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Study Evaluating the Efficacy and Safety of Fluticasone Furoate/Vilanterol Inhalation Powder (FF/VI) Compared With Vilanterol Inhalation Powder (VI) in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

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ClinicalTrials.gov Identifier: NCT02105974
Recruitment Status : Completed
First Posted : April 7, 2014
Results First Posted : April 13, 2016
Last Update Posted : January 24, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Pulmonary Disease, Chronic Obstructive
Interventions Drug: Fluticasone Furoate/Vilanterol
Drug: Vilanterol
Enrollment 1621
Recruitment Details Par meeting continuation criteria during the run-in period were randomized (1:1) to receive fluticasone furoate (FF)/vilanterol (VI) or VI. Of the 2423 par screened, 1622 were randomized. 1620 received at least one dose of double-blind study medication and comprised the Intent-to-Treat population.
Pre-assignment Details Participants(par) with a history of chronic obstructive pulmonary disease(COPD) meeting eligibility criteria at screening were enrolled in a 2-week, single-blind(placebo) run-in period to obtain baseline use of albuterol(salbutamol), COPD symptom scores and disease stability.
Arm/Group Title Placebo Run-In FF/VI 100/25 µg QD VI 25 µg QD
Hide Arm/Group Description Participants received placebo once daily (QD) in the morning for 2 weeks. In addition, participants were provided an inhaled short-acting beta2-receptor agonist (SABA), albuterol (salbutamol) (metered dose inhaler [MDI] or nebules), to be used as a rescue medication for relief of chronic obstructive pulmonary disease (COPD) symptoms during the Run-in and Treatment Periods. Participants received fluticasone furoate/vilaterol (FF/VI) 100/25 microgram(µg) inhalation via a dry powder inhaler (DPI) once daily (QD) in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler [MDI] or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods. Participants received VI 25 µg inhalation QD via a DPI in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler [MDI] or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods.
Period Title: 2 Week Run-in Period
Started 2423 0 0
Completed 1622 0 0
Not Completed 801 0 0
Reason Not Completed
Withdrew during pre-screen period             158             0             0
Did not meet inclusion/exclusion criteri             603             0             0
Adverse Event             6             0             0
Study closed/terminated             1             0             0
Lost to Follow-up             2             0             0
Withdrew consent             23             0             0
Investigator discretion             8             0             0
Period Title: 12 Week (Wk) Treatment Period (TP)
Started 0 806 814
Completed the Treatment(Trt) Period 0 764 [1] 754 [1]
Completed 0 764 [2] 756 [2]
Not Completed 0 42 58
Reason Not Completed
Adverse Event             0             14             18
Lack of Efficacy             0             6             9
Protocol deviation             0             2             6
Participant reached stopping criteria             0             1             2
Lost to Follow-up             0             0             1
Physician Decision             0             7             4
Withdrawal by Subject             0             12             18
[1]
Par completed TP if attended Visit (V7, Wk12), did not withdraw at V7 and did not stop trt before V7
[2]
Par. completed study if attended visit 7, had follow-up contact and no early withdrawal
Arm/Group Title FF/VI 100/25 µg QD VI 25 µg QD Total
Hide Arm/Group Description Participants received fluticasone furoate/vilaterol (FF/VI) 100/25 microgram(µg) inhalation via a dry powder inhaler (DPI) once daily (QD) in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler (MDI) or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods. Participants received VI 25 µg inhalation QD via a DPI in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler (MDI) or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods. Total of all reporting groups
Overall Number of Baseline Participants 806 814 1620
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 806 participants 814 participants 1620 participants
65.3  (8.58) 65.4  (9.02) 65.3  (8.80)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 806 participants 814 participants 1620 participants
Female
201
  24.9%
189
  23.2%
390
  24.1%
Male
605
  75.1%
625
  76.8%
1230
  75.9%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 806 participants 814 participants 1620 participants
African American/African Heritage 6 10 16
Asian - East Asian Heritage 77 77 154
Asian - Japanese Heritage 185 185 370
White - White/Caucasian/European Heritage 538 541 1079
Mixed Race 0 1 1
1.Primary Outcome
Title Mean Change From Baseline (BL) in Clinic Visit Trough (Pre-bronchodilator and Pre-dose) FEV1, on Treatment Day 84
Hide Description Pulmonary function was measured by forced expiratory volume in one second (FEV1), defined as the maximal amount of air that can be forcefully exhaled from the lungs in one second. Trough FEV1 measurements were taken electronically by spirometry on Days 2, 14, 28, 56 and 84. BL was defined as the mean of the assessments made 30 minutes pre-dose and immediately pre-dose on Treatment Day 1.Trough FEV1 was defined as the mean of the FEV1 values obtained 23 and 24 hours after previous morning's dosing. Change from BL was calculated as the average at each visit minus the BL value. Analysis was performed using a repeated measures model with covariates of treatment, reversibility status (stratum), BL, region, day, day by BL and day by treatment interactions.
