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A Study to Evaluate Annual Rate of Exacerbations and Safety of 3 Dosage Strengths of Fluticasone Furoate (FF)/GW642444 Inhalation Powder in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01017952
First received: November 19, 2009
Last updated: June 29, 2016
Last verified: June 2016
Results First Received: May 30, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Condition: Pulmonary Disease, Chronic Obstructive
Interventions: Drug: FF/GW642444 Inhalation Powder
Drug: GW642444 Inhalation Powder

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
At Visit (V) 1, eligible participants (par.) entered a 4-week, open-label Run-in Period (RIP) to establish a stable Baseline. At V 2, eligible par. were randomized to a 52-week, double-blind Treatment Period. 2635 par. were screened, 2092 par. entered the RIP, and 1635 par. were randomized, out of which 1633 par. received >=1 study treatment dose.

Reporting Groups
  Description
FP/SAL 250/50 µg BID Participants (Par.) were instructed to take open label Fluticasone Propionate and Salmeterol (FP/SAL) 250/50 microgram (µg) twice daily (BID) from the ACCUHALER/DISKUS, one inhalation each morning and evening with approximately 12 hours between doses. In addition, all par. were provided supplemental albuterol/salbutamol (metered dose inhaler [MDI] and/or nebules) to be used as needed throughout the study.
VI 25 µg QD Participants received a Vilanterol (VI) 25 µg dry inhalation powder once daily (QD) in the morning from the Dry Powder Inhaler (DPI) for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 50/25 µg QD Participants received a Fluticasone Furoate/Vilanterol (FF/VI) 50/25 µg inhalation powder QD in the morning from the NDPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 100/25 µg QD Participants received a FF/VI 100/25 µg inhalation powder QD in the morning from the NDPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 200/25 µg QD Participants received a FF/VI 200/25 µg inhalation powder QD in the morning from the NDPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.

Participant Flow for 2 periods

Period 1:   4-week, Open-label Run-In Period
    FP/SAL 250/50 µg BID   VI 25 µg QD   FF/VI 50/25 µg QD   FF/VI 100/25 µg QD   FF/VI 200/25 µg QD
STARTED   2092   0   0   0   0 
COMPLETED   1633   0   0   0   0 
NOT COMPLETED   459   0   0   0   0 
Did Not Meet Continuation Criteria                356                0                0                0                0 
Adverse Event                23                0                0                0                0 
Study Closed/Tterminated                1                0                0                0                0 
Lost to Follow-up                6                0                0                0                0 
Physician Decision                10                0                0                0                0 
Withdrawal by Subject                63                0                0                0                0 

Period 2:   52-week, Double-blind Treatment Period
    FP/SAL 250/50 µg BID   VI 25 µg QD   FF/VI 50/25 µg QD   FF/VI 100/25 µg QD   FF/VI 200/25 µg QD
STARTED   0   409   412   403   409 
Completed the Treatment Period   0   285 [1]   305 [1]   293 [1]   307 [1] 
COMPLETED   0   284 [2]   303 [2]   291 [2]   306 [2] 
NOT COMPLETED   0   125   109   112   103 
Adverse Event                0                25                32                35                30 
Withdrawal by Subject                0                30                22                25                25 
Lack of Efficacy                0                35                14                16                14 
Protocol Violation                0                7                11                9                8 
Met Protocol-Defined Stopping Criteria                0                11                13                12                9 
Study Closed/Terminated                0                1                1                0                0 
Lost to Follow-up                0                6                8                6                10 
Physician Decision                0                10                8                9                7 
[1] Par. completed the treatment period if they attended the last treatment visit (Visit 11).
[2] Par. completed the study if they completed the treatment period and safety follow-up phone contact.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups
  Description
VI 25 µg QD Participants received a Vilanterol (VI) 25 µg dry inhalation powder once daily (QD) in the morning from the Dry Powder Inhaler (DPI) for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 50/25 µg QD Participants received a Fluticasone Furoate/Vilanterol (FF/VI) 50/25 µg inhalation powder QD in the morning from the NDPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 100/25 µg QD Participants received a FF/VI 100/25 µg inhalation powder QD in the morning from the NDPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 200/25 µg QD Participants received a FF/VI 200/25 µg inhalation powder QD in the morning from the NDPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
Total Total of all reporting groups

Baseline Measures
   VI 25 µg QD   FF/VI 50/25 µg QD   FF/VI 100/25 µg QD   FF/VI 200/25 µg QD   Total 
Overall Participants Analyzed 
[Units: Participants]
 409   412   403   409   1633 
Age 
[Units: Years]
Mean (Standard Deviation)
 63.6  (9.29)   63.7  (9.56)   64.0  (9.28)   63.5  (8.84)   63.7  (9.24) 
Gender 
[Units: Participants]
         
