A Study to Compare the Impact of Fulticasone Furoate/Vilanterol vs. Tiotropium on Arterial Stiffness in COPD

A 12 Week Study to Evaluate the Effect of Fluticasone Furoate (FF, GW685698)/Vilanterol (VI, GW642444) 100/25 mcg Inhalation Powder Delivered Once Daily Via a Novel Dry Powder Inhaler (NDPI) on Arterial Stiffness Compared With Tiotropium Bromide 18 mcg Delivered Once Daily Via a HandiHaler in Subjects With Chronic Obstructive Pulmonary Disease (COPD).

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) 100/25 mcg Novel Dry Powder Inhaler (NDPI); Drug: Tiotropium

Detailed Description

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:

• FF (100 mcg)/VI (25 mcg) administered QD via a NDPI in the morning
• Tiotropium (18 mcg) administered QD via a HandiHaler in the morning

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:

• Each morning take 1 inhalation from NDPI containing FF (100 mcg)/VI (25 mcg) followed by 1 inhalation from placebo capsule delivered via HandiHaler.
• Each morning take 1 inhalation from matching placebo NDPI followed by 1 inhalation from a capsule containing tiotropium 18 mcg delivered via HandiHaler.

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).

• Study Type: Interventional
• Enrollment (Actual): 260
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1424BSF
    • GSK Investigational Site
  • Buenos Aires, Argentina, C1425BEN
    • GSK Investigational Site
  • Ciudad Autónoma de Buenos Aires, Argentina, C1426ABP
    • GSK Investigational Site
  • Mendoza, Argentina, M5500CCG
    • GSK Investigational Site
  • Mendoza, Argentina, 5500
    • GSK Investigational Site
  • San Juan, Argentina, 5400
    • GSK Investigational Site
  • Tucuman, Argentina, 4000
    • GSK Investigational Site
  • Tucumán, Argentina, T4000DGF
    • GSK Investigational Site
  • Buenos Aires
    • Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina, C1056ABJ
      • GSK Investigational Site
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000JKR
      • GSK Investigational Site
• France
  • Bethune Cedex, France, 62408
    • GSK Investigational Site
  • Grenoble Cedex 09, France, 38043
    • GSK Investigational Site
  • Lille, France, 59000
    • GSK Investigational Site
  • Montpellier cedex 5, France, 34295
    • GSK Investigational Site
  • Reims Cedex, France, 51092
    • GSK Investigational Site
  • Saint-Michel, France, 16470
    • GSK Investigational Site
• Germany
  • Berlin, Germany, 13125
    • GSK Investigational Site
  • Berlin, Germany, 10787
    • GSK Investigational Site
  • Berlin, Germany, 10789
    • GSK Investigational Site
  • Hamburg, Germany, 20354
    • GSK Investigational Site
  • Hessen
    • Immenhausen, Hessen, Germany, 34376
      • GSK Investigational Site
  • Mecklenburg-Vorpommern
    • Schwerin, Mecklenburg-Vorpommern, Germany, 19055
      • GSK Investigational Site
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30159
      • GSK Investigational Site
  • Nordrhein-Westfalen
    • Goch, Nordrhein-Westfalen, Germany, 47574
      • GSK Investigational Site
  • Sachsen-Anhalt
    • Magdeburg, Sachsen-Anhalt, Germany, 39112
      • GSK Investigational Site
  • Schleswig-Holstein
    • Geesthacht, Schleswig-Holstein, Germany, 21502
      • GSK Investigational Site
• Italy
  • Campania
    • Eboli (SA), Campania, Italy, 84025
      • GSK Investigational Site
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40138
      • GSK Investigational Site
  • Lombardia
    • Crema, Lombardia, Italy, 26013
      • GSK Investigational Site
    • Pavia, Lombardia, Italy, 27100
      • GSK Investigational Site
  • Puglia
    • Cassano Murge (BA), Puglia, Italy, 70020
      • GSK Investigational Site
• Norway
  • Bergen, Norway, N-5021
    • GSK Investigational Site
  • Bergen, Norway, 5017
    • GSK Investigational Site
  • Drammen, Norway, 3004
    • GSK Investigational Site
  • Fredrikstad, Norway, 1606
    • GSK Investigational Site
  • Skedsmokorset, Norway, N-2020
    • GSK Investigational Site
• Russian Federation
  • Chita, Russian Federation, 672000
    • GSK Investigational Site
  • Kemerovo, Russian Federation, 650002
    • GSK Investigational Site
  • Kokhma, Russian Federation, 153511
    • GSK Investigational Site
  • Moscow, Russian Federation, 105077
    • GSK Investigational Site
  • Moscow, Russian Federation, 115093
    • GSK Investigational Site
  • Penza, Russian Federation, 440067
    • GSK Investigational Site
  • Saratov, Russian Federation, 410053
    • GSK Investigational Site
  • St. Petersburg, Russian Federation, 197022
    • GSK Investigational Site
  • Vladivostok, Primorskiy Kray, Russian Federation, 690022
    • GSK Investigational Site
  • Voronezh, Russian Federation, 394018
    • GSK Investigational Site
  • Yaroslavl, Russian Federation, 150003
    • GSK Investigational Site
  • Yaroslavl, Russian Federation, 150062
    • GSK Investigational Site
• Ukraine
  • Cherkassy, Ukraine, 18009
    • GSK Investigational Site
  • Donetsk, Ukraine, 83099
    • GSK Investigational Site
  • Kharkiv, Ukraine, 61035
    • GSK Investigational Site
  • Kiev, Ukraine, 03680
    • GSK Investigational Site
  • Kyiv, Ukraine, 03038
    • GSK Investigational Site
  • Kyiv, Ukraine, 03049
    • GSK Investigational Site
  • Yalta, Ukraine, 98603
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Type of subject: Outpatient
• Informed consent: Subjects must give their signed and dated written informed consent to participate.
• Gender: Male or female subjects.
• Age: greater then or equal to 40 years of age at Screening (Visit 1)
• COPD diagnosis: Subjects with a clinical history of COPD in accordance with the following definition by the American Thoracic Society (ATS) /European Respiratory Society(ERS).
• Subjects with a current or prior history ofgreater then or equal to 10 pack-years of cigarette smoking at Screening (Visit 1).
• Subjects with a measured post-albuterol/salbutamol FEV1 less then 70% of predicted at Screening (Visit 1).
• Subjects with a measured post-albuterol/salbutamol FEV1/FVC ratio of less then or equal to 0.70 at Screening (Visit 1).
• Exacerbation History: Subjects who have been hospitalised or have been treated with oral corticosteroids or antibiotics for their COPD within the last 3 years prior to Screening (V1).
• Baseline aPWV: subjects with a measured aPWV greater then 12.0 m/s at Screening (Visit 1).