Time Frame Baseline to Day 84
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-Treat (ITT) Population: all randomized par. who received at least one dose of study medication. Number of par. presented represent those with data available at the time point being presented; however, all par. in the ITT population without missing covariate information and with at least one post BL measurement are included in the analysis
Arm/Group Title FF/VI 100/25 µg QD VI 25 µg QD
Hide Arm/Group Description:
Participants received fluticasone furoate/vilaterol (FF/VI) 100/25 microgram(µg) inhalation via a dry powder inhaler (DPI) once daily (QD) in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler (MDI) or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods.
Participants received VI 25 µg inhalation QD via a DPI in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler (MDI) or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods.
Overall Number of Participants Analyzed 759 749
Least Squares Mean (Standard Error)
Unit of Measure: Liter
0.116  (0.0074) 0.082  (0.0075)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/VI 100/25 µg QD, VI 25 µg QD
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments [Not Specified]
Method Mixed Models Analysis
Comments Restricted maximum likelihood (REML)-based repeated measures approach (MMRM)
Method of Estimation Estimation Parameter Least Squares Mean Difference
Estimated Value 0.034
Confidence Interval (2-Sided) 95%
0.014 to 0.055
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Rescue-free 24-hour Periods Over the Entire 12-week Treatment Period
Hide Description Participants were given daily record cards for daily completion from BL (Week -1) through Week 12 (Visit 7) each morning and prior prior to taking study medication (i.e., single-blind and double-blind study medication), supplemental medication (albuterol [salbutamol] if received). Participants recorded number of occasions supplemental albuterol/salbutamol (MDI and/or nebules) or oxitropium bromide (applicable sites in Japan) used over the previous 24 hours and any medical problems that they had experienced and any medication used to treat these medical problems over the previous 24 hours. Rescue-free 24-hour periods are defined as the 24-hour periods in which the rescue medication (albuterol [salbutamol]) was not used. The percentage of 24-hour periods are summarized for the entire treatment period (12 weeks). Analysis was performed using an analysis of covariance (ANCOVA) model with covariates of treatment, reversibility status (stratum), baseline (week -1) and region.
Time Frame BL (Week -1), Week 1 to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population, all randomized participants who received at least one dose of study medication. Only those participants with at least 1 on treatment rescue medication measurement during the treatment period and without missing covariate information were analyzed.
Arm/Group Title FF/VI 100/25 µg QD VI 25 µg QD
Hide Arm/Group Description:
Participants received fluticasone furoate/vilaterol (FF/VI) 100/25 microgram(µg) inhalation via a dry powder inhaler (DPI) once daily (QD) in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler (MDI) or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods.
Participants received VI 25 µg inhalation QD via a DPI in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler (MDI) or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods.
Overall Number of Participants Analyzed 801 802
Least Squares Mean (Standard Error)
Unit of Measure: Percentage of rescue-free periods
47.03  (1.070) 44.41  (1.069)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/VI 100/25 µg QD, VI 25 µg QD
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.084
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares Mean Difference
Estimated Value 2.62
Confidence Interval (2-Sided) 95%
-0.35 to 5.59
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Time to First On-treatment Occurrence of Moderate or Severe COPD Exacerbation
Hide Description Time to first on-treatment exacerbation was analysed using a Cox proportional hazards model with terms for treatment, reversibility status and percent predicted FEV1 at screening. Exacerbation of COPD is defined by a worsening of symptoms requiring additional treatment. Moderate COPD exacerbation is worsening symptoms of COPD that require treatment with antibiotics and/or systemic corticosteroids. Severe COPD exacerbation is worsening symptoms of COPD that require treatment with in-patient hospitalization. The number of participants with On-Treatment moderate or severe COPD exacerbations are presented.
