Trial Outcomes & Findings for Comparative Study of Fluticasone Furoate(FF)/Umeclidinium Bromide (UMEC)/ Vilanterol (VI) Closed Therapy Versus FF/VI Plus UMEC Open Therapy in Subjects With Chronic Obstructive Pulmonary Disease (COPD) (NCT NCT02729051)

Last Updated: 2019-07-15

Results Overview

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. It was measured using centralized spirometry. FEV1 values at Week 0, pre-dose were considered as Baseline values. Change from Baseline was calculated by subtracting Baseline value from the value at indicated time point. Modified Per Protocol (mPP) Population was used which comprised of all participants in the Intent-to-Treat (ITT) Population, who do not have a full protocol deviation considered to impact efficacy. Data following a moderate/severe COPD exacerbation or pneumonia was excluded from analysis due to the potential impact of the exacerbation or the medications used to treat it. Participants with partial protocol deviations considered to impact efficacy were included in the mPP Population but had their data excluded from analysis from the time of deviation onwards. Analysis was performed using a mixed model repeated measures (MMRM) method.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1055 participants

Primary outcome timeframe

Baseline and Week 24

Results posted on

2019-07-15

Participant Flow

This was a 24-week, randomized, double-blind, parallel group multicenter study to compare closed triple therapy Fluticasone Furoate/ Umeclidinium/ Vilanterol Trifenatate (FF/UMEC/VI) with open triple therapy (FF/VI + UMEC), in participants with chronic obstructive pulmonary disease (COPD). This study was conducted across 12 countries.

A total of 1311 participants were pre-screened, of which 1278 participants were screened (33 pre-screen failures). There were 175 screen failures and 48 Run-in failures. A total of 1055 participants were randomized and received the study treatment.

Participant milestones

Participant milestones
Measure	FF/UMEC/VI 100/62.5/25 Participants received FF/UMEC/VI, 100 micrograms (mcg)/62.5 mcg/25 mcg via ELLIPTA dry powder inhaler (DPI) once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	FF/VI 100/25 + UMEC 62.5 Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
Overall Study STARTED	527	528
Overall Study COMPLETED	497	496
Overall Study NOT COMPLETED	30	32

Reasons for withdrawal

Reasons for withdrawal
Measure	FF/UMEC/VI 100/62.5/25 Participants received FF/UMEC/VI, 100 micrograms (mcg)/62.5 mcg/25 mcg via ELLIPTA dry powder inhaler (DPI) once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	FF/VI 100/25 + UMEC 62.5 Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
Overall Study Adverse Event	21	11
Overall Study Lack of Efficacy	1	1
Overall Study Lost to Follow-up	1	2
Overall Study Physician Decision	1	1
Overall Study Withdrawal by Subject	6	17

Baseline Characteristics

Comparative Study of Fluticasone Furoate(FF)/Umeclidinium Bromide (UMEC)/ Vilanterol (VI) Closed Therapy Versus FF/VI Plus UMEC Open Therapy in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	FF/UMEC/VI 100/62.5/25 n=527 Participants Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	FF/VI 100/25 + UMEC 62.5 n=528 Participants Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	Total n=1055 Participants Total of all reporting groups
Age, Continuous	66.7 Years STANDARD_DEVIATION 8.46 • n=5 Participants	65.9 Years STANDARD_DEVIATION 8.77 • n=7 Participants	66.3 Years STANDARD_DEVIATION 8.62 • n=5 Participants
Sex: Female, Male Female	136 Participants n=5 Participants	134 Participants n=7 Participants	270 Participants n=5 Participants
Sex: Female, Male Male	391 Participants n=5 Participants	394 Participants n=7 Participants	785 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	18 Participants n=5 Participants	14 Participants n=7 Participants	32 Participants n=5 Participants
Race/Ethnicity, Customized Asian - East Asian Heritage	29 Participants n=5 Participants	30 Participants n=7 Participants	59 Participants n=5 Participants
Race/Ethnicity, Customized Asian - Japanese Heritage	41 Participants n=5 Participants	38 Participants n=7 Participants	79 Participants n=5 Participants
Race/Ethnicity, Customized Asian - South East Asian Heritage	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized White - Arabic/North African Heritage	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized White - White/Caucasian/European Heritage	416 Participants n=5 Participants	416 Participants n=7 Participants	832 Participants n=5 Participants
Race/Ethnicity, Customized American Indian/Alaska Native and Asian and White	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native and White	20 Participants n=5 Participants	25 Participants n=7 Participants	45 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Week 24

Population: mPP Population

Outcome measures

Outcome measures
Measure	FF/UMEC/VI 100/62.5/25 n=307 Participants Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	FF/VI 100/25 + UMEC 62.5 n=287 Participants Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 24	0.113 Liter Standard Error 0.0112	0.095 Liter Standard Error 0.0116

SECONDARY outcome

Timeframe: Week 24

Population: ITT Population. Only those participants with data available at the specified time points were analyzed.

