A Study to Compare the Efficacy and Safety of Umeclidinium/Vilanterol With Fluticasone Propionate/Salmeterol in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

DB2114951: A Randomized, Multi-center, Double-blind, Double-dummy, Parallel Group Study to Evaluate the Efficacy Umeclidinium/Vilanterol Compared With Fluticasone Propionate/Salmeterol Over 12 Weeks in Subjects With COPD

Umeclidinium/vilanterol (UMEC/VI) is a combination product under development that is used for the treatment of airflow obstruction in patients with COPD. Fluticasone propionate/salmeterol (FSC) is an approved drug that is already in use for the treatment of COPD. This is a multicenter, randomized, double-blind, double-dummy, parallel group study to evaluate the efficacy and safety of UMEC/VI 62.5/25 microgram [mcg] once daily administered via Novel Dry Powder Inhaler (NDPI) compared with fluticasone propionate /salmeterol (FSC) 250/50 mcg twice-daily when administered via ACCUHALER/DISKUS inhaler over a treatment period of 12 weeks in subjects with COPD. Eligible subjects will be equally randomized to UMEC/VI 62.5/25 mcg or FSC 250/50 mcg for 12 weeks. A safety follow-up assessment will be conducted approximately 7 days after the end of the study treatment.

Study Overview

• Status: Completed
• Conditions: Pulmonary Disease, Chronic Obstructive
• Intervention / Treatment: Drug: UMEC/VI Inhalation Powder 62.5/25 mcg via NDPI; Drug: Placebo DISKUS; Drug: FSC Inhalation Powder 250/50 mcg via ACCUHALER/DISKUS; Drug: Placebo NDPI

