NCT02164513

A Study Comparing the Efficacy, Safety and Tolerability of Fixed Dose Combination (FDC) of FF/UMEC/VI With the FDC of FF/VI and UMEC/VI; Administered Once-daily Via a Dry Powder Inhaler (DPI) in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Completed Phase 3 Results posted Last updated 10 October 2018

What this trial tests

Phase 3 trial testing fluticasone furoate (FF) in Pulmonary Disease, Chronic Obstructive in 10,355 participants. Completed in 17 July 2017.

Timeline

30 June 2014

Primary endpoint
17 July 2017

17 July 2017

Quick facts

Lead sponsor	GlaxoSmithKline
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	10,355
Start date	30 June 2014
Primary completion	17 July 2017
Estimated completion	17 July 2017
Sites	998 locations across Hong Kong, Colombia, Finland, Japan, Vietnam, Poland, South Korea, Philippines

Drugs / interventions tested

• fluticasone furoate (FF) — full drug profile →
• vilanterol (VI) — full drug profile →
• umeclidinium bromide (UMEC) — full drug profile →

Conditions studied

• Pulmonary Disease, Chronic Obstructive — all drugs for Pulmonary Disease, Chronic Obstructive →

Sponsor

GlaxoSmithKline — full company profile →

Who can join

40 and older, any sex, with Pulmonary Disease, Chronic Obstructive. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Annual Rate of On-treatment Moderate/Severe Exacerbations Comparing FF/UMEC/VI With UMEC/VI and FF/VI Primary · Up to Week 52

The annual rate of moderate or severe COPD exacerbations which occurred during treatment was assessed. Moderate exacerbations were defined as exacerbations that required treatment with oral/systemic corticosteroids and/or antibiotics (not involving hospitalization or resulting in death). Severe exacerbations were defined as exacerbations that required hospitalization or resulted in death. Analysis performed using a generalized linear model assuming a negative binomial distribution. ITT population was used which comprised of all randomized participants, excluding those who were randomized in er

Group	Value	95% CI
FF/UMEC/VI	0.91	0.87 – 0.95
FF/VI	1.07	1.02 – 1.12
UMEC/VI	1.21	1.14 – 1.29

Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1), at Week 52 Comparing FF/UMEC/VI With FF/VI Secondary · Baseline and Week 52

FEV1 was defined as the amount of air a person exhales in one second. Change from Baseline was calculated as the value of FEV1 at Week 52 minus the value at Baseline. Baseline for trough FEV1 was defined as Day 1 (Pre-dose). Only those participants with non-missing co-variates were included in the analysis. The analysis was performed using a Repeated measures model with covariates of treatment group, smoking status (Screening), geographical region, visit, Baseline, Baseline by visit and treatment group by visit interactions.

Group	Value	95% CI
FF/UMEC/VI	0.094	± 0.0042
FF/VI	-0.003	± 0.0044

Change From Baseline in St. George's Respiratory Questionnaire for (SGRQ) Total Score at Week 52 Comparing FF/UMEC/VI With FF/VI Secondary · Baseline and Week 52

SGRQ is a disease specific-questionnaire, designed to measure impact of respiratory disease and its treatment on a COPD participant's Health Related Quality of Life (HRQoL). SGRQ contains 14 questions with total of 40 items grouped into three domains (Symptoms, Activity, and Impacts). The overall summary score along with scores for the individual domains of symptoms, activity and impacts were assessed. Score was calculated by summing the pre-assigned weights of answers, dividing by sum of maximum weights for items in SGRQ. Total scores ranged from 0 to 100. A decrease in score indicates improv

Group	Value	95% CI
FF/UMEC/VI	-5.5	± 0.23
FF/VI	-3.7	± 0.24

Time to First On-treatment Moderate/Severe Exacerbation Comparing FF/UMEC/VI With FF/VI and With UMEC/VI Secondary · Up to Week 52

This measures the number of days, to the first onset of moderate or severe exacerbations. Moderate exacerbations, were defined as exacerbations that required treatment with oral/systemic corticosteroids and/or antibiotics (not involving hospitalization or resulting in death). Severe exacerbations, were defined as exacerbations that required hospitalization or resulted in death. The Hazard ratio from Cox proportional hazards model with covariates of treatment group, sex, exacerbation history (\<=1, \>=2 moderate/severe), smoking status (Screening), geographical region and post-bronchodilator pe

