Phase 3
Completed N=1,810
A Comparison Study Between the Fixed Dose Triple Combination of Fluticasone Furoate/ Umeclidinium/ Vilanterol Trifenatate (FF/UMEC/VI) With Budesonide/Formoterol in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
Pulmonary Disease, Chronic Obstructive
Source: ClinicalTrials.gov NCT02345161 ↗
Enrolled (actual)
1,810
Serious AEs
6.9%
Results posted
Jul 2018
Primary outcomePrimary: Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 24 — 0.142; -0.029 Liters (L) — p=<0.001
◆ Published Evidence
Established
32citations · ~4 / year
Once-Daily Triple Therapy in Patients with COPD: Patient-Reported Symptoms and Quality of Life.
Summary
This is a phase IIIa, randomised, double-blind, double-dummy, parallel group multicenter study evaluating once daily FF/UMEC/VI (100 microgram [mcg]/62.5 mcg/25 mcg) inhalation powder versus twice daily budesonide/formoterol (400 mcg/12 mcg). The primary purpose of this study is to demonstrate improvements in lung function and health status for subjects treated with FF/UMEC/VI compared with budesonide/formoterol for 24 weeks. Once-daily 'closed' triple therapy of a Inhaled Corticosteroid/ Long-acting Muscarinic Receptor Antagonists/ Long Acting Beta-Agonist (ICS/LAMA/LABA) combination FF/UMEC/VI (100 mcg/62.5 mcg/25 mcg) in a single device is being developed with the aim of providing a new treatment option for the management of advanced (GOLD Group D) COPD which will reduce the exacerbation frequency, allow for a reduced burden of polypharmacy, convenience, and increase the potential for improvement in lung function, Health Related Quality of Life (HRQoL) and symptom control over established dual/monotherapies.
Subjects meeting all inclusion/exclusion criteria and who have successfully completed all protocol procedures at the Screening Visit will enter the two-week run-in period. Following the run-in period, eligible subjects will be randomised (1:1) to one of the following double-blind treatment groups: FF/UMEC/VI 100 mcg/62.5 mcg/25 mcg via the ELLIPTA™ dry powder inhaler (DPI) once daily in the morning and placebo via reservoir inhaler twice daily OR Budesonide/formoterol 400 mcg/12 mcg via reservoir inhaler twice daily and placebo via the ELLIPTA DPI once daily in the morning.
The target enrollment is 1800 randomised subjects at approximately 200 study centers globally. The total duration of subject participation will be approximately 27 weeks, consisting of a 2-week run-in period, 24-week treatment period and a 1-week follow-up period. Subjects will run-in on their existing COPD medications for 2 weeks and in addition will be provided with short acting albuterol/salbutamol to be used on an as-needed basis (rescue medication) throughout the study. Subjects will discontinue all existing COPD medications during the randomised treatment period but may continue their study supplied rescue albuterol/salbutamol. A sub-set of approximately 400 subjects will remain on blinded study treatment for up to a total of 52 weeks to provide additional long term safety data.
ELLIPTA and NUBULES are a trade marks of the GlaxoSmithKline Group of Companies. Other company or product names mentioned herein may be the property of their respective owners
Linked Publications (5)
-
Once-Daily Triple Therapy in Patients with COPD: Patient-Reported Symptoms and Quality of Life.
-
Preventing clinically important deterioration with single-inhaler triple therapy in COPD.
-
Cost-Effectiveness Analysis of a Once-Daily Single-Inhaler Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease (COPD) Using the FULFIL Trial: A Spanish Perspective.
-
Population Pharmacokinetic Analysis of Fluticasone Furoate/Umeclidinium Bromide/Vilanterol in Patients with Chronic Obstructive Pulmonary Disease.
-
24-Hour Serial Spirometric Assessment of Once-Daily Fluticasone Furoate/Umeclidinium/Vilanterol Versus Twice-Daily Budesonide/Formoterol in Patients with COPD: Analysis of the FULFIL Study.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 24 |
0.142; -0.029 | <0.001 sig |
| PRIMARY Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 52 |
0.126; -0.053 | <0.001 sig |
| PRIMARY Change From Baseline in St George's Respiratory Questionnaire-Chronic Obstructive Pulmonary Disease (COPD; SGRQ) Total Score for COPD Participants at Week 24 |
-6.6; -4.3 | <0.001 sig |
| PRIMARY Change From Baseline in St George's Respiratory Questionnaire-COPD; SGRQ Total Score for COPD Participants at Week 52 |
-4.6; -1.9 | 0.065 |
| SECONDARY Transitional Dyspnea Index (TDI) Focal Score Expressed as Least Square Mean at Week 24 |
2.29; 1.72 | <0.001 sig |
| SECONDARY Transitional Dyspnea Index (TDI) Focal Score Expressed as Least Square Mean at Week 52 |
1.74; 1.39 | 0.279 |
| SECONDARY Daily Activity Question Percentage of Days Reporting a Score of 2 up to Week 24 |
0.0; -0.1 | 0.817 |
| SECONDARY Daily Activity Question Percentage of Days Reporting a Score of 2 up to Week 52 |
0.0; 0.3 | 0.767 |
| SECONDARY Mean Annual On-treatment Moderate and/or Severe COPD Exacerbations up to Week 24 |
0.22; 0.34 | 0.002 sig |
| SECONDARY Mean Annual On-treatment Moderate and/or Severe COPD Exacerbations up to Week 52 |
0.20; 0.36 | 0.006 sig |
| SECONDARY Assessment of Respiratory Symptoms by Change From Baseline in 4-weekly Mean Exacerbations of Chronic Pulmonary Disease Tool (EXACT)-RS Scores up to Week 24 |
-1.45; -0.50; -2.00; -0.77; -2.23; -1.05 | <0.001 sig |
| SECONDARY Assessment of Respiratory Symptoms by Change From Baseline in 4-weekly Mean EXACT-RS Scores up to Week 52 |
-1.24; -0.72; -1.97; -0.90; -2.18; -1.21 | 0.094 |
| SECONDARY Number of Participants With Any On-treatment Adverse Event (AE) and Serious Adverse Event (SAE) in the Treatment Period |
354; 339; 49; 51 | — |
| SECONDARY Number of Participants With Any On-treatment AE/SAEs in the Extension Part of the Study |
100; 122; 21; 28 | — |
| SECONDARY Number of Participants With an On-treatment Penumonia Event in the Treatment Period |
20; 7 | — |
| SECONDARY Number of Participants With an On-treatment Penumonia Event in the Extension Part of the Study |
4; 4 | — |
| SECONDARY Number of Participants With Any On-treatment Cardiovascular (CV) Events (Including Supraventricular Arrhythmia and Non Fatal Myocardial Infarction) in the Treatment Period |
4; 7; 12; 11 | — |
| SECONDARY Number of Participants With Any On-treatment CV Events (Including Supraventricular Arrhythmia and Non Fatal Myocardial Infarction) in the Extension Part of the Study |
5; 2; 7; 5 | — |
| SECONDARY Change From Baseline in Heart Rate at Week 24 |
-1.1; -1.2 | — |
| SECONDARY Change From Baseline in Heart Rate at Week 52 |
0.2; -1.0 | — |
| SECONDARY Change From Baseline in Corrected QT Interval Using Fridericia's Correction (QTcF) and PR Interval at Week 24 |
2.5; 0.6; -0.1; 0.5 | 0.023 sig |
| SECONDARY Change From Baseline in QTcF and PR Interval at Week 52 |
1.4; 2.4; 1.6; 1.4 | 0.564 |
| SECONDARY Change From Baseline in QT Interval Corrected for Heart Rate According to Bazett's Formula (QTcB) at Week 24 |
1.5; -0.7 | — |
| SECONDARY Change From Baseline in QTcB at Week 52 |
0.9; 2.2 | — |
| SECONDARY Change From Baseline in Systolic and Diastolic Blood Pressures (BP) at Week 24 |
-1.0; -1.1; -0.3; -0.5 | 0.849 |
| SECONDARY Change From Baseline in Systolic and Diastolic Blood Pressures (BP) at Week 52 |
-1.3; 0.3; -0.4; 0.4 | 0.183 |
| SECONDARY Number of Participants With Any Abnormal Holter Electrocardiogram (ECG) Finding at Week 24 |
180; 165 | — |
| SECONDARY Change From Baseline in Pulse Rate at Week 24 |
-0.5; -0.8 | 0.526 |
| SECONDARY Change From Baseline in Pulse Rate at Week 52 |
0.7; -1.9 | 0.007 sig |
| SECONDARY Change From Baseline in Basophils, Eosinophils, Monocytes, Neutrophils, Leukocytes, Lymphocytes, and Platelets at Week 24 |
-0.001; -0.001; 0.005; 0.005; -0.008; -0.015 | — |
| SECONDARY Change From Baseline in Basophils, Eosinophils, Monocytes, Neutrophils, Leukocytes, Lymphocytes, and Platelets at Week 52 |
0.002; 0.003; 0.011; 0.010; 0.002; -0.011 | — |
| SECONDARY Change From Baseline in Erythrocytes at Week 24 |
-0.02; -0.04; 0.06; 0.04 | — |
| SECONDARY Change From Baseline in Erythrocytes at Week 52 |
0.02; 0.00; 0.11; 0.07 | — |
| SECONDARY Change From Baseline in Hemoglobin at Week 24 |
-0.9; -1.0; 1.5; 1.5 | — |
| SECONDARY Change From Baseline in Hemoglobin at Week 52 |
-2.5; -2.5; 2.2; 1.9 | — |
| SECONDARY Change From Baseline in Hematocrit at Week 24 |
0.0024; 0.0024; 0.0115; 0.0123 | — |
| SECONDARY Change From Baseline in Hematocrit at Week 52 |
-0.0056; -0.0056; 0.0153; 0.0149 | — |
| SECONDARY Change From Baseline in Albumin and Protein at Week 24 |
-0.7; -0.5; 0.1; 0.2; -0.6; -1.0 | — |
| SECONDARY Change From Baseline in Albumin and Protein at Week 52 |
-0.8; -0.7; 0.4; 0.2; -1.1; -1.6 | — |
| SECONDARY Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Gamma Glutamyl Aminotransferase (GGT), Alkaline Phosphatase (ALP), and Creatine Kinase at Week 24 |
1.4; 3.8; 3.0; 5.5; 1.1; 4.0 | — |
| SECONDARY Change From Baseline in ALT, AST, GGT, ALP, and Creatine Kinase at Week 52 |
1.7; 1.3; 5.4; 4.5; 1.7; 0.8 | — |
| SECONDARY Change From Baseline in Glucose, Calcium, Carbon Dioxide (CO2), Chloride, Phosphate, Potassium, Sodium, and Urea at Week 24 |
-0.016; -0.014; 0.013; 0.012; -0.4; -0.7 | — |
| SECONDARY Change From Baseline in Glucose, Calcium, CO2, Chloride, Magnesium, Phosphate, Potassium, Sodium, and Urea at Week 52 |
-0.033; -0.040; 0.026; 0.008; -0.1; -0.2 | — |
| SECONDARY Change From Baseline in Bilirubin, Creatinine, and Urate at Week 24 |
-0.2; 0.1; 1.1; 1.2; 1.05; 1.14 | — |
| SECONDARY Change From Baseline in Bilirubin, Creatinine, and Urate at Week 52 |
0.3; 0.1; 2.0; 2.3; 2.95; 1.28 | — |
| SECONDARY Number of Participants Reporting an Adverse Event of Special Interest (AESI) of Oropharyngeal Origin in the Treatment Period |
2; 4; 1; 4; 2; 3 | — |
| SECONDARY Number of Participants Reporting an AESI of Oropharyngeal Origin in the Extension Part of the Study |
0; 3; 0; 2 | — |
| SECONDARY Number of Participants With at Least One On-treatment Bone Fracture Incident in the Treatment Period |
4; 6 | — |
| SECONDARY Number of Participants With at Least One On-treatment Bone Fracture Incident in the Extension Part of the Study |
0; 1 | — |
Eligibility Criteria
Inclusion Criteria
- Informed Consent: A signed and dated written informed consent prior to study participation.
- Type of subject: Outpatient.
- Age: Subjects 40 years of age or older at Screening (Visit 1).
- Gender: Male or female subjects. A female is eligible to enter and participate in the study if she is of: Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g. age appropriate, >45 years, in the absence of hormone replacement therapy. OR Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the following acceptable contraceptive methods used consistently and correctly (i.e. in accordance with the approved product label and the instructions of the physician for the duration of the study - screening to safety follow-up contact): Abstinence, Oral Contraceptive, either combined or progestogen alone, Injectable progestogen, Implants of levonorgestrel, Estrogenic vaginal ring, Percutaneous contraceptive patches, Intrauterine device (IUD) or intrauterine system (IUS), Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for that subject. For this definition, "documented" refers to the outcome of the investigator's/designee's medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records.; Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)
- COPD Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society.
- Smoking History: Current or former cigarette smokers with a history of cigarette smoking of >10 pack-years at Screening (Visit 1) [number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)]. Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Note: Pipe and/or cigar use cannot be used to calculate pack-year history.
- Severity of COPD symptoms: A score of >=10 on the COPD Assessment Test (CAT) at Screening (Visit 1).
- Severity of Disease: Subjects must demonstrate at Screening: =2 moderate exacerbations or one severe (hospitalized) exacerbation in the previous 12 months. Subjects must also have a measured post albuterol/salbutamol FEV1/FVC ratio of 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin 120 Beats Per Minute (BPM); sustained or non-sustained ventricular tachycardia (VT); Second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been inserted); QT interval corrected for heart rate by Fridericia's formula (QTcF) >=500 milliseconds (msec) in subjects with QRS =530 msec in subjects with QRS >=120 msec.
- Contraindications: A history of allergy or hypersensitivity to any corticosteroid, anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that, in the opinion of the Investigator, contraindicates study participation.
- Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years. Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be exc
Data sourced from ClinicalTrials.gov (NCT02345161) and the linked publication. Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.