• Study Type: Interventional
• Enrollment (Actual): 700
• Phase: Phase 3

Contacts and Locations

Study Locations

• Chile
  • Talcahuano, Chile, 4270918
    • GSK Investigational Site
  • Región De La Araucania
    • Temuco, Región De La Araucania, Chile
      • GSK Investigational Site
  • Región Del Biobio
    • Concepción, Región Del Biobio, Chile, 4070038
      • GSK Investigational Site
  • Región Metro De Santiago
    • Puente Alto - Santiago, Región Metro De Santiago, Chile, 8207257
      • GSK Investigational Site
    • Santiago, Región Metro De Santiago, Chile, 7500551
      • GSK Investigational Site
    • Santiago, Región Metro De Santiago, Chile, 7500710
      • GSK Investigational Site
    • Santiago, Región Metro De Santiago, Chile, 8880465
      • GSK Investigational Site
    • Talca, Región Metro De Santiago, Chile, 3460001
      • GSK Investigational Site
• Mexico
  • México DF, Mexico, 14050
    • GSK Investigational Site
  • Oaxaca, Mexico, 68000
    • GSK Investigational Site
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44100
      • GSK Investigational Site
  • Nuevo León
    • Monterrey, Nuevo León, Mexico, 64020
      • GSK Investigational Site
    • Monterrey, Nuevo León, Mexico, 64000
      • GSK Investigational Site
• Norway
  • Bergen, Norway, N-5021
    • GSK Investigational Site
  • Bodø, Norway, 8005
    • GSK Investigational Site
  • Hamar, Norway, 2317
    • GSK Investigational Site
  • Kløfta, Norway, 2040
    • GSK Investigational Site
  • Stavanger, Norway, 4005
    • GSK Investigational Site
  • Trondheim, Norway, 7030
    • GSK Investigational Site
• Romania
  • Braila, Romania, 810003
    • GSK Investigational Site
  • Bucharest, Romania, 030317
    • GSK Investigational Site
  • Bucuresti, Romania, 010457
    • GSK Investigational Site
  • Cluj Napoca, Romania, 400371
    • GSK Investigational Site
  • Comuna Alexandru cel Bun, Romania, 617507
    • GSK Investigational Site
  • Constanta, Romania, 900002
    • GSK Investigational Site
  • Craiova, Romania, 200515
    • GSK Investigational Site
  • Focsani, Romania, 620043
    • GSK Investigational Site
• Russian Federation
  • Arkhangelsk, Russian Federation, 153000
    • GSK Investigational Site
  • Barnaul, Russian Federation, 656 045
    • GSK Investigational Site
  • Chelyabinsk, Russian Federation, 454091
    • GSK Investigational Site
  • Chita, Russian Federation, 672000
    • GSK Investigational Site
  • Ekaterinburg, Russian Federation, 620039
    • GSK Investigational Site
  • Ekaterinburg, Russian Federation, 620109
    • GSK Investigational Site
  • Ivanovo, Russian Federation, 153005
    • GSK Investigational Site
  • Izhevsk, Russian Federation, 426063
    • GSK Investigational Site
  • Moscow, Russian Federation, 105229
    • GSK Investigational Site
  • Omsk, Russian Federation, 644112
    • GSK Investigational Site
  • Saratov, Russian Federation, 410053
    • GSK Investigational Site
  • Smolensk, Russian Federation, 214 019
    • GSK Investigational Site
  • St. Petersburg, Russian Federation, 194356
    • GSK Investigational Site
  • St. Petersburg, Russian Federation, 198216
    • GSK Investigational Site
  • Tomsk, Russian Federation, 634 050
    • GSK Investigational Site
  • Ulyanovsk, Russian Federation, 432063
    • GSK Investigational Site
  • Vladimir, Russian Federation, 600023
    • GSK Investigational Site
  • Vladivostok, Russian Federation, 690950
    • GSK Investigational Site
  • Voronezh, Russian Federation, 394066
    • GSK Investigational Site
  • Yaroslavl, Russian Federation, 150003
    • GSK Investigational Site
  • Yaroslavl, Russian Federation, 150010
    • GSK Investigational Site
  • Yaroslavl, Russian Federation, 150002
    • GSK Investigational Site
• South Africa
  • Bloemfontein, South Africa, 9301
    • GSK Investigational Site
  • Die Wilgers, South Africa, 0041
    • GSK Investigational Site
  • Durban, South Africa, 4001
    • GSK Investigational Site
  • Gatesville, South Africa, 7764
    • GSK Investigational Site
  • Mowbray, South Africa, 7700
    • GSK Investigational Site
  • Reiger Park, South Africa, 1459
    • GSK Investigational Site
  • Somerset West, South Africa, 7130
    • GSK Investigational Site
  • Gauteng
    • Meyerspark, Gauteng, South Africa, 0184
      • GSK Investigational Site
• United States
  • Arizona
    • Tucson, Arizona, United States, 85723
      • GSK Investigational Site
  • California
    • Newport Beach, California, United States, 92663
      • GSK Investigational Site
    • Riverside, California, United States, 92506
      • GSK Investigational Site
  • Florida
    • DeLand, Florida, United States, 32720
      • GSK Investigational Site
  • Idaho
    • Coeur d'Alene, Idaho, United States, 83814
      • GSK Investigational Site
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • GSK Investigational Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • GSK Investigational Site
  • Oregon
    • Medford, Oregon, United States, 97504
      • GSK Investigational Site
  • South Carolina
    • Charleston, South Carolina, United States, 29406-7108
      • GSK Investigational Site
    • Easley, South Carolina, United States, 29640
      • GSK Investigational Site
    • Greenville, South Carolina, United States, 29615
      • GSK Investigational Site
    • Seneca, South Carolina, United States, 29678
      • GSK Investigational Site
    • Union, South Carolina, United States, 29379
      • GSK Investigational Site
  • Virginia
    • Newport News, Virginia, United States, 23606
      • GSK Investigational Site
  • Washington
    • Renton, Washington, United States, 98055
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Type of subject: Outpatient
• Informed Consent: A signed and dated written informed consent prior to study participation.
• Age: Subjects 40 years of age or older at 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). Or if of child bearing potential, has a negative pregnancy test at screening, and agrees to one of the acceptable contraceptive methods mentioned in the protocol used consistently and correctly:
• Diagnosis: An established clinical history of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society as follows: COPD is a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences.
• Smoking history: Current or former cigarette smokers with a history of cigarette smoking of >=10 pack-years [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. Pipe and/or cigar use cannot be used to calculate pack year history.
• Severity of disease: A pre and post-salbutamol FEV1/FVC ratio of <0.70 and a post-salbutamol FEV1 of >=30% and <=70% of predicted normal values calculated using National Health and Nutrition Examination Survey (NHANES) III reference equations at Visit 1.
• Dyspnea: A score of >=2 on the Modified Medical Research Council Dyspnea Scale (mMRC) at Visit 1.

Exclusion Criteria:

• Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.
• Asthma: A current diagnosis of asthma.
• Other Respiratory Disorders: Known alpha-1 antitrypsin deficiency, active lung infections (such as tuberculosis), and lung cancer are absolute exclusionary conditions. A subject, who, in the opinion of the investigator, has any other significant respiratory condition in addition to COPD should be excluded. Examples may include clinically significant bronchiectasis, pulmonary hypertension, sarcoidosis, or interstitial lung disease. Inactive tuberculosis in more than one lobe is exclusionary. Allergic rhinitis is not exclusionary.
• Other Diseases/Abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled and/or a previous history of cancer in remission for <5 years prior to Visit 1 (localized carcinoma of the skin that has been resected for cure is not exclusionary). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study.
• Contraindications: A history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, corticosteroid, 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 study physician contraindicates study participation or use of an inhaled anticholinergic.
• Hospitalization: Hospitalization for pneumonia within 12 weeks prior to Visit 1.
• History of COPD Exacerbation: A documented history of at least one COPD exacerbation in the 12 months prior to Visit 1 that required either oral corticosteroids, antibiotics, and/or hospitalization. Prior use of antibiotics alone does not qualify as an exacerbation history unless the use was associated with treatment of worsening symptoms of COPD, such as increased dyspnea, sputum volume, or sputum purulence.
• Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1).
• 12-Lead electrocardiogram (ECG): An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1. Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility.
• Medication Prior to Spirometry: Unable to withhold salbutamol for the 4 hour period required prior to spirometry testing at each study visit.
• Medications Prior to Screening: Use of the following medications according to the following defined time intervals prior to Visit 1: Depot corticosteroids - 12 weeks, Systemic, oral or parenteral corticosteroids - 6 weeks, Antibiotics (for lower respiratory tract infection) - 6 weeks, Cytochrome P450 3A4 strong inhibitors - 6 weeks, Herbal medications potentially containing oral or systemic steroids - 6 weeks, Inhaled corticosteroids (ICS) - 30 days, Long-acting beta2-agonist (LABA)/ICS combination products - 30 days, Phosphodiesterase 4 (PDE4) inhibitors (e.g., roflumilast) - 14 days, Inhaled long-acting anticholinergics - 7 days, Olodaterol and Indacaterol - 10days, Theophyllines - 48 hours, Oral leukotriene inhibitors (zafirlukast, montelukast, zileuton) - 48 hours, Oral beta2-agonists Long-acting-48 hours/Short-acting - 12 hours, Inhaled long acting beta2-agonists (LABA, e.g., salmeterol, formoterol, indacaterol) - 48 hours, Inhaled sodium cromoglycate or nedocromil sodium - 24 hours, Inhaled short acting beta2-agonists - 4 hours, Inhaled short-acting anticholinergics - 4 hours, Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products - 4 hours, Any other investigational medication - 30 days or within 5 drug half-lives (whichever is longer).
• Oxygen: Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed for greater than 12 hours a day. As-needed oxygen use (i.e., <=12 hours per day) is not ex-clusionary.
• Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (e.g., salbutamol) via nebulized therapy.
• Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.
• Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1.
• Affiliation with Investigator Site: A subject will not be eligible for this study if he/she is an immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator.
• Inability to read: A subject will not be eligible for the study if in the opinion of the investigator the subject cannot read.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: UMEC/ VI via NDPI + placebo ACCUHALER/DISKUS arm; Subjects will receive one inhalation of UMEC/VI 62.5/25 mcg once-daily in the morning via the NDPI and one inhalation of placebo in the morning and evening via ACCUHALER/DISKUS inhaler	Drug: UMEC/VI Inhalation Powder 62.5/25 mcg via NDPI; The drug is administered via NDPI as one inhalation once daily in the morning. NDPI has two strips, each containing 30 blisters of medication. The first strip has UMEC blended with lactose and magnesium stearate in the form of dry white powder with a dosage of 62.5 mcg per blister and the second strip has VI blended with lactose and magnesium stearate in the form of dry white powder with a dosage of 25 mcg per blister.; Drug: Placebo DISKUS; Placebo is administered via ACCUHALER/DISKUS inhaler as one inhalation each morning and evening. The inhaler contains 1 strip with 60 blisters of placebo in the form of dry white powder.
ACTIVE_COMPARATOR: FSC via ACCUHALER/DISKUS + placebo NDPI arm; Subjects will receive one inhalation of FSC 250/50 mcg in the morning and evening via ACCUHALER/DISKUS inhaler and one inhalation of placebo administered once-daily in the morning via NDPI	Drug: FSC Inhalation Powder 250/50 mcg via ACCUHALER/DISKUS; The drug is administered via ACCUHALER/DISKUS inhaler as one inhalation each morning and evening. The inhaler contains a single strip with 60 blisters of medication. The strip has 250 mcg of fluticasone propionate and 50 mcg of salmeterol per blister in the form of dry white powder.; Drug: Placebo NDPI; Placebo is administered via NDPI as one inhalation once daily in the morning. The inhaler contains 2 strips with 30 blisters of placebo per strip in the form of dry white powder.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline (BL) in 0 to 24 Hour Weighted Mean Forced Expiratory Volume Over 1 Second (FEV1) at Day 84	FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The weighted mean was calculated from the pre-dose FEV1 and post-dose FEV1 measurements at 5 and 15 minutes and 1, 3, 6, 9, 12 hours (pre-evening dose), 13, 15, 18, 23, and 24 hours after the morning dose. Baseline is defined as the mean of the assessments made 30 and 5 minutes (min) pre-dose on treatment Day 1. Analysis was performed using an analysis of covariance model with covariates of baseline FEV1 (mean of the two assessments made 30 mins and 5 mins pre-dose on Day 1), smoking status, and treatment. Change from baseline was calculated as the value at Day 84 minus the value at Baseline.	Baseline and Day 84

