A 24-week Evaluation of GSK573719/Vilanterol (125/25mcg) and Components in COPD

Pulmonary Disease, Chronic Obstructive Clinical Trial

— DB2113361  

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: NCT01313637
• Other study ID #: 113361
• Secondary ID: 2010-023348-33
• Status: Completed
• Phase: Phase 3
• First received: March 10, 2011
• Last updated: January 25, 2018
• Start date: March 1, 2011
• Est. completion date: April 19, 2012

Study information

• Verified date: January 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: 1493
• Est. completion date: April 19, 2012
• Est. primary completion date: March 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 adequately controlled

• Significant allergy or hypersensitivity to anticholinergics, beta2-agonists, 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 GW642444

Related Conditions & MeSH terms

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

Intervention

Drug:
• GSK573719/GW642444 125/25mcg
125/25mcg
• GSK573719 125mcg
125mcg
• GW642444 25mcg
25mcg
• Placebo only
Placebo

Locations

Country	Name	City	State
Belgium	GSK Investigational Site	Aalst
Belgium	GSK Investigational Site	Edegem
Belgium	GSK Investigational Site	Genk
Belgium	GSK Investigational Site	Kortrijk
Belgium	GSK Investigational Site	Liège
Denmark	GSK Investigational Site	Aalborg
Denmark	GSK Investigational Site	Hvidovre
Denmark	GSK Investigational Site	København
Denmark	GSK Investigational Site	Naestved
Denmark	GSK Investigational Site	Odense C
Denmark	GSK Investigational Site	Roedovre
Denmark	GSK Investigational Site	Roskilde
Estonia	GSK Investigational Site	Haapsalu
Estonia	GSK Investigational Site	Parnu
Estonia	GSK Investigational Site	Rakvere
Estonia	GSK Investigational Site	Tallinn
Estonia	GSK Investigational Site	Tallinn
Estonia	GSK Investigational Site	Tartu
France	GSK Investigational Site	Lyon cedex 04
France	GSK Investigational Site	Montauban cedex
France	GSK Investigational Site	Nice
France	GSK Investigational Site	Perpignan
France	GSK Investigational Site	Reims Cedex
France	GSK Investigational Site	Tarbes Cedex 09
France	GSK Investigational Site	Toulon
France	GSK Investigational Site	Toulouse cedex 9
France	GSK Investigational Site	Tours cedex 9
France	GSK Investigational Site	Vieux Condé
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Dillingen	Bayern
Germany	GSK Investigational Site	Dresden	Sachsen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Geesthacht	Schleswig-Holstein
Germany	GSK Investigational Site	Gelnhausen	Hessen
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Koeln	Nordrhein-Westfalen
Germany	GSK Investigational Site	Kuenzing	Bayern
Germany	GSK Investigational Site	Leipzg	Sachsen
Germany	GSK Investigational Site	Leipzig	Sachsen
Germany	GSK Investigational Site	Magdeburg	Sachsen-Anhalt
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Neu-Isenburg	Hessen
Germany	GSK Investigational Site	Rodgau	Hessen
Germany	GSK Investigational Site	Schmoelln	Thueringen
Germany	GSK Investigational Site	Schwabach	Bayern
Hungary	GSK Investigational Site	Balassagyarmat
Hungary	GSK Investigational Site	Budapest
Hungary	GSK Investigational Site	Debrecen
Hungary	GSK Investigational Site	Deszk
Hungary	GSK Investigational Site	Farkasgyepu
Hungary	GSK Investigational Site	Gödöllo
Hungary	GSK Investigational Site	Gyöngyös
Hungary	GSK Investigational Site	Nyíregyháza
Hungary	GSK Investigational Site	Sátoraljaújhely
Hungary	GSK Investigational Site	Szikszó
Hungary	GSK Investigational Site	Szombathely
Hungary	GSK Investigational Site	Törökbálint
Japan	GSK Investigational Site	Aichi
Japan	GSK Investigational Site	Aichi
Japan	GSK Investigational Site	Aichi
Japan	GSK Investigational Site	Chiba
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Hokkaido
Japan	GSK Investigational Site	Ibaraki
Japan	GSK Investigational Site	Kanagawa
Japan	GSK Investigational Site	Miyagi
Japan	GSK Investigational Site	Okayama