First quartile time to onset

Group	Value	95% CI
FF/UMEC/VI	112
FF/VI	81
UMEC/VI	73

Median time to onset

Group	Value	95% CI
FF/UMEC/VI	NA
FF/VI	NA
UMEC/VI	306

Annual Rate of On-treatment Moderate/Severe Exacerbations Comparing FF/UMEC/VI With UMEC/VI in the Subset of Participants With a Blood Eosinophil Count >=150 Cells Per Microliter Secondary · Up to Week 52

The annual rate of moderate or severe COPD exacerbations during the treatment, for participants with blood eosinophil count \>=150 cells per microliter , has been reported. Moderate exacerbations, were defined as exacerbations that required treatment with oral/systemic corticosteroids and/or antibiotics (not involving hospitalization or resulting in death). Severe exacerbations were defined as exacerbations that required hospitalization or resulted in death. Only those participants with non-missing co-variates and non-missing eosinophil, at Baseline were included in the analysis.

Group	Value	95% CI
FF/UMEC/VI	0.95	0.90 – 1.01
UMEC/VI	1.39	1.29 – 1.51

Time to First On-treatment Moderate/Severe Exacerbation Comparing FF/UMEC/VI With UMEC/VI in the Subset of Particpants With a Blood Eosinophil Count >=150 Cells Per Microliter at Baseline Secondary · Up to Week 52

This measures the number of days, to the first onset of moderate or severe exacerbations for participants with blood eosinophil count \>=150 cells per microliter, at Baseline has been reported. Moderate exacerbations, were defined as exacerbations that required treatment with oral/systemic corticosteroids and/or antibiotics (not involving hospitalization or resulting in death). Severe exacerbations, were defined as exacerbations that required hospitalization or resulted in death. Only those participants with non-missing co-variates and non missing eosinophils at Baseline were included in the a

First quartile time to onset

Group	Value	95% CI
FF/UMEC/VI	107
UMEC/VI	55

Median time to onset

Group	Value	95% CI
FF/UMEC/VI	NA
UMEC/VI	253

Annual Rate of On-treatment Severe Exacerbations Comparing FF/UMEC/VI With FF/VI and With UMEC/VI Secondary · Up to Week 52

The annual rate of severe COPD exacerbations during the treatment, has been reported. Severe exacerbations were defined as exacerbations that required hospitalization or resulted in death. The covariates of treatment group, sex, exacerbation history (\<=1, \>=2 moderate/severe), smoking status (Screening), geographical region and post-bronchodilator percent predicted FEV1 (Screening) were used. Only those participants with non-missing co-variates were included in the analysis

Group	Value	95% CI
FF/UMEC/VI	0.13	0.12 – 0.14
FF/VI	0.15	0.13 – 0.16
UMEC/VI	0.19	0.17 – 0.22

Adverse events — posted to ClinicalTrials.gov

Time frame: On-treatment Serious adverse events (SAEs) and Adverse events (AEs) are reported from the first dose of randomized medication up to Week 52.. Reporting threshold: 3%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

FF/UMEC/VI 100/62.5/25

Serious: 895/4151 (22%)

Deaths: 68/4151

FF/VI 100/25

Serious: 850/4134 (21%)

Deaths: 76/4134

UMEC/VI 62.5/25

Serious: 470/2070 (23%)

Deaths: 49/2070

Serious adverse events (640 terms)

Reaction	System	FF/UMEC/VI 100/62.5/25	FF/VI 100/25	UMEC/VI 62.5/25
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	—	—	—
Pneumonia	Infections and infestations	—	—	—
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—
Cardiac failure congestive	Cardiac disorders	—	—	—
Infective exacerbation of chronic obstructive airways disease	Infections and infestations	—	—	—
Acute myocardial infarction	Cardiac disorders	—	—	—
Cardiac failure	Cardiac disorders	—	—	—
Pneumothorax	Respiratory, thoracic and mediastinal disorders	—	—	—
Myocardial infarction	Cardiac disorders	—	—	—
Non-cardiac chest pain	General disorders	—	—	—
Bronchitis	Infections and infestations	—	—	—
Lung neoplasm malignant	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
Pneumonia bacterial	Infections and infestations	—	—	—
Sepsis	Infections and infestations	—	—	—
Rib fracture	Injury, poisoning and procedural complications	—	—	—
Osteoarthritis	Musculoskeletal and connective tissue disorders	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—
Transient ischaemic attack	Nervous system disorders	—	—	—
Angina unstable	Cardiac disorders	—	—	—
Chest pain	General disorders	—	—	—
Influenza	Infections and infestations	—	—	—
Lower respiratory tract infection	Infections and infestations	—	—	—
Urinary tract infection	Infections and infestations	—	—	—

