Trial Outcomes & Findings for 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) (NCT NCT01017952)

Last Updated: 2018-08-31

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1635 participants

Primary outcome timeframe

From the start of the double blind study medication until Visit 11 (Week 52)/Early Withdrawal

Results posted on

2018-08-31

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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.
4-week, Open-label Run-In Period STARTED	2092	0	0	0	0
4-week, Open-label Run-In Period COMPLETED	1633	0	0	0	0
4-week, Open-label Run-In Period NOT COMPLETED	459	0	0	0	0
52-week, Double-blind Treatment Period STARTED	0	409	412	403	409
52-week, Double-blind Treatment Period Completed the Treatment Period	0	285	305	293	307
52-week, Double-blind Treatment Period COMPLETED	0	284	303	291	306
52-week, Double-blind Treatment Period NOT COMPLETED	0	125	109	112	103

Reasons for withdrawal

Reasons for withdrawal
Measure	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.
4-week, Open-label Run-In Period Did Not Meet Continuation Criteria	356	0	0	0	0
4-week, Open-label Run-In Period Adverse Event	23	0	0	0	0
4-week, Open-label Run-In Period Study Closed/Tterminated	1	0	0	0	0
4-week, Open-label Run-In Period Lost to Follow-up	6	0	0	0	0
4-week, Open-label Run-In Period Physician Decision	10	0	0	0	0
4-week, Open-label Run-In Period Withdrawal by Subject	63	0	0	0	0
52-week, Double-blind Treatment Period Adverse Event	0	25	32	35	30
52-week, Double-blind Treatment Period Withdrawal by Subject	0	30	22	25	25
52-week, Double-blind Treatment Period Lack of Efficacy	0	35	14	16	14
52-week, Double-blind Treatment Period Protocol Violation	0	7	11	9	8
52-week, Double-blind Treatment Period Met Protocol-Defined Stopping Criteria	0	11	13	12	9
52-week, Double-blind Treatment Period Study Closed/Terminated	0	1	1	0	0
52-week, Double-blind Treatment Period Lost to Follow-up	0	6	8	6	10
52-week, Double-blind Treatment Period Physician Decision	0	10	8	9	7

Baseline Characteristics

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)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	VI 25 µg QD n=409 Participants 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 n=412 Participants 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 n=403 Participants 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 n=409 Participants 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 n=1633 Participants Total of all reporting groups
Age, Continuous	63.6 Years STANDARD_DEVIATION 9.29 • n=93 Participants	63.7 Years STANDARD_DEVIATION 9.56 • n=4 Participants	64.0 Years STANDARD_DEVIATION 9.28 • n=27 Participants	63.5 Years STANDARD_DEVIATION 8.84 • n=483 Participants	63.7 Years STANDARD_DEVIATION 9.24 • n=36 Participants
Sex: Female, Male Female	174 Participants n=93 Participants	181 Participants n=4 Participants	181 Participants n=27 Participants	191 Participants n=483 Participants	727 Participants n=36 Participants
Sex: Female, Male Male	235 Participants n=93 Participants	231 Participants n=4 Participants	222 Participants n=27 Participants	218 Participants n=483 Participants	906 Participants n=36 Participants
Race/Ethnicity, Customized White	360 participants n=93 Participants	359 participants n=4 Participants	353 participants n=27 Participants	359 participants n=483 Participants	1431 participants n=36 Participants
Race/Ethnicity, Customized African American/ African Heritage	9 participants n=93 Participants	14 participants n=4 Participants	7 participants n=27 Participants	9 participants n=483 Participants	39 participants n=36 Participants
Race/Ethnicity, Customized Asian	4 participants n=93 Participants	3 participants n=4 Participants	5 participants n=27 Participants	3 participants n=483 Participants	15 participants n=36 Participants
Race/Ethnicity, Customized African American/African Heritage & White	0 participants n=93 Participants	1 participants n=4 Participants	1 participants n=27 Participants	0 participants n=483 Participants	2 participants n=36 Participants
Race/Ethnicity, Customized American Indian or Alaska Native & White	20 participants n=93 Participants	19 participants n=4 Participants	21 participants n=27 Participants	20 participants n=483 Participants	80 participants n=36 Participants
Race/Ethnicity, Customized Asian & White	0 participants n=93 Participants	0 participants n=4 Participants	0 participants n=27 Participants	1 participants n=483 Participants	1 participants n=36 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	0 participants n=93 Participants	0 participants n=4 Participants	0 participants n=27 Participants	1 participants n=483 Participants	1 participants n=36 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	16 participants n=93 Participants	16 participants n=4 Participants	16 participants n=27 Participants	16 participants n=483 Participants	64 participants n=36 Participants