Japan	GSK Investigational Site	Osaka
Japan	GSK Investigational Site	Shizuoka
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Netherlands	GSK Investigational Site	Alkmaar
Netherlands	GSK Investigational Site	Almelo
Netherlands	GSK Investigational Site	Almere
Netherlands	GSK Investigational Site	Beek
Netherlands	GSK Investigational Site	EDE
Netherlands	GSK Investigational Site	Eindhoven
Netherlands	GSK Investigational Site	Enschede
Netherlands	GSK Investigational Site	Groningen
Netherlands	GSK Investigational Site	Helmond
Netherlands	GSK Investigational Site	Hoorn
Netherlands	GSK Investigational Site	Tubbergen
Netherlands	GSK Investigational Site	Veldhoven
Netherlands	GSK Investigational Site	Zutphen
Norway	GSK Investigational Site	Bekkestua
Norway	GSK Investigational Site	Bergen
Norway	GSK Investigational Site	Bodø
Norway	GSK Investigational Site	Elverum
Norway	GSK Investigational Site	Kløfta
Norway	GSK Investigational Site	Skedsmokorset
Norway	GSK Investigational Site	Stavanger
Norway	GSK Investigational Site	Trondheim
Norway	GSK Investigational Site	Trondheim
Philippines	GSK Investigational Site	Cebu City
Philippines	GSK Investigational Site	Dasmariñas, Cavite
Philippines	GSK Investigational Site	Marikina City
Philippines	GSK Investigational Site	Marilao, Bulacan
Philippines	GSK Investigational Site	Quezon City
Slovakia	GSK Investigational Site	Bardejov
Slovakia	GSK Investigational Site	Humenne
Slovakia	GSK Investigational Site	Poprad
Slovakia	GSK Investigational Site	Revuca
Slovakia	GSK Investigational Site	Spisska Nova Ves
Slovakia	GSK Investigational Site	Vrable
Sweden	GSK Investigational Site	Göteborg
Sweden	GSK Investigational Site	Göteborg
Sweden	GSK Investigational Site	Höllviken
Sweden	GSK Investigational Site	Linköping
Sweden	GSK Investigational Site	Luleå
Sweden	GSK Investigational Site	Lund
Sweden	GSK Investigational Site	Malmö
Sweden	GSK Investigational Site	Stockholm
Sweden	GSK Investigational Site	Stockholm
Sweden	GSK Investigational Site	Vällingby
Ukraine	GSK Investigational Site	Donetsk
Ukraine	GSK Investigational Site	Ivano-Frankivsk
Ukraine	GSK Investigational Site	Kharkiv
Ukraine	GSK Investigational Site	Kharkiv
Ukraine	GSK Investigational Site	Kiev
Ukraine	GSK Investigational Site	Kyiv
Ukraine	GSK Investigational Site	Simferopol
Ukraine	GSK Investigational Site	Zaporizhia
United States	GSK Investigational Site	Charlotte	North Carolina
United States	GSK Investigational Site	Cherry Hill	New Jersey
United States	GSK Investigational Site	Clearwater	Florida
United States	GSK Investigational Site	DeLand	Florida
United States	GSK Investigational Site	Easley	South Carolina
United States	GSK Investigational Site	Greenville	South Carolina
United States	GSK Investigational Site	Jasper	Alabama
United States	GSK Investigational Site	Lincoln	Nebraska
United States	GSK Investigational Site	Livonia	Michigan
United States	GSK Investigational Site	Long Beach	California
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Palo Alto	California
United States	GSK Investigational Site	Panama City	Florida
United States	GSK Investigational Site	Phoenix	Arizona
United States	GSK Investigational Site	Plymouth	Minnesota
United States	GSK Investigational Site	Richmond	Virginia
United States	GSK Investigational Site	Riverside	California
United States	GSK Investigational Site	San Diego	California
United States	GSK Investigational Site	San Diego	California
United States	GSK Investigational Site	Spartanburg	South Carolina
United States	GSK Investigational Site	Topeka	Kansas
United States	GSK Investigational Site	Torrance	California
United States	GSK Investigational Site	Union	South Carolina

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Belgium,  Denmark,  Estonia,  France,  Germany,  Hungary,  Japan,  Netherlands,  Norway,  Philippines,  Slovakia,  Sweden,  Ukraine, 

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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