Exclusion Criteria:

• Body Mass Index of less then or equal to 35

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Relovair; Inhaled long-acting bronchodilator and corticosteroid combination	Drug: fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) 100/25 mcg Novel Dry Powder Inhaler (NDPI); fluticasone furoate (FF, GW685698)/vilanterol (VI, GW642444) 100/25 mcg Inhalation Powder delivered once daily via a Novel Dry Powder Inhaler (NDPI)
Active Comparator: Tiotropium; Inhaled long-acting anticholinergic	Drug: Tiotropium; • Tiotropium (18 mcg) administered QD via a HandiHaler

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline to Day 84 (Early Withdrawal)

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Pepin JL, Cockcroft JR, Midwinter D, Sharma S, Rubin DB, Andreas S. Long-acting bronchodilators and arterial stiffness in patients with COPD: a comparison of fluticasone furoate/vilanterol with tiotropium. Chest. 2014 Dec;146(6):1521-1530. doi: 10.1378/chest.13-2859.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start: June 30, 2011
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): August 6, 2012

Study Registration Dates

• First Submitted: July 14, 2011
• First Submitted That Met QC Criteria: July 14, 2011
• First Posted (Estimate): July 18, 2011

Study Record Updates

• Last Update Posted (Actual): February 15, 2018
• Last Update Submitted That Met QC Criteria: January 18, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Anti-Inflammatory Agents; Dermatologic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Anti-Allergic Agents; Fluticasone; Xhance; Tiotropium Bromide
• Other Study ID Numbers: 115247

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Dataset Specification
   Information identifier: 115247
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Study Protocol
   Information identifier: 115247
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Informed Consent Form
   Information identifier: 115247
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Annotated Case Report Form
   Information identifier: 115247
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Clinical Study Report
   Information identifier: 115247
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Statistical Analysis Plan
   Information identifier: 115247
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Individual Participant Data Set
   Information identifier: 115247
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register