Time Frame From the start of double blind study medication until visit 7 (week 12)/Early withdrawal
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title FF/VI 100/25 µg QD VI 25 µg QD
Hide Arm/Group Description:
Participants received fluticasone furoate/vilaterol (FF/VI) 100/25 microgram(µg) inhalation via a dry powder inhaler (DPI) once daily (QD) in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler (MDI) or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods.
Participants received VI 25 µg inhalation QD via a DPI in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler (MDI) or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods.
Overall Number of Participants Analyzed 806 814
Measure Type: Number
Unit of Measure: Participants
69 114
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection FF/VI 100/25 µg QD, VI 25 µg QD
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Nominal p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.58
Confidence Interval (2-Sided) 95%
0.43 to 0.78
Estimation Comments [Not Specified]
Time Frame On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of double-blind (DB) study treatment (Visit 2) through the follow up contact (up to 13 weeks).
Adverse Event Reporting Description On-treatment AE or SAE is defined as an AE with an onset date on or after the start date of DB study medication, but not later than one day after the last dose of DB study medication. AEs are reported for participants of the ITT, comprised of all randomized participants who received at least one dose of study medication during the treatment period
 
Arm/Group Title FF/VI 100/25 µg QD VI 25 µg QD
Hide Arm/Group Description Participants received fluticasone furoate/vilaterol (FF/VI) 100/25 microgram(µg) inhalation via a dry powder inhaler (DPI) once daily (QD) in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler (MDI) or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods. Participants received VI 25 µg inhalation QD via a DPI in the morning for 12 weeks. In addition, all participants were provided with albuterol (salbutamol) or oxitropium bromide (applicable sites in Japan) to be used as rescue medication (via metered-dose inhaler (MDI) or nebules) for relief of COPD symptoms during the Run-In and Treatment Periods.
All-Cause Mortality
FF/VI 100/25 µg QD VI 25 µg QD
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
FF/VI 100/25 µg QD VI 25 µg QD
Affected / at Risk (%) Affected / at Risk (%)
Total   27/806 (3.35%)   35/814 (4.30%) 
Cardiac disorders     
Any event  1  2/806 (0.25%)  3/814 (0.37%) 
Myocardial infarction  1  1/806 (0.12%)  1/814 (0.12%) 
Atrial fibrillation  1  1/806 (0.12%)  0/814 (0.00%) 
Cardiac failure  1  0/806 (0.00%)  1/814 (0.12%) 
Cardiac failure congestive  1  0/806 (0.00%)  1/814 (0.12%) 
Eye disorders     
Any event  1  2/806 (0.25%)  0/814 (0.00%) 
Cataract  1  2/806 (0.25%)  0/814 (0.00%) 
Gastrointestinal disorders     
Any event  1  1/806 (0.12%)  1/814 (0.12%) 
Gastric ulcer  1  1/806 (0.12%)  0/814 (0.00%) 
Large intestine polyp  1  0/806 (0.00%)  1/814 (0.12%) 
Hepatobiliary disorders     
Any event  1  0/806 (0.00%)  1/814 (0.12%) 
Cholecystitis acute  1  0/806 (0.00%)  1/814 (0.12%) 
Infections and infestations     
Any event  1  6/806 (0.74%)  7/814 (0.86%) 
