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: August 15, 2013
Last verified: August 2013
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
No text entered.

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.
No text entered.

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  
Number of Participants  
[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 ]
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Measure Type Primary
Measure Title Annual Rate of Moderate and Severe COPD Exacerbations Expressed as Least Square Mean
Measure Description The annual rate of moderate and severe chronic obstructive pulmonary disease (COPD) exacerbations during the treatment (trt) period (per participant [par.] per year) was assessed. 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. The COPD exacerbation was categorized as mild, moderate and severe by the investigator. Mild: worsening symptoms of COPD that were self-managed by the par. without the use of oral corticosteroids or antibiotics; Moderate: worsening symptoms of COPD that required treatment with oral corticosteroids and/or antibiotics; Severe: worsening symptoms of COPD that required treatment with in-patient hospitalization.
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.
Intent-to-Treat (ITT) Population: all par. randomized who received at least 1 dose of study drug and with available data for analysis. Analysis used a negative binomial regression model with covariates of trt, smoking status at Screening, Baseline pre-dose Day 1 % predicted FEV1 and region and with logarithm of time on trt as an offset variable.

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  
Number of Participants Analyzed  
[units: participants]
  409     412     403     409  
Annual Rate of Moderate and Severe COPD Exacerbations Expressed as Least Square Mean  
[units: Exacerbations per participant per year]
Least Squares Mean ( 95% Confidence Interval )
  1.14  
  ( 0.99 to 1.32 )  
  0.92  
  ( 0.79 to 1.07 )  
  0.90  
  ( 0.77 to 1.05 )  
  0.79  
  ( 0.67 to 0.92 )  


Statistical Analysis 1 for Annual Rate of Moderate and Severe COPD Exacerbations Expressed as Least Square Mean
Groups [1] VI 25 µg QD vs. FF/VI 50/25 µg QD
Method [2] Generalized Linear Model
P Value [3] 0.040
Risk Ratio (RR) [4] 0.81
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:
  Assuming Negative Binomial distribution with logarithm of time on treatment as an offset variable.
[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:
  No text entered.

Statistical Analysis 2 for Annual Rate of Moderate and Severe COPD Exacerbations Expressed as Least Square Mean
Groups [1] VI 25 µg QD vs. FF/VI 100/25 µg QD
Method [2] Generalized Linear Model
P Value [3] 0.024
Risk Ratio (RR) [4] 0.79
95% Confidence Interval ( 0.64 to 0.97 )
[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:
  Assuming Negative Binomial distribution with logarithm of time on treatment as an offset variable.
[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:
  No text entered.

Statistical Analysis 3 for Annual Rate of Moderate and Severe COPD Exacerbations Expressed as Least Square Mean
Groups [1] VI 25 µg QD vs. FF/VI 200/25 µg QD
Method [2] Generalized Linear Model
P Value [3] <0.001
Risk Ratio (RR) [4] 0.69
95% Confidence Interval ( 0.56 to 0.85 )
[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:
  Assuming Negative Binomial distribution with logarithm of time on treatment as an offset variable.
[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:
  No text entered.



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 ]

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


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Limitations and Caveats
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
No text entered.  


Results Point of Contact:  
Name/Title: GSK Response Center
Organization: GlaxoSmithKline
phone: 866-435-7343


No publications provided by GlaxoSmithKline

Publications automatically indexed to this study:

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01017952     History of Changes
Other Study ID Numbers: 102970
Study First Received: November 19, 2009
Results First Received: May 30, 2013
Last Updated: August 15, 2013
Health Authority: United States: Food and Drug Administration