational Site	Plzen
Czechia	GSK Investigational Site	Praha 5
Czechia	GSK Investigational Site	Praha 5 - Radotin
Czechia	GSK Investigational Site	Rokycany
Czechia	GSK Investigational Site	Teplice
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Haidari / Athens
Greece	GSK Investigational Site	Heraklion, Crete
Greece	GSK Investigational Site	Larissa
Greece	GSK Investigational Site	Serres
Greece	GSK Investigational Site	Thessaloniki
Greece	GSK Investigational Site	Thessaloniki
Japan	GSK Investigational Site	Fukushima
Japan	GSK Investigational Site	Hyogo
Japan	GSK Investigational Site	Ibaraki
Japan	GSK Investigational Site	Ibaraki
Japan	GSK Investigational Site	Kanagawa
Japan	GSK Investigational Site	Kumamoto
Japan	GSK Investigational Site	Kyoto
Japan	GSK Investigational Site	Osaka
Japan	GSK Investigational Site	Osaka
Japan	GSK Investigational Site	Saitama
Japan	GSK Investigational Site	Shimane
Japan	GSK Investigational Site	Shimane
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Mexico	GSK Investigational Site	Guadalajara	Jalisco
Mexico	GSK Investigational Site	Monterrey	Nuevo León
Mexico	GSK Investigational Site	Puebla, Pue	Puebla
Mexico	GSK Investigational Site	Zapopan	Jalisco
Poland	GSK Investigational Site	Bydgoszcz
Poland	GSK Investigational Site	Gidle
Poland	GSK Investigational Site	Grudziadz
Poland	GSK Investigational Site	Ilawa
Poland	GSK Investigational Site	Krakow
Poland	GSK Investigational Site	Lomza
Poland	GSK Investigational Site	Olsztyn
Poland	GSK Investigational Site	Poznan
Poland	GSK Investigational Site	Szczecin
Poland	GSK Investigational Site	Warszawa
Russian Federation	GSK Investigational Site	Arkhangelsk
Russian Federation	GSK Investigational Site	Barnaul
Russian Federation	GSK Investigational Site	Blagoveshchensk
Russian Federation	GSK Investigational Site	Krasnoyarsk
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Nizhniy Novgorod
Russian Federation	GSK Investigational Site	Novosibirsk
Russian Federation	GSK Investigational Site	Perm
Russian Federation	GSK Investigational Site	Pyatigorsk
Russian Federation	GSK Investigational Site	Saint-Petersburg
Russian Federation	GSK Investigational Site	Saint-Petersburg
Russian Federation	GSK Investigational Site	Saratov
Russian Federation	GSK Investigational Site	Tomsk
Russian Federation	GSK Investigational Site	Ufa
Russian Federation	GSK Investigational Site	Yaroslavl
South Africa	GSK Investigational Site	Benoni	Gauteng
South Africa	GSK Investigational Site	Bloemfontein
South Africa	GSK Investigational Site	Durban
South Africa	GSK Investigational Site	Gatesville
South Africa	GSK Investigational Site	Meyerspark	Gauteng
South Africa	GSK Investigational Site	Mowbray
South Africa	GSK Investigational Site	Newtown
South Africa	GSK Investigational Site	Somerset West
South Africa	GSK Investigational Site	Tygerberg
Spain	GSK Investigational Site	Alicante
Spain	GSK Investigational Site	Badalona
Spain	GSK Investigational Site	Badalona / Barcelona
Spain	GSK Investigational Site	Barakaldo (Vizcaya)
Spain	GSK Investigational Site	Cáceres
Spain	GSK Investigational Site	Centelles
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Palma de Mallorca
Spain	GSK Investigational Site	Pamplona
Spain	GSK Investigational Site	Pozuelo De Alarcón/Madrid
Spain	GSK Investigational Site	Salt (gerona)
Spain	GSK Investigational Site	Sant Boi De Llobregat - Barcelona
Spain	GSK Investigational Site	Santander
Spain	GSK Investigational Site	Santiago de Compostela
Spain	GSK Investigational Site	Valencia
Thailand	GSK Investigational Site	Bangkok
Thailand	GSK Investigational Site	Bangkok
Thailand	GSK Investigational Site	Chiangmai
Thailand	GSK Investigational Site	Khon Kaen
Thailand	GSK Investigational Site	Nonthaburi
Thailand	GSK Investigational Site	Songkhla
United States	GSK Investigational Site	Abingdon	Virginia
United States	GSK Investigational Site	Albuquerque	New Mexico
United States	GSK Investigational Site	Atlanta	Georgia
United States	GSK Investigational Site	Beaver	Pennsylvania
United States	GSK Investigational Site	Cadillac	Michigan
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Coeur d'Alene	Idaho
United States	GSK Investigational Site	Columbus	Ohio
United States	GSK Investigational Site	Dayton	Ohio
United States	GSK Investigational Site	Erie	Pennsylvania
United States	GSK Investigational Site	Gaffney	South Carolina
United States	GSK Investigational Site	Greenville	South Carolina
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Johnson City	Tennessee
United States	GSK Investigational Site	Kingwood	Texas
United States	GSK Investigational Site	Lafayette	Indiana
United States	GSK Investigational Site	Larchmont	New York
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	New Orleans	Louisiana
United States	GSK Investigational Site	Newport News	Virginia
United States	GSK Investigational Site	Olathe	Kansas
United States	GSK Investigational Site	Omaha	Nebraska
United States	GSK Investigational Site	Ormond Beach	Florida
United States	GSK Investigational Site	Pelzer	South Carolina
United States	GSK Investigational Site	Phoenixville	Pennsylvania
United States	GSK Investigational Site	Rapid City	South Dakota
United States	GSK Investigational Site	Richmond	Virginia
United States	GSK Investigational Site	Saint Louis	Missouri
United States	GSK Investigational Site	Spartanburg	South Carolina
United States	GSK Investigational Site	Sunset	Louisiana
United States	GSK Investigational Site	Tampa	Florida
United States	GSK Investigational Site	Topeka	Kansas
United States	GSK Investigational Site	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Bulgaria,  Canada,  Chile,  Czechia,  Greece,  Japan,  Mexico,  Poland,  Russian Federation,  South Africa,  Spain,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change From Baseline 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
Primary	Change From Baseline (BL) in Trough Forced Expiratory Volume in One Second (FEV1) on Day 169 (Week 24)	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 (ie., 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; par.=participants.	Baseline and Day 169
Secondary	Mean Transition Dyspnea Index (TDI) Focal Score at Day 168 (Week 24)	Considered an 'other' endpoint by the FDA. The TDI is an interviewer-administered instrument which measures the changes in the participant's dyspnea from Baseline. This questionnaire was collected on Days 28, 84 and 168. The scores in the TDI evaluate ratings for 3 different categories (functional impairment, magnitude of task in exertional capacity, and magnitude of effort). TDI scores ranged from -3 (major deterioration) to +3 (major improvement); total score = -9 to 9. Analysis was performed using a repeated measures model with covariates of treatment, Baseline dyspnea index (BDI) focal score,smoking status, center group, day, day by BDI focal score and day by treatment interactions.	Day 168 (Week 24)
Secondary	Change From Baseline 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, 28, 84, and 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 min, 30 min, 1 hour, 3 hours, and 6 hours. Change from Baseline at a particular visit was calculated as the WM at that visit minus Baseline. Analysis was performed using a repeated measures model with covariates of treatment, Baseline (mean of the two assessments made 30 min and 5 min pre-dose on Day 1), smoking status, center group, day, and day by Baseline and day by treatment interactions.	Baseline and Day 168

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