A Study to Compare the Efficacy and Safety of Umeclidinium/Vilanterol and Fluticasone Propionate/Salmeterol in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive
Intervention: Umeclidinium/vilanterol; Fluticasone propionate/salmeterol; Placebo
Intervention description: Dry white powder delivered via NDPI (2 strips with 30 blisters each, first containing UMEC 62.5 mcg per blister and second containing VI 25 mcg per blister), administered as one inhalation of UMEC/VI 62.5/25 mcg once-daily in the morning; Dry white powder delivered via ACCUHALER/DISKUS (1 strip with 60 blisters, containing 250 mcg fluticasone propionate and 50 mcg salmeterol per blister), administered as one inhalation of FSC 250/50 mcg each morning and evening; Placebo will be administered via ACCUHALER/DISKUS or NDPI. Dry white powder administered as one inhalation each morning and evening via ACCUHALER/DISKUS (1 strip with 60 blisters containing placebo) OR once-daily in the morning via NDPI (2 strips with 30 blisters each, containing placebo)
Intervention MeSH terms: Fluticasone; Xhance; Salmeterol Xinafoate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 707.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: umeclidinium bromide (UMEC); vilanterol (VI); salmeterol (SAL); fluticasone propionate (FP); Novel Dry Powder Inhaler (NDPI); Chronic obstructive pulmonary disease; GW642444; GSK573719; lung function

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 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 250/50 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

          -  A signed and dated written informed consent prior to study participation

          -  Male or female subjects, 40 years of age or older at Visit 1

          -  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). - A female is eligible to enter
             and participate in the study if she is of: Child bearing potential, has a negative
             pregnancy test at screening, and agrees to one of the following acceptable
             contraceptive methods as listed in the protocol used consistently and correctly.

          -  An 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 use cannot be used to calculate
             pack year history

          -  Severity of disease: A pre and post-salbutamol FEV1/Forced Vital Capacity (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:

          -  Women who are pregnant or lactating or are planning on becoming pregnant during the
             study

          -  A current diagnosis of asthma

          -  Other Respiratory Disorders: Known α-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 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, 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