SGRQ is a disease-specific questionnaire designed to measure impact of respiratory disease and its treatment on health related quality of life (HRQoL) of participants with COPD. It contains 14 questions with a total of 40 items grouped into domains (Symptoms, Activity and Impacts). SGRQ total score was calculated as 100 multiplied by summed weights from all positive items divided by sum of weights for all items in questionnaire. It ranges from 0 to 100, higher score indicates poor HRQoL. Response was defined as an SGRQ total score of \>=4 units below Baseline. Non response was defined as a SGRQ total score \<4 units below Baseline or a missing SGRQ total score with no subsequent on treatment scores. ITT Population comprised of randomized participants, excluding those who were randomized in error. A participant screened or run-in failure and also randomized was considered to be randomized in error. Analysis was performed using a generalized linear mixed model with a logit link function.

Outcome measures

Outcome measures
Measure	FF/UMEC/VI 100/62.5/25 n=489 Participants Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	FF/VI 100/25 + UMEC 62.5 n=483 Participants Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
Percentage of Responders Based on the Saint (St) George Respiratory Questionnaire (SGRQ) Total Score at Week 24	50 Percentage of Participants	51 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: ITT Population. Only those participants with data available at the specified time points were analyzed.

SGRQ is a disease-specific questionnaire designed to measure impact of respiratory disease and its treatment on HRQoL of participants with COPD. It contains 14 questions with a total of 40 items grouped into domains (Symptoms, Activity and Impacts). SGRQ total score was calculated as 100 multiplied by summed weights from all positive items divided by sum of weights for all items in questionnaire. It ranges from 0 to 100, higher score indicates poor HRQoL. Values at Week 0, pre-dose were considered as Baseline values. Change from Baseline was calculated by subtracting Baseline value from the value at indicated time point. Analysis was performed using a MMRM method including covariates of Baseline SGRQ Total score, stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), visit, geographical region, treatment, visit by treatment and visit by Baseline interaction.

Outcome measures

Outcome measures
Measure	FF/UMEC/VI 100/62.5/25 n=489 Participants Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	FF/VI 100/25 + UMEC 62.5 n=483 Participants Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
Change From Baseline in SGRQ Total Score at Week 24	-5.841 Scores on a scale Standard Error 0.5870	-4.935 Scores on a scale Standard Error 0.5904

SECONDARY outcome

Timeframe: Week 24

Population: ITT Population. Only those participants with data available at the specified time points were analyzed.

The TDI measures changes in the participant's dyspnea. TDI focal score was calculated as the sum of the ratings recorded for each of the 3 individual scales (Functional Impairment, Magnitude of Task, Magnitude of Effort). Each of these scales had a possible score ranging from -6 to +6. lower scores indicating more impairment. TDI focal score was calculated as the sum of the 3 individual scores and then divided by 2 (so the range of the TDI focal score is -9 to +9). The lower the score, the more deterioration in severity of dyspnea. If a score is missing for any of the three scales, then the TDI focal score was set to missing. A participant was considered as a responder if the on-treatment TDI focal score was at least 1 unit at that visit. Non-response was defined as a TDI focal score of less than 1 unit or a missing TDI focal score with no subsequent non-missing on-treatment scores. Analysis was performed using a generalized linear mixed model with a logit link function.

Outcome measures

Outcome measures
Measure	FF/UMEC/VI 100/62.5/25 n=482 Participants Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	FF/VI 100/25 + UMEC 62.5 n=481 Participants Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
Percentage of Responders Based on Transitional Dyspnea Index (TDI) Focal Score at Week 24	56 Percentage of Participants	56 Percentage of Participants

SECONDARY outcome

Timeframe: Week 24

Population: ITT Population. Only those participants with data available at the specified time points were analyzed.

The TDI measures changes in the participant's dyspnoea. TDI focal score was calculated as the sum of the ratings recorded for each of the 3 individual scales (Functional Impairment, Magnitude of Task, Magnitude of Effort). Each of these scales had a possible score ranging from -6 to +6. lower scores indicating more impairment. TDI focal score was calculated as the sum of the 3 individual scores and then divided by 2 (so the range of the TDI focal score is -9 to +9). The lower the score, the more deterioration in severity of dyspnea. If a score is missing for any of the three scales, then the TDI focal score was set to missing. Analysis was performed using a repeated measures model.

