NCT03478683

A Randomized Study, Comparing Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) Single Inhaler Triple Therapy, Versus Multiple Inhaler Therapy (Budesonide/Formoterol Plus Tiotropium) in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Completed Phase 4 Results posted Last updated 28 October 2020

What this trial tests

Phase 4 trial testing budesonide/formoterol in Pulmonary Disease, Chronic Obstructive in 729 participants. Completed in 14 March 2019.

Timeline

25 June 2018

Primary endpoint
14 March 2019

14 March 2019

Quick facts

Lead sponsor	GlaxoSmithKline
Phase	Phase 4
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	729
Start date	25 June 2018
Primary completion	14 March 2019
Estimated completion	14 March 2019
Sites	57 locations across Netherlands, United States, Germany, Czechia

Drugs / interventions tested

• budesonide/formoterol
• albuterol/salbutamol — full drug profile →
• FF/UMEC/VI — full drug profile →
• Placebo to match budesonide/formoterol — full drug profile →
• tiotropium — full drug profile →
• Placebo to match FF/UMEC/VI
• placebo to match tiotropium — full drug profile →
• ELLIPTA
• MDI
• HandiHaler

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.

Weighted Mean Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Over 0-24 Hours at Week 12 for Modified Per Protocol (mPP) Population Primary · Baseline and Week 12

FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. Serial FEV1 assessments were performed at multiple time points (-30 and -5 minutes pre-dose, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 15 hours, 21 hours, 23 hours and 24 hours post-dose) over 24-hour period at Week 12. Weighted mean change from Baseline at week 12 was calculated by subtracting weighted mean FEV1 at week 12 from Baseline FEV1, where Baseline FEV1 is the average o

Group	Value	95% CI
Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg	0.045	± 0.0101
Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg	0.030	± 0.0101

Change From Baseline in Trough FEV1 on Day 2, Day 28, Day 84 and Day 85 Secondary · Baseline, Days 2, 28, 84 and 85

FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. For Day 2 and Day 85, trough FEV1 was defined as the mean of the 23-hour and 24-hour serial spirometry FEV1 measurements. For Day 28 and Day 84, trough FEV1 was defined as the average of the pre-dose FEV1 measurements recorded before the morning dose of randomized study treatment. Change from Baseline in trough FEV1 was calculated by subtracting post-dose trough FEV1 value from Baseline FEV1, where Baseline FEV1

Day 2, n=358,359

Group	Value	95% CI
Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg	0.008	± 0.0098
Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg	0.018	± 0.0098

Day 28, n=355,353

Group	Value	95% CI
Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg	0.046	± 0.0088
Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg	-0.015	± 0.0088

Day 84, n=344,340

Group	Value	95% CI
Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg	0.040	± 0.0094
Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg	-0.018	± 0.0094

Day 85, n=341,337

Group	Value	95% CI
Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg	0.026	± 0.0099
Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg	-0.012	± 0.0099

Weighted Mean Change From Baseline in FEV1 Over 0-24 Hours on Day 1 Secondary · Baseline and Day 1

FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. Serial FEV1 assessments were performed at multiple time points (-30 and -5 minutes pre-dose, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 15 hours, 21 hours, 23 hours and 24 hours post-dose) over 24-hour period on Day 1. Weighted mean change from Baseline on Day 1 was calculated by subtracting weighted mean FEV1 on Day 1 from Baseline FEV1, where Baseline FEV1 is the average of the

Group	Value	95% CI
Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg	0.054	± 0.0078
Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg	0.063	± 0.0077

Weighted Mean Change From Baseline in FEV1 Over 0-24 Hours at Week 12 for ITT Population Primary · Baseline and Week 12

FEV1 is an important measure of pulmonary function and is the maximum amount of air that can be forced out in one second after taking a deep breath. FEV1 was measured using spirometry. Serial FEV1 assessments were performed at multiple time points (-30 and -5 minutes pre-dose, and 5 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, 15 hours, 21 hours, 23 hours and 24 hours post-dose) over 24-hour period at Week 12. Weighted mean change from Baseline at week 12 was calculated by subtracting weighted mean FEV1 at week 12 from Baseline FEV1, where Baseline FEV1 is the average o

Group	Value	95% CI
Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg	0.046	± 0.0097
Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg	0.032	± 0.0098

Adverse events — posted to ClinicalTrials.gov

Time frame: Serious adverse events (SAEs) and non-SAEs were reported from start of study treatment and up to Week 13. Reporting threshold: 3%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Fluticasone Furoate/Umeclidinium/Vilanterol 100/62.5/25 mcg

Serious: 29/363 (8%)

Deaths: 0/363

Budesonide/Formoterol 320/9 mcg Plus Tiotropium 18 mcg

Serious: 16/365 (4%)

Deaths: 0/365

Serious adverse events (29 terms)