Other adverse events (8 terms — click to expand)

Reaction	System	FF/UMEC/VI 100/62.5/25	FF/VI 100/25	UMEC/VI 62.5/25
Viral upper respiratory tract infection	Infections and infestations	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—
Headache	Nervous system disorders	—	—	—
Oral candidiasis	Infections and infestations	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Bronchitis	Infections and infestations	—	—	—
Pneumonia	Infections and infestations	—	—	—

Most-reported serious reactions: Chronic obstructive pulmonary disease, Pneumonia, Acute respiratory failure, Respiratory failure, Atrial fibrillation, Cardiac failure congestive, Infective exacerbation of chronic obstructive airways disease, Acute myocardial infarction.

Data from ClinicalTrials.gov NCT02164513 adverse events section.

Sponsor's own description

The study evaluates the efficacy of fluticasone furoate/umeclidinium bromide/vilanterol (FF/UMEC/VI) to reduce the annual rate of moderate and severe exacerbations compared with dual therapy of FF/VI or UMEC/VI in subjects with COPD. Published studies which assessed the use of an 'open' triple therapy (use of Inhaled Corticosteroid \[ICS\]/ Long-acting Muscarinic Receptor Antagonists \[LAMA\])/ Long Acting Beta-Agonist \[LABA\] delivered via multiple inhalers) in moderate-severe COPD patients, reported improvements in lung function, Health Related Quality of Life (HRQoL), hospitalization rates and rescue medication use, compared to dual therapy (ICS/LABA) or LAMA alone. These studies have also shown similar safety profile with dual or monotherapy doses for periods of up to one year. Given the clinical experience with FF, UMEC and VI, and that the associated risks with these compounds are anticipated from their known pharmacology, the potential benefit of a new therapy option in patients with moderate to severe COPD supports the further development of the closed triple combination (delivered via one inhaler). In the current study subjects meeting all inclusion/exclusion criteria will complete 2-week run-in period; 52 week treatment period and a 1-week safety follow-up period. Eligible subjects will be randomized to one of the following double-blind treatment groups FF/UMEC/VI 100 micrograms (mcg)/62.5 mcg/25 mcg once daily (QD), FF/VI 100 mcg/25 mcg QD, or UMEC/VI 62.5 mcg/25 mcg QD

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD.
   Lipson DA, Barnhart F, Brealey N, Brooks J, et al · · 2018 · cited 832× · PMID 29668352 · DOI 10.1056/nejmoa1713901
2. Reduction in All-Cause Mortality with Fluticasone Furoate/Umeclidinium/Vilanterol in Patients with Chronic Obstructive Pulmonary Disease.
   Lipson DA, Crim C, Criner GJ, Day NC, et al · · 2020 · cited 166× · PMID 32162970 · DOI 10.1164/rccm.201911-2207oc
3. Blood eosinophils and treatment response with triple and dual combination therapy in chronic obstructive pulmonary disease: analysis of the IMPACT trial.
   Pascoe S, Barnes N, Brusselle G, Compton C, et al · · 2019 · cited 156× · PMID 31281061 · DOI 10.1016/s2213-2600(19)30190-0
4. Management of locally advanced non-small cell lung cancer: State of the art and future directions.
   Miao D, Zhao J, Han Y, Zhou J, et al · · 2024 · cited 99× · PMID 37985191 · DOI 10.1002/cac2.12505
5. Blood Eosinophil Counts in Clinical Trials for Chronic Obstructive Pulmonary Disease.
   Singh D, Bafadhel M, Brightling CE, Sciurba FC, et al · · 2020 · cited 77× · PMID 32186896 · DOI 10.1164/rccm.201912-2384pp
6. A phase III randomised controlled trial of single-dose triple therapy in COPD: the IMPACT protocol.
   Pascoe SJ, Lipson DA, Locantore N, Barnacle H, et al · · 2016 · cited 74× · PMID 27418551 · DOI 10.1183/13993003.02165-2015
7. Time-Dependent Risk of Cardiovascular Events Following an Exacerbation in Patients With Chronic Obstructive Pulmonary Disease: Post Hoc Analysis From the IMPACT Trial.
   Dransfield MT, Criner GJ, Halpin DMG, Han MK, et al · · 2022 · cited 61× · PMID 36102236 · DOI 10.1161/jaha.121.024350
8. New combination bronchodilators for chronic obstructive pulmonary disease: current evidence and future perspectives.
   Singh D. · · 2015 · cited 52× · PMID 25377687 · DOI 10.1111/bcp.12545