Pneumonia  1  2/806 (0.25%)  4/814 (0.49%) 
Appendicitis  1  1/806 (0.12%)  0/814 (0.00%) 
Bronchitis  1  0/806 (0.00%)  1/814 (0.12%) 
Cellulitis  1  1/806 (0.12%)  0/814 (0.00%) 
Epididymitis  1  0/806 (0.00%)  1/814 (0.12%) 
Hepatitis B  1  0/806 (0.00%)  1/814 (0.12%) 
Lower respiratory tract infection  1  1/806 (0.12%)  0/814 (0.00%) 
Pneumonia bacterial  1  1/806 (0.12%)  0/814 (0.00%) 
Injury, poisoning and procedural complications     
Any event  1  1/806 (0.12%)  3/814 (0.37%) 
Contusion  1  1/806 (0.12%)  0/814 (0.00%) 
Femoral neck fracture  1  0/806 (0.00%)  1/814 (0.12%) 
Femur fracture  1  0/806 (0.00%)  1/814 (0.12%) 
Humerus fracture  1  0/806 (0.00%)  1/814 (0.12%) 
Pelvic fracture  1  0/806 (0.00%)  1/814 (0.12%) 
Investigations     
Any event  1  0/806 (0.00%)  2/814 (0.25%) 
Blood pressure increased  1  0/806 (0.00%)  1/814 (0.12%) 
Hepatic enzyme increased  1  0/806 (0.00%)  1/814 (0.12%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Any event  1  4/806 (0.50%)  4/814 (0.49%) 
Pancreatic carcinoma  1  1/806 (0.12%)  1/814 (0.12%) 
Adenocarcinoma pancreas  1  0/806 (0.00%)  1/814 (0.12%) 
Breast cancer  1  0/806 (0.00%)  1/814 (0.12%) 
Colon adenoma  1  1/806 (0.12%)  0/814 (0.00%) 
Hepatic cancer  1  1/806 (0.12%)  0/814 (0.00%) 
Lung neoplasm malignant  1  1/806 (0.12%)  0/814 (0.00%) 
Urethral adenoma  1  0/806 (0.00%)  1/814 (0.12%) 
Nervous system disorders     
Any event  1  2/806 (0.25%)  1/814 (0.12%) 
Cerebral infarction  1  0/806 (0.00%)  1/814 (0.12%) 
Cerebrovascular accident  1  1/806 (0.12%)  0/814 (0.00%) 
Transient ischaemic attack  1  1/806 (0.12%)  0/814 (0.00%) 
Psychiatric disorders     
Any event  1  1/806 (0.12%)  0/814 (0.00%) 
Bipolar disorder  1  1/806 (0.12%)  0/814 (0.00%) 
Reproductive system and breast disorders     
Any event  1  2/806 (0.25%)  0/814 (0.00%) 
Benign prostatic hyperplasia  1  2/806 (0.25%)  0/814 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Any event  1  10/806 (1.24%)  19/814 (2.33%) 
Chronic obstructive pulmonary disease  1  10/806 (1.24%)  17/814 (2.09%) 
Chronic respiratory failure  1  1/806 (0.12%)  0/814 (0.00%) 
Epistaxis  1  0/806 (0.00%)  1/814 (0.12%) 
Pneumonia aspiration  1  0/806 (0.00%)  1/814 (0.12%) 
Pneumothorax  1  0/806 (0.00%)  1/814 (0.12%) 
Pulmonary embolism  1  1/806 (0.12%)  0/814 (0.00%) 
Vascular disorders     
Any event  1  0/806 (0.00%)  1/814 (0.12%) 
Aortic dissection  1  0/806 (0.00%)  1/814 (0.12%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 3%
FF/VI 100/25 µg QD VI 25 µg QD
Affected / at Risk (%) Affected / at Risk (%)
Total   72/806 (8.93%)   64/814 (7.86%) 
Infections and infestations     
Nasopharyngitis  1  49/806 (6.08%)  48/814 (5.90%) 
Nervous system disorders     
Headache  1  29/806 (3.60%)  19/814 (2.33%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
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.
GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Results Point of Contact
Name/Title: GSK Response Center
Organization: GlaxoSmithKline
Phone: 866-435-7343
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02105974     History of Changes
Other Study ID Numbers: 200820
First Submitted: April 3, 2014
First Posted: April 7, 2014
Results First Submitted: March 3, 2016
Results First Posted: April 13, 2016
Last Update Posted: January 24, 2018