Reaction	System	Fluticasone Furoate/Umecli…	Budesonide/Formoterol 320/…
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	—	—
Pneumonia	Infections and infestations	—	—
Acute myocardial infarction	Cardiac disorders	—	—
Cellulitis	Infections and infestations	—	—
Sepsis	Infections and infestations	—	—
Cerebrovascular accident	Nervous system disorders	—	—
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Acute coronary syndrome	Cardiac disorders	—	—
Cardiac failure acute	Cardiac disorders	—	—
Cardiac failure congestive	Cardiac disorders	—	—
Coronary artery disease	Cardiac disorders	—	—
Myocardial infarction	Cardiac disorders	—	—
Chest pain	General disorders	—	—
Cholelithiasis	Hepatobiliary disorders	—	—
Influenza	Infections and infestations	—	—
Pneumonia bacterial	Infections and infestations	—	—
Psoas abscess	Infections and infestations	—	—
Femur fracture	Injury, poisoning and procedural complications	—	—
Lumbar vertebral fracture	Injury, poisoning and procedural complications	—	—
Rib fracture	Injury, poisoning and procedural complications	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Prostate cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Seizure	Nervous system disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—

Other adverse events (1 terms — click to expand)

Reaction	System	Fluticasone Furoate/Umecli…	Budesonide/Formoterol 320/…
Nasopharyngitis	Infections and infestations	—	—

Most-reported serious reactions: Chronic obstructive pulmonary disease, Pneumonia, Acute myocardial infarction, Cellulitis, Sepsis, Cerebrovascular accident, Acute respiratory failure, Respiratory failure.

Data from ClinicalTrials.gov NCT03478683 adverse events section.

Sponsor's own description

The primary purpose of this study is to evaluate lung function and health related quality of life (HRQoL) after 84 days of treatment with a single inhaler triple therapy combination of FF/UMEC/VI \[100/62.5/25 microgram (mcg)\] once daily via the ELLIPTA™ compared with a multiple inhaler combination therapy of Symbicort Metered Dose Inhaler (MDI) (budesonide/formoterol 320/9 mcg) twice daily plus Spiriva HandiHaler (tiotropium 18 mcg) once daily. The study will inform healthcare providers that subjects can be effectively and safely switched to FF/UMEC/VI single inhaler therapy from a multiple inhaler triple therapy regimen of Symbicort MDI and Spiriva Handihaler. Eligible subjects will enter a 4-week run-in period during which they will be administered budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) once daily plus placebo via ELLIPTA. Following the run-in period, subjects will be randomized to receive one of the following study treatments for 84 days: 1) FF/UMEC/VI 100/62.5/25 mcg via ELLIPTA once daily in the morning plus two inhalations of placebo to match budesonide/formoterol via MDI, twice daily plus placebo to match tiotropium via HandiHaler once daily in the morning or 2) Budesonide/formoterol 320/9 mcg via MDI, twice daily plus tiotropium 18 mcg via HandiHaler once daily in the morning plus placebo via ELLIPTA once daily in the morning. Subjects will then enter a one week follow-up period. The total duration for a subject in the study will be approximately 17 weeks. ELLIPTA is a registered trademark of the GlaxoSmithKline group of companies.

Publications & conference data

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

1. Once-daily single-inhaler versus twice-daily multiple-inhaler triple therapy in patients with COPD: lung function and health status results from two replicate randomized controlled trials.
   Ferguson GT, Brown N, Compton C, Corbridge TC, et al · · 2020 · cited 30× · PMID 32471423 · DOI 10.1186/s12931-020-01360-w
2. Peak Inspiratory Flow Rate in COPD: An Analysis of Clinical Trial and Real-World Data.
   Anderson M, Collison K, Drummond MB, Hamilton M, et al · · 2021 · cited 17× · PMID 33883890 · DOI 10.2147/copd.s291554
3. Inhaled corticosteroids with combination inhaled long-acting beta2-agonists and long-acting muscarinic antagonists for chronic obstructive pulmonary disease.
   van Geffen WH, Tan DJ, Walters JA, Walters EH. · · 2023 · cited 15× · PMID 38054551 · DOI 10.1002/14651858.cd011600.pub3
4. Eligibility of patients with chronic obstructive pulmonary disease for inclusion in randomised control trials investigating triple therapy: a study using routinely collected data.
   Whittaker HR, Torkpour A, Quint J. · · 2024 · cited 4× · PMID 38238769 · DOI 10.1186/s12931-024-02672-x
5. Different inhaled corticosteroid doses in triple therapy for chronic obstructive pulmonary disease: systematic review and Bayesian network meta-analysis.
   Lee HW, Park HM, Jang EJ, Lee CH. · · 2022 · cited 4× · PMID 36127353 · DOI 10.1038/s41598-022-18353-y