Outcome measures

Outcome measures
Measure	FF/UMEC/VI 100/62.5/25 n=482 Participants Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	FF/VI 100/25 + UMEC 62.5 n=481 Participants Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
TDI Focal Score at Week 24	2.029 Scores on a scale Standard Error 0.1252	1.892 Scores on a scale Standard Error 0.1254

SECONDARY outcome

Timeframe: Up to 25 weeks

Population: ITT Population

COPD exacerbations were identified based on the investigator's clinical judgment. Worsening symptoms of COPD that required treatment with oral/systemic corticosteroids and/or antibiotics were considered as moderate exacerbation. Worsening symptoms of COPD that required treatment with in-subject hospitalization was considered as severe exacerbation. Hazard ratio and 95% confidence interval (CI) is from a Cox proportional hazards model with covariates of treatment group, sex, exacerbation history (0, 1, \>=2 moderate/severe exacerbations, prior year), smoking status (screening), stratum (number of long-acting bronchodilators per day during the run-in: 0/1 or 2), geographical region and percent predicted FEV1 at Baseline. Median and inter-quartile range (first and third quartile) have been presented.

Outcome measures

Outcome measures
Measure	FF/UMEC/VI 100/62.5/25 n=527 Participants Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	FF/VI 100/25 + UMEC 62.5 n=528 Participants Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
Time to First Moderate or Severe Exacerbation	NA Days Interval 166.0 to As \<50% of participants experienced the event within a treatment, median and third-quartile of time to first moderate or severe exacerbation are displayed as NA (not applicable) for that treatment.	NA Days Interval 150.0 to As \<50% of participants experienced the event within a treatment, median and third-quartile of time to first moderate or severe exacerbation are displayed as NA (not applicable) for that treatment.

Adverse Events

FF/UMEC/VI 100/62.5/25

Serious events: 55 serious events

Other events: 122 other events

Deaths: 7 deaths

FF/VI 100/25 + UMEC 62.5

Serious events: 60 serious events

Other events: 125 other events

Deaths: 5 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	FF/UMEC/VI 100/62.5/25 n=527 participants at risk Participants received FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg via ELLIPTA DPI once daily in morning and placebo inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.	FF/VI 100/25 + UMEC 62.5 n=528 participants at risk Participants received FF/VI, 100 mcg/25 mcg via ELLIPTA DPI once daily in morning and UMEC 62.5 mcg inhalation powder via ELLIPTA DPI, once daily in the morning. Participants also received albuterol/salbutamol as a rescue medication when needed during the treatment period.
Infections and infestations Viral upper respiratory tract infection	10.6% 56/527 • On-treatment serious adverse events (SAEs) and non-serious AEs (nSAEs) were collected from start of study treatment (Week 0) until Week 25 including 1 Week of follow-up. On-treatment SAEs and nSAEs were reported for ITT Population.	9.8% 52/528 • On-treatment serious adverse events (SAEs) and non-serious AEs (nSAEs) were collected from start of study treatment (Week 0) until Week 25 including 1 Week of follow-up. On-treatment SAEs and nSAEs were reported for ITT Population.
Infections and infestations Upper respiratory tract infection	3.4% 18/527 • On-treatment serious adverse events (SAEs) and non-serious AEs (nSAEs) were collected from start of study treatment (Week 0) until Week 25 including 1 Week of follow-up. On-treatment SAEs and nSAEs were reported for ITT Population.	4.5% 24/528 • On-treatment serious adverse events (SAEs) and non-serious AEs (nSAEs) were collected from start of study treatment (Week 0) until Week 25 including 1 Week of follow-up. On-treatment SAEs and nSAEs were reported for ITT Population.
Infections and infestations Influenza	3.0% 16/527 • On-treatment serious adverse events (SAEs) and non-serious AEs (nSAEs) were collected from start of study treatment (Week 0) until Week 25 including 1 Week of follow-up. On-treatment SAEs and nSAEs were reported for ITT Population.	3.2% 17/528 • On-treatment serious adverse events (SAEs) and non-serious AEs (nSAEs) were collected from start of study treatment (Week 0) until Week 25 including 1 Week of follow-up. On-treatment SAEs and nSAEs were reported for ITT Population.
Infections and infestations Pharyngitis	2.3% 12/527 • On-treatment serious adverse events (SAEs) and non-serious AEs (nSAEs) were collected from start of study treatment (Week 0) until Week 25 including 1 Week of follow-up. On-treatment SAEs and nSAEs were reported for ITT Population.	3.0% 16/528 • On-treatment serious adverse events (SAEs) and non-serious AEs (nSAEs) were collected from start of study treatment (Week 0) until Week 25 including 1 Week of follow-up. On-treatment SAEs and nSAEs were reported for ITT Population.
Nervous system disorders Headache	6.1% 32/527 • On-treatment serious adverse events (SAEs) and non-serious AEs (nSAEs) were collected from start of study treatment (Week 0) until Week 25 including 1 Week of follow-up. On-treatment SAEs and nSAEs were reported for ITT Population.	6.2% 33/528 • On-treatment serious adverse events (SAEs) and non-serious AEs (nSAEs) were collected from start of study treatment (Week 0) until Week 25 including 1 Week of follow-up. On-treatment SAEs and nSAEs were reported for ITT Population.

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Email: [email protected]

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