PRIMARY outcome

Timeframe: From the start of the double blind study medication until Visit 11 (Week 52)/Early Withdrawal

Population: 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.

Outcome measures

Outcome measures
Measure	VI 25 µg QD n=409 Participants 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 n=412 Participants 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 n=403 Participants 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 n=409 Participants 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.
Annual Rate of Moderate and Severe COPD Exacerbations Expressed as Least Square Mean	1.14 Exacerbations per participant per year Interval 0.99 to 1.32	0.92 Exacerbations per participant per year Interval 0.79 to 1.07	0.90 Exacerbations per participant per year Interval 0.77 to 1.05	0.79 Exacerbations per participant per year Interval 0.67 to 0.92

SECONDARY outcome

Timeframe: From the start of the double blind study medication until Visit 11 (Week 52)/Early Withdrawal

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	VI 25 µg QD n=409 Participants 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 n=412 Participants 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 n=403 Participants 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 n=409 Participants 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.
Time to First Occurrence of Moderate or Severe COPD Exacerbation	197 Participants	198 Participants	177 Participants	160 Participants

SECONDARY outcome

Timeframe: From the start of the double blind study medication until Visit 11 (Week 52)/Early Withdrawal

The annual rate of COPD exacerbations during the treatment period (per participant per year) that required systemic/oral corticosteroids 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 symptom (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 participant. Mild exacerbations were not associated with 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.

Outcome measures

Outcome measures
Measure	VI 25 µg QD n=409 Participants 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 n=412 Participants 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 n=403 Participants 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 n=409 Participants 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.
Annual Rate of Exacerbations Requiring Systemic/Oral Corticosteroids Expressed as Least Square Mean	0.86 Exacerbations per participant per year Interval 0.72 to 1.03	0.72 Exacerbations per participant per year Interval 0.6 to 0.86	0.66 Exacerbations per participant per year Interval 0.55 to 0.8	0.56 Exacerbations per participant per year Interval 0.46 to 0.68

SECONDARY outcome

Timeframe: Baseline to Visit 11 (Week 52)/Early Withdrawal

Population: ITT Population. Number of participants presented represent those with data available at the time point being presented, however all participants in the ITT population without missing covariate information and with at least one post Baseline measurement are included in the analysis.

Pulmonary function was measured by forced expiratory volume in one second (FEV1). Trough FEV1 was defined as the 24-hour post-dose FEV1 assessment, which was obtained at each visit. Analysis performed using a repeated measures model with covariates of treatment, smoking status at Screening (stratum), baseline (pre-dose Day 1), centre grouping, Week, Week by Baseline, and Week by treatment interactions.

Outcome measures

Outcome measures
Measure	VI 25 µg QD n=276 Participants 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 n=304 Participants 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 n=287 Participants 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 n=300 Participants 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.
Change From Baseline in Trough FEV1 at Week 52 (Visit 11)	-0.019 Liters Standard Error 0.0116	0.015 Liters Standard Error 0.0113	0.005 Liters Standard Error 0.0115	0.006 Liters Standard Error 0.0113

Adverse Events

VI 25 µg QD

Serious events: 66 serious events

Other events: 211 other events

Deaths: 0 deaths

FF/VI 50/25 µg QD

Serious events: 71 serious events

Other events: 229 other events

Deaths: 0 deaths

FF/VI 100/25 µg QD

Serious events: 67 serious events

Other events: 239 other events

Deaths: 0 deaths

FF/VI 200/25 µg QD

Serious events: 61 serious events

Other events: 249 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER