A Study to Evaluate the Efficacy and Safety of Umeclidinium Bromide/Vilanterol Compared With Fluticasone Propionate/Salmeterol Over 12 Weeks in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive
Intervention: Umeclidinium bromide/Vilanterol; Placebo ACCUHALER/DISKUS; Fluticasone propionate/Salmeterol; Placebo NDPI
Intervention description: Dry white powder of UMEC 62.5 mcg per blister and VI 25 mcg per blister as NDPI with 30 doses (2 strips with 30 blisters per strip).; Dry white powder of matching placebo as multidose dry powder inhaler containing a foil strip with 60 blisters (1 strip with 60 blisters per strip).; Dry white powder of fluticasone propionate 500 mcg per blister 50 mcg salmeterol per blister as multidose dry powder inhaler containing a foil strip with 60 blisters (1 strip with 60 blisters per strip).; Dry white powder of matching placebo as NDPI with 30 doses (2 strips with 30 blisters per strip).
Intervention MeSH terms: Fluticasone; Xhance; Bromides; Salmeterol Xinafoate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 717.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: Novel Dry Powder Inhaler (NDPI); umeclidinium bromide (UMEC); GSK573719; lung function; GW642444; salmeterol (SAL); fluticasone propionate (FP); vilanterol (VI); Chronic obstructive pulmonary disease

Summary:

      This is a multicenter, randomized, double-blind, double-dummy, parallel group study. The
      purpose of this study is to compare the efficacy and safety of umeclidinium/vilanterol
      (UMEC/VI) and fluticasone propionate/salmeterol (FSC) in subjects with Chronic Obstructive
      Pulmonary Disease (COPD). Subjects who meet the eligibility criteria at Screening will
      complete a 7 to 14 day Run-in period. At the end of the run-in period, approximately 710
      eligible subjects will be equally randomized (to complete at least 568 evaluable subjects) to
      one of the 2 treatment groups for 12 weeks: 1. UMEC/VI 62.5/25 micrograms (mcg) administered
      as one inhalation once-daily in the morning via the Novel dry powder inhaler (NDPI) + placebo
      administered as one inhalation each morning and evening via single multidose powdered inhaler
      (ACCUHALER/DISKUS) or 2. FSC 500/50 mcg administered as one inhalation each morning and
      evening via ACCUHALER/DISKUS + placebo administered once-daily in the morning via NDPI. A
      safety Follow-up assessment will be conducted approximately 7 days after the end of the study
      treatment (Early Withdrawal, if applicable). The total duration of subject participation will
      be approximately 15 weeks.
    

Eligibility criteria:

        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 Child bearing potential, has a negative pregnancy test at screening, and agrees to
             one of the acceptable contraceptive methods listed in the protocol used consistently
             and correctly

          -  Diagnosis: established clinical history of COPD in accordance with the definition by
             the American Thoracic Society/European Respiratory Society as follows: Chronic
             obstructive pulmonary disease 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 smoking 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
             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 ECG: An abnormal and significant electrocardiogram (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, 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 exclusionary.

          -  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.