A Phase 3 interventional study of fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) 100/25 mcg Novel Dry Powder Inhaler (NDPI) and Tiotropium in Pulmonary Disease, Chronic Obstructive, sponsored by GlaxoSmithKline. Completed at 55 sites in 7 countries. Open to participants aged 40 Years to 80 Years. Per ClinicalTrials.gov, last updated 2018-02-15.
Sponsored by GlaxoSmithKline · Phase 3, Interventional, and Treatment
This study is designed to evaluate the effect of fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) Inhalation Powder once daily (QD) on arterial stiffness compared with Tiotropium QD over 12 week treatment period in subjects with COPD and aortic pulse wave velocity (aPWV) > 12.0 m/s at Visit 1. Arterial stiffness will be measured as aPWV. This is a comparator, randomised, double-blind, double-dummy, parallel group, multi-centre study. Subjects who meet the eligibility criteria at Screening and meet the randomization criteria at the end of a 2-week Run-In period will enter a 12-week treatment period. There will be an approximate 7-day Follow-up period after the treatment period.
This is a Phase IIIb comparator, double-blind, double-dummy, randomised (1:1), parallel group, multi-centre study. At Visit 1 (Screening Visit), subjects who meet the pre-defined Inclusion Criteria and none of the Exclusion Criteria will enter a 2-week, single-blind placebo Run-in Period. The purpose of the Run-In Period is to monitor albuterol/salbutamol use at baseline, and to ensure that subjects' COPD is at a stable stage at randomization. Subject's adherence with study procedures, diary completion will also be evaluated during the Run-In Period. At the end of the Run-in period, subjects will be assessed and those who meet the randomisation criteria will receive one of the following two double-blind treatments for 12 weeks:
To ensure blinding of the treatments and to ensure a double-dummy design matching NDPI and HandiHaler will be utilised. Each subject will be instructed to self administer blinded study drug during the double blind treatment period as follows:
An inhaled short acting beta2-receptor agonist, salbutamol/albuterol will be provided to subjects to use as needed throughout the Run-in and Treatment periods for relief of COPD symptoms. Ipratropium bromide is permitted if the subject is on a stable dose from Screening (Visit 1) and remains on the stable dose throughout the study. Subjects who experience an exacerbation of their COPD (which requires medication in addition to an increase in rescue medication) or a lower respiratory tract infection (LRTI) during the run-in period are not eligible to enter the treatment period. Any subject who experiences a similar COPD exacerbation (sec 4.4) or LRTI at any time on therapy will be withdrawn from the study. The aPWV will be measured at Screening and clinic Visits 3-5. Disease specific health status will be evaluated using the St. George's Respiratory Questionnaire (SGRQ-C), Euro Qol Questionnaire (EQ-5D) for COPD patients and the COPD Assessment Test (CAT) at Visit 2 (Day 1) and at Visit 5 (Weeks 12). The 12-lead ECG will be evaluated at Visit 1 (Screening) only. Vital signs (blood pressure and pulse rate), spirometry measurements, and clinical laboratory tests (hematology and chemistry) and other study-specific safety assessments will be obtained at selected clinic visits. A follow-up phone call will occur approximately 7 days after the last clinic visit. The overall study duration from Screening to Follow-up for each subject is approximately 15 weeks. Subjects will be considered to have completed the study upon completion of assessments and procedures up to and including completion of Follow-up Phone Contact (7 ± 2 days post Visit 5).
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Exclusion Criteria:
Inhaled long-acting bronchodilator and corticosteroid combination
Drug: fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) 100/25 mcg Novel Dry Powder Inhaler (NDPI)
Inhaled long-acting anticholinergic
Drug: Tiotropium
fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) 100/25 mcg Inhalation Powder delivered once daily via a Novel Dry Powder Inhaler (NDPI)
• Tiotropium (18 mcg) administered QD via a HandiHaler
Mean Change From Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the End of the 12-week Treatment Period (Day 84)
PWV is defined as the speed of travel of the pressure pulse along an arterial segment and can be obtained for any arterial segment accessible to palpation. aPWV is measured with tonometers positioned transcutaneously at the base of the common carotid artery and over the femoral artery. PWV increases with arterial stiffness and is defined by the Moens-Korteweg equation: PWV=square root of Eh/2pR, where E is Young's modulus of the arterial wall, h is the wall thickness, R is the arterial radius at the end of diastole, and p is the blood density. Change from Baseline was calculated as the Day 84 value minus the Baseline value. The analysis was performed using a repeated measures model with covariates of treatment, visit, age, gender, smoking status at screening, geographical region, Baseline aPWV, and interaction terms of Baseline by visit and treatment by visit.
Time frame: Baseline to Day 84 (Early Withdrawal)
A total of 260 participants were randomized. Three of these participants were randomized in error (they were determined not to have met entry criteria and were classified as run-in/screen failures); thus, they did not receive investigational product and are not captured in the Treatment Period table of the Participant Flow module.
| Milestone | Salb/Alb + IBr | FF/VI 100/25 µg | Tiotropium Bromide 18 µg |
|---|---|---|---|
| Started | 279 | 0 | 0 |
| Completed | 257 | 0 | 0 |
| Not completed | 22 | 0 | 0 |
| Withdrew: Adverse event | 2 | 0 | 0 |
| Withdrew: Continuation criteria not met | 13 | 0 | 0 |
| Withdrew: Lost to follow-up | 1 | 0 | 0 |
| Withdrew: Protocol violation | 2 | 0 | 0 |
| Withdrew: Withdrawal by subject | 4 | 0 | 0 |
| Milestone | Salb/Alb + IBr | FF/VI 100/25 µg | Tiotropium Bromide 18 µg |
|---|---|---|---|
| Started | 0 | 127 | 130 |
| Completed the treatment period | 0 | 112 | 113 |
| Completed | 0 | 112 | 113 |
| Not completed | 0 | 15 | 17 |
| Withdrew: Adverse event | 0 | 7 | 6 |
| Withdrew: Lack of efficacy | 0 | 4 | 3 |
| Withdrew: Protocol violation | 0 | 1 | 5 |
| Withdrew: Met protocol-defined stopping criteria | 0 | 1 | 0 |
| Withdrew: Withdrawal by subject | 0 | 2 | 3 |
PWV is defined as the speed of travel of the pressure pulse along an arterial segment and can be obtained for any arterial segment accessible to palpation. aPWV is measured with tonometers positioned transcutaneously at the base of the common carotid artery and over the femoral artery. PWV increases with arterial stiffness and is defined by the Moens-Korteweg equation: PWV=square root of Eh/2pR, where E is Young's modulus of the arterial wall, h is the wall thickness, R is the arterial radius at the end of diastole, and p is the blood density. Change from Baseline was calculated as the Day 84 value minus the Baseline value. The analysis was performed using a repeated measures model with covariates of treatment, visit, age, gender, smoking status at screening, geographical region, Baseline aPWV, and interaction terms of Baseline by visit and treatment by visit.
| meters per second (m/sec) | FF/VI 100/25 µg | Tiotropium Bromide 18 µg |
|---|---|---|
| Mean Change From Baseline (BL) in Aortic Pulse Wave Velocity (aPWV) at the End of the 12-week Treatment Period (Day 84) | -0.859 ± 0.2590 | -1.118 ± 0.2620 |
Non-serious events are listed at a 3% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| FF/VI 100/25 µg | — | 7/127 (5.5%) | 8/127 (6.3%) |
| Tiotropium Bromide 18 µg | — | 8/130 (6.2%) | 8/130 (6.2%) |
| Event | FF/VI 100/25 µg | Tiotropium Bromide 18 µg |
|---|---|---|
| Chronic obstructive pulmonary diseaseRespiratory, thoracic and mediastinal disorders | 2/127 | 5/130 |
| PneumoniaInfections and infestations | 2/127 | 0/130 |
| Acute abdomenGastrointestinal disorders | 1/127 | 0/130 |
| PancreatolithiasisGastrointestinal disorders | 1/127 | 0/130 |
| PyrexiaGeneral disorders | 1/127 | 0/130 |
| Bile duct obstructionHepatobiliary disorders | 1/127 | 0/130 |
| Bronchial carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/127 | 0/130 |
| Altered state of consciousnessNervous system disorders | 1/127 | 0/130 |
| Pulmonary embolismRespiratory, thoracic and mediastinal disorders | 0/127 | 1/130 |
| Peritonsillar abscessInfections and infestations | 0/127 | 1/130 |
| Event | FF/VI 100/25 µg | Tiotropium Bromide 18 µg |
|---|---|---|
| NasopharyngitisInfections and infestations | 5/127 | 4/130 |
| HeadacheNervous system disorders | 3/127 | 5/130 |
| Age, Continuous(Years) | FF/VI 100/25 µg | Tiotropium Bromide 18 µg | Total |
|---|---|---|---|
| Mean | 66.7 ± 7.20 | 67.7 ± 7.34 | 67.3 ± 7.28 |
| Sex: Female, Male(Participants) | FF/VI 100/25 µg | Tiotropium Bromide 18 µg | Total |
|---|---|---|---|
| Female | 19 | 18 | 37 |
| Male | 108 | 112 | 220 |
| Race/Ethnicity, Customized(participants) | FF/VI 100/25 µg | Tiotropium Bromide 18 µg | Total |
|---|---|---|---|
| White - White/Caucasian/European | 127 | 130 | 257 |
Plan to share: Yes — Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
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