A 24-week Study to Compare Umeclidinium/Vilanterol (UMEC/VI), UMEC and Salmeterol in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: UMEC/VI 62.5/25 mcg via ELLIPTA; UMEC 62.5 mcg via ELLIPTA; Salmeterol 50 mcg via DISKUS; Placebo via ELLIPTA; Placebo via DISKUS
Intervention description: ELLIPTA DPI inhaler will contain two individual blister strips with 30 blisters per strip; the first strip contains umeclidinium bromide (62.5 mcg per blister) blended with lactose monohydrate and magnesium stearate and second strip contains vilanterol trifenatae (25 mcg per blister) blended with lactose monohydrate and magnesium stearate.; The ELLIPTA inhaler will contain one blister strip, which will have 30 blisters of umeclidinium bromide (62.5 mcg).; The DISKUS inhaler will contain one blister strip, which will have 60 blisters of salmeterol xinafoate (50 mcg). The DISKUS will provide a total of 60 doses (60 blisters) and will deliver, when actuated, the contents of a single blister strip.; Lactose dry powder will be administered using ELLIPTA for both treatment periods. ELLIPTA DPI inhaler will contain two individual blister strips with 30 blisters per strip; containing lactose dry powder.; Lactose dry powder will be administered using DISKUS for both treatment periods. The DISKUS inhaler will contain one blister strip, which will have 60 blisters of lactose dry powder. The DISKUS will provide a total of 60 doses (60 blisters) and will deliver, when actuated, the contents of a single blister strip.
Intervention MeSH terms: Salmeterol Xinafoate
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 2696.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: Vilanterol; COPD; HRQoL; Salmeterol; Umeclidinium

Summary:

      COPD is characterized by an airflow limitation, which is not fully reversible, usually
      progressive and accompanied by chronic cough, sputum production and dyspnea, which can be a
      major cause of disability and anxiety associated with the disease. In addition, COPD is
      associated with poor health-related quality of life (HRQoL). Pharmacologic therapy is used to
      improve lung function, reduce symptoms, reduce the frequency and severity of exacerbations,
      and also to improve health status and exercise tolerance.

      This is a multi-center, randomized, double blind, double dummy, 3-arm parallel group study to
      compare umeclidinium/vilanterol (62.5/25 microgram [mcg], once daily), umeclidinium (62.5
      mcg, once daily), and salmeterol (50 mg, twice daily) in male and female subjects with COPD.
      The primary purpose of this study is to demonstrate improvements in lung function for
      subjects treated with UMEC/VI compared with UMEC for 24 weeks.

      Approximately 2424 subjects will be randomized across 3 parallel arms in 1:1:1 ratio.
      Subjects will be stratified based on long-acting bronchodilator usage during the run-in
      period (none, one or 2 long-acting bronchodilators per day). Subjects will receive either
      UMEC/VI inhalation powder (62.5/25 microgram [mcg] once daily) administered via the ELLIPTA®
      dry powder inhaler (DPI) and placebo twice daily via DISKUS® DPI; or UMEC (62.5 mcg once
      daily) administered via the ELLIPTA DPI and placebo twice daily via DISKUS DPI or salmeterol
      (50 mcg twice daily [BID]) administered via the DISKUS DPI and placebo once daily via ELLIPTA
      DPI. The duration of the study will be 29 to 31 weeks including a pre-screening period of 2
      weeks, run-in period of 4 weeks, treatment period of 24 weeks and follow-up period of 1 week.

      ELLIPTA and DISKUS are trademarks of GSK group of companies.
    

Eligibility criteria:

        Inclusion Criteria

          -  40 years or older at date of signing informed consent at Screening Visit 1

          -  Outpatient with a diagnosis of COPD

          -  Persistent airflow limitations as indicated by a pre and post-albuterol/salbutamol
             FEV1/FVC ratio of <0.70 and a post-albuterol/salbutamol FEV1 of >=30% to <=80%
             predicted normal values at Screening Visit 1.

          -  A CAT score of >=10 at Screening Visit 1

          -  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] multiplied by
             number of years smoked [e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per
             day for 20 years both equal 10 pack-years]). Former 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.

          -  Male and female subjects are eligible to participate in the study. A female subject is
             eligible to participate if she is not pregnant (as confirmed by a negative urine human
             chorionic gonadotrophin test), not lactating, and at least one of the following
             conditions applies: non-reproductive potential defined as pre-menopausal females with
             documented tubal ligation or documented hysteroscopic tubal occlusion procedure with
             follow-up confirmation of bilateral tubal occlusion or hysterectomy or documented
             bilateral oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea.
             In questionable cases, a blood sample with simultaneous follicle stimulating hormone
             and estradiol levels consistent with menopause must be tested. Females on hormone
             replacement therapy (HRT) and whose menopausal status is in doubt will be required to
             use one of the highly effective contraception methods if they wish to continue their
             HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of
             post-menopausal status prior to study enrolment.

        A female subject with reproductive potential is eligible to participate if she is not
        pregnant and agrees to follow one of the highly effective methods for avoiding pregnancy in
        females of reproductive potential from 30 days prior to the first dose of study medication
        and until (at least five terminal half-lives or until any continuing pharmacologic effect
        has ended, whichever is longer) after the last dose of study medication and completion of
        the follow-up visit. The investigator is responsible for ensuring that subjects understand
        how to properly use methods of contraception.

          -  Capable of giving signed informed consent prior to study participation.

        Exclusion criteria

          -  A current diagnosis of asthma (Subjects with a prior history of asthma are eligible if
             they have a current diagnosis of COPD, which is the primary cause of their respiratory
             symptoms).

          -  Subjects with known alpha-antitrypsin deficiency as the underlying cause of COPD

          -  Subjects with active tuberculosis are excluded. Subjects with other respiratory
             disorders (e.g., clinically significant: bronchiectasis, sarcoidosis, lung fibrosis,
             pulmonary hypertension, interstitial lung diseases) are excluded if these conditions
             are the primary cause of their respiratory symptoms.

          -  Current active liver or biliary disease (with the exception of Gilbert's syndrome or
             asymptomatic gallstones or otherwise stable chronic liver disease as per investigator
             assessment); stable chronic liver disease should generally be defined by the absence
             of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric
             varices, or persistent jaundice, or cirrhosis; chronic stable hepatitis B and C (e.g.,
             presence of hepatitis B surface antigen or positive hepatitis C antibody test result
             or within 3 months prior to first dose of study treatment) are acceptable if subject
             otherwise meets entry criteria.

          -  Subjects with unstable or life threatening cardiac disease. The investigational
             product should be used with caution in subjects with severe cardiovascular disease. In
             the opinion of the investigator, use will only be considered if the benefit is likely
             to outweigh the risk in conditions such as myocardial infarction or unstable angina in
             the last 6 months, or unstable or life threatening cardiac arrhythmia requiring
             intervention in the last 3 months, or New York Heart Association Class IV heart
             failure.

          -  The investigator will determine the clinical significance of each abnormal
             electrocardiogram (ECG) finding in relation to the subject's medical history and
             exclude subjects who would be at undue risk by participating in the trial. Subjects
             with the following abnormalities are excluded from participation in the study: atrial
             fibrillation with rapid ventricular rate >120 beats per minute (bpm), sustained or
             non-sustained ventricular tachycardia, second degree heart block Mobitz type II or
             third degree heart block (unless pacemaker or defibrillator had been inserted).

          -  Subjects with medical conditions such as narrow-angle glaucoma, urinary retention,
             prostatic hypertrophy, or bladder neck obstruction will be excluded unless, in the
             opinion of the study physician, the benefit outweighs the risk.

          -  Any subject who is considered unlikely to survive the duration of the study period or
             has any rapidly progressing disease or immediate life-threatening illness (e.g.,
             cancer). In addition, any subject who has any other condition (e.g., neurological
             condition) that is likely to affect respiratory function will not be included in the
             study.

          -  Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1. Pneumonia
             and/or moderate or severe COPD exacerbation that has not resolved at least 14 days
             prior to Screening Visit 1and at least 30 days following the last dose of
             oral/systemic corticosteroids (if applicable).

          -  Subjects who had received inhaled corticosteroids (ICS) or ICS/ long-acting
             beta-agonist for the treatment of COPD in the 6 weeks prior to Screening Visit1.

          -  Subjects who had >1 moderate exacerbation in the 12 months prior to Screening Visit 1,
             or one severe exacerbation requiring hospitalization in the 12 months prior to
             Screening Visit 1.

          -  Other respiratory tract infections that have not resolved at least 7 days prior to
             Screening Visit 1.

          -  Subjects with lung volume reduction surgery (including procedures such as
             endobronchial valves) within the 12 months prior to Screening Visit 1.

          -  Use of long-term oxygen therapy described as resting oxygen therapy >3 Liter
             (L)/minute (min) at screening required to maintain adequate oxygenation (e.g., oxygen
             saturation in arterial blood [SaO2] >90%; oxygen use <=3 L/min flow is not
             exclusionary, and subjects may adjust oxygen levels up or down as needed during the
             study.)

          -  Use of ICS within 6 weeks prior to Screening Visit 1; use of depot corticosteroids
             within 12 weeks prior to Screening Visit 1; use of systemic, oral or parenteral
             corticosteroids within 6 weeks prior to Screening Visit 1 (Localized corticosteroid
             injections [e.g., intra-articular and epidural] are permitted); use of antibiotics
             (for lower respiratory tract infection) within 6 weeks prior to Screening Visit 1; use
             of phosphodiesterase 4 (PDE4) inhibitor (e.g., roflumilast) within 14 days prior to
             Screening Visit 1; use of long-acting beta-agonist/ ICS combination products within 6
             weeks prior to Screening Visit 1; use of theophyllines within 48 hours prior to
             Screening Visit 1; use of oral long-acting beta2-agonists within 48 hours and
             short-acting beta2-agonists within 12 hours prior to Screening Visit 1; use of inhaled
             short-acting beta2-agonists within 4 hours prior to Screening Visit 1 (use of study
             provided albuterol/salbutamol is permitted during the study, except in the 4-hour
             period prior to spirometry testing); use of inhaled short-acting anticholinergics
             within 4 hours prior to Screening Visit 1; use of inhaled short-acting
             anticholinergic/short-acting beta2-agonist combination products within 4 hours prior
             to Screening Visit 1; use of any other investigational medication within 30 days or
             within 5 drug half-lives (whichever is longer) prior to Screening Visit 1.

          -  Subject unable to withhold albuterol/salbutamol for the 4-hour period required prior
             to spirometry testing at each study visit.

          -  Regular use (prescribed for daily/ regular use, not for as-needed use) of short-acting
             bronchodilators (e.g., albuterol/salbutamol).

          -  A known or suspected history of alcohol or drug abuse within 2 years prior to
             Screening Visit 1 that in the opinion of the investigator would prevent the subject
             from completing the study procedures.

          -  Any history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor
             antagonist, sympathomimetic, lactose/milk protein or magnesium stearate.

          -  Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks
             prior to Screening Visit 1. Subjects who are in the maintenance phase of a pulmonary
             rehabilitation program are not excluded.

          -  Subject is an investigator, sub-investigator, study coordinator, employee of a
             participating investigator or study site, or immediate family member of the
             aforementioned that is involved in this study.

          -  In the opinion of the investigator, any subject who is unable to read and/or would not
             be able to complete questionnaires on the electronic diary.