Female   174   181   181   191   727 
Male   235   231   222   218   906 
Race/Ethnicity, Customized 
[Units: Participants]
         
White   360   359   353   359   1431 
African American/ African Heritage   9   14   7   9   39 
Asian   4   3   5   3   15 
African American/African Heritage & White   0   1   1   0   2 
American Indian or Alaska Native & White   20   19   21   20   80 
Asian & White   0   0   0   1   1 
Native Hawaiian or other Pacific Islander   0   0   0   1   1 
American Indian or Alaska Native   16   16   16   16   64 


  Outcome Measures
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1.  Primary:   Annual Rate of Moderate and Severe COPD Exacerbations Expressed as Least Square Mean   [ Time Frame: From the start of the double blind study medication until Visit 11 (Week 52)/Early Withdrawal ]

2.  Secondary:   Time to First Occurrence of Moderate or Severe COPD Exacerbation   [ Time Frame: From the start of the double blind study medication until Visit 11 (Week 52)/Early Withdrawal ]
  Hide Outcome Measure 2

Measure Type Secondary
Measure Title Time to First Occurrence of Moderate or Severe COPD Exacerbation
Measure Description Time to first occurrence analyzed by using a Cox proportional hazards model with covariates of treatment, smoking status at screening (stratum), baseline disease severity (pre-dose Day 1 % predicted FEV1) and centre grouping. An exacerbation of COPD is defined as the worsening of two or more major symptoms (dyspnea, sputum volume, sputum purulence [color]) for at least two consecutive days; or the worsening of any one major symptom together with any one of the minor symptoms (sore throat, cold, fever without other cause, increased cough, increased wheeze) for at least two consecutive days. A moderate exacerbation is defined as worsening symptoms of COPD that required treatment with oral corticosteroids and/or antibiotics. A severe exacerbation is defined as worsening symptoms of COPD that required treatment with in-patient hospitalization. The number of participants with a moderate or severe COPD exacerbation while on treatment are presented.
Time Frame From the start of the double blind study medication until Visit 11 (Week 52)/Early Withdrawal  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT Population

Reporting Groups
  Description
VI 25 µg QD Participants received a Vilanterol (VI) 25 µg dry inhalation powder once daily (QD) in the morning from the Dry Powder Inhaler (DPI) for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 50/25 µg QD Participants received a Fluticasone Furoate/Vilanterol (FF/VI) 50/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 100/25 µg QD Participants received a FF/VI 100/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
FF/VI 200/25 µg QD Participants received a FF/VI 200/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.

Measured Values
   VI 25 µg QD   FF/VI 50/25 µg QD   FF/VI 100/25 µg QD   FF/VI 200/25 µg QD 
Participants Analyzed 
[Units: Participants]
 409   412   403   409 
Time to First Occurrence of Moderate or Severe COPD Exacerbation 
[Units: Participants]
 197   198   177   160 


Statistical Analysis 1 for Time to First Occurrence of Moderate or Severe COPD Exacerbation
Groups [1] VI 25 µg QD vs. FF/VI 50/25 µg QD
Method [2] Regression, Cox
P Value [3] 0.177
Hazard Ratio (HR) [4] 0.87
95% Confidence Interval 0.71 to 1.06
[1] Additional details about the analysis, such as null hypothesis and power calculation:
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[2] Other relevant method information, such as adjustments or degrees of freedom:
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[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
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[4] Other relevant estimation information:
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Statistical Analysis 2 for Time to First Occurrence of Moderate or Severe COPD Exacerbation
Groups [1] VI 25 µg QD vs. FF/VI 100/25 µg QD
Method [2] Regression, Cox
P Value [3] 0.036
Hazard Ratio (HR) [4] 0.88
95% Confidence Interval 0.66 to 0.99
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
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Statistical Analysis 3 for Time to First Occurrence of Moderate or Severe COPD Exacerbation
Groups [1] VI 25 µg QD vs. FF/VI 200/25 µg QD
Method [2] Regression, Cox
P Value [3] <0.001
Hazard Ratio (HR) [4] 0.66
95% Confidence Interval 0.54 to 0.82
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
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[4] Other relevant estimation information:
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3.  Secondary:   Annual Rate of Exacerbations Requiring Systemic/Oral Corticosteroids Expressed as Least Square Mean   [ Time Frame: From the start of the double blind study medication until Visit 11 (Week 52)/Early Withdrawal ]

4.  Secondary:   Change From Baseline in Trough FEV1 at Week 52 (Visit 11)   [ Time Frame: Baseline to Visit 11 (Week 52)/Early Withdrawal ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information