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline(BL) in Trough Forced Expiratory Volume in One Second (FEV1) at Day 85	FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Baseline is defined as the mean of the assessments made 30 and 5 minutes (min) pre-dose on treatment Day 1. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained 23 and 24 hours after morning dosing on Day 84. Analysis was performed using a repeated measures model with covariates of treatment, Baseline (mean of the 2 assessments made 30 min and 5 min pre-dose on Day 1), smoking status, day, day by baseline and day by treatment interactions. The model used all available trough FEV1 values recorded on Days 28, 56, 84, and 85. Missing data were not directly imputed in this analysis; however, all non-missing data for a participant were used within the analysis to estimate the treatment effect for trough FEV1 at Day 85. Change from baseline was calculated as the value at Day 84 minus the value at Baseline.	Baseline and Day 85

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Donohue JF, Worsley S, Zhu CQ, Hardaker L, Church A. Improvements in lung function with umeclidinium/vilanterol versus fluticasone propionate/salmeterol in patients with moderate-to-severe COPD and infrequent exacerbations. Respir Med. 2015 Jul;109(7):870-81. doi: 10.1016/j.rmed.2015.04.018. Epub 2015 May 8.

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 13, 2013
• Primary Completion (ACTUAL): January 1, 2014
• Study Completion (ACTUAL): January 9, 2014

Study Registration Dates

• First Submitted: June 13, 2013
• First Submitted That Met QC Criteria: June 13, 2013
• First Posted (ESTIMATE): June 17, 2013

Study Record Updates

• Last Update Posted (ACTUAL): November 8, 2017
• Last Update Submitted That Met QC Criteria: October 9, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: lung function; Chronic obstructive pulmonary disease; GSK573719; GW642444; Novel Dry Powder Inhaler (NDPI); umeclidinium bromide (UMEC); vilanterol (VI); salmeterol (SAL); fluticasone propionate (FP)
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: 114951

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. Individual Participant Data Set
   Information identifier: 114951
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Statistical Analysis Plan
   Information identifier: 114951
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Clinical Study Report
   Information identifier: 114951
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Study Protocol
   Information identifier: 114951
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Dataset Specification
   Information identifier: 114951
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Informed Consent Form
   Information identifier: 114951
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Annotated Case Report Form
   Information identifier: 114951
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register