A Study to Evaluate the Effect of the Combination of Umeclidinium (UMEC) and Vilanterol (VI) on Exercise Endurance Time (EET) in Participants With Chronic Obstructive Pulmonary Disease (COPD)
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive
Intervention: UMEC/VI DPI; Placebo DPI; Albuterol/salbutamol MDI
Intervention description: The DPI will contain a total of 30 doses. Each DPI will be comprised of two double-foil, laminate blister strips. Each blister of one strip will consist of 62.5mcg of UMEC blended with lactose and magnesium stearate while each blister of other strip will consist of 25 mcg of VI blended with lactose and magnesium stearate. Each actuation of the DPI will deliver the contents of one blister from each strip simultaneously; The placebo DPI, identical in appearance to the inhaler containing active study medication, will have two blister strips, each containing 30 blisters of lactose and magnesium stearate.; Albuterol/salbutamol MDI (metered-dose inhaler) or nebules will be permitted throughout the study as rescue medication, for use as-needed. Albuterol/salbutamol will be sourced from local commercial stock or provided centrally from GlaxoSmithKline. Nebules will not be supplied.
Intervention MeSH terms: Albuterol
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 198.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: shuttle walk test; umeclidinium; beta2-agonist; exercise endurance time; anticholinergic; combination product; vilanterol; exercise; COPD

Summary:

      This is a multicenter, randomized, double-blind, placebo-controlled, 2-period, complete block
      design cross-over study.

      The purpose of this study is to evaluate the effect of UMEC/VI 62.5/25 microgram (mcg) on EET
      as measured by the Endurance Shuttle Walk Test (ESWT) compared to placebo. Additionally, the
      effect of UMEC/VI compared to placebo on lung function and lung volumes in COPD patients will
      be characterized.

      Approximately 298 participants will be screened and, assuming 35% of these will not be
      eligible for randomization; approximately 194 participants will be randomized.

      Eligible participants will be randomized 1:1 to one of 2 treatment sequences. In sequence 1
      participants will receive UMEC/VI 62.5/25 mcg in Treatment Period 1 and placebo in Treatment
      Period 2. In sequence 2 participants will receive placebo in Treatment Period 1 and UMEC/VI
      62.5/25 mcg in Treatment Period 2. Treatments will be delivered once-daily via a dry powder
      inhaler (DPI). Each treatment period will be for 12 weeks and will be separated by a wash out
      period of 12-17 days. The total duration of patient participation, including the Follow-Up
      will be approximately 30 weeks. All participants will be provided with albuterol for use on
      an "as needed (prn)" basis throughout the run-in, washout and study treatment periods while
      on investigational product.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Type of participant: Outpatient.

          -  Informed Consent: A signed and dated written informed consent prior to study
             participation.

          -  Age: 40 years of age or older at Visit 1.

          -  Gender: Male or female participants. 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).
             Surgically sterile females are defined as those with a documented hysterectomy and/or
             bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being
             amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g. age
             appropriate, >45 years, in the absence of hormone replacement therapy. OR Child
             bearing potential, has a negative pregnancy test at screening, and agrees to one of
             the following acceptable contraceptive methods used consistently and correctly (i.e.
             in accordance with the approved product label and the instructions of the physician
             for the duration of the study - screening to follow-up contact): Abstinence; Oral
             Contraceptive, either combined or progestogen alone; Injectable progestogen; Implants
             of levonorgestrel; Estrogenic vaginal ring; Percutaneous contraceptive patches;
             Intrauterine device (IUD) or intrauterine system (IUS) that meets the standard
             operating procedures (SOP); effectiveness criteria as stated in the product label;
             Male partner sterilization (vasectomy with documentation of azoospermia) prior to the
             female participant's entry into the study, and this male is the sole partner for that
             subject. For this definition, "documented" refers to the outcome of the
             investigator's/designee's medical examination of the participant or review of the
             participant's medical history for study eligibility, as obtained via a verbal
             interview with the participant or from the participant's medical records; Double
             barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a
             vaginal spermicidal agent (foam/gel/film/cream/suppository)

          -  Diagnosis: A diagnosis of COPD in accordance with the definition by the American
             Thoracic Society/European Respiratory Society

          -  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]). Former smokers are defined as those who have stopped smoking for
             at least 6 months prior to Visit 1.

          -  Severity of Disease: A pre- and post-albuterol Forced Expiratory Volume in One
             Second/Forced Vital Capacity (FEV1/FVC) ratio of <0.70 and a postalbuterol FEV1 of
             >=30% and <=70% of predicted normal values

          -  Dyspnea: A score of >=2 on the Modified Medical Research Council Dyspnea Scale (mMRC)
             at Visit 1.

          -  Resting Lung Volumes: A resting FRC of >=120% of predicted normal FRC at Visit 1.
             Predicted values for FRC will be obtained using predicted normal values

        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 in remission for <5 years are
             absolute exclusionary conditions. A participant who, in the opinion of the
             investigator, has any other significant respiratory conditions in addition to COPD
             should be excluded. Examples may include clinically significant bronchiectasis,
             pulmonary hypertension, sarcoidosis, or interstitial lung disease. Allergic rhinitis
             is not exclusionary.

          -  Other Diseases/Abnormalities: Any participant 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 participant who has any
             condition besides COPD that is likely to affect respiratory function or the ability to
             perform exercise testing such as peripheral vascular disease should not be included in
             the study.

          -  Severe Hepatic Impairment: Patients with severe hepatic impairment (Child-Pugh class
             C) should be excluded unless, in the opinion of the investigator, the benefit is
             likely to outweigh the risk.

          -  Unstable or life threatening cardiac disease: Umeclidinium/vilanterol should be used
             with caution in participants with severe cardiovascular disease. In the opinion of the
             investigator, use should 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; Unstable or life threatening cardiac arrhythmia requiring intervention in the
             last 3 months; New York Heart Association (NYHA) Class IV heart failure

          -  Contraindications: Any history of allergy or hypersensitivity to any
             anticholinergic/muscarinic receptor antagonist, beta2-agonist, sympathomimetic,
             lactose/milk protein or magnesium stearate.

          -  Antimuscarinic effects: Participants with medical conditions such as narrow-angle
             glaucoma, urinary retention, prostatic hypertrophy, or bladder neck obstruction should
             only be included if, in the opinion of the study physician, the benefit outweighs the
             risk.

          -  Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior to Visit
             1

          -  Lung Resection: Participants with lung volume reduction surgery within the 12 months
             prior to Screening (Visit 1).

          -  12-Lead Electrocardiogram (ECG): Investigators will be provided with ECG reviews
             conducted by a centralized independent cardiologist to assist in evaluation of
             participant eligibility. The Investigator will determine the clinical significance of
             each abnormal ECG finding in relation to the participant's medical history and exclude
             participants who would be at undue risk by participating in the trial. Participants
             with the following abnormalities are excluded from participation in the study: Atrial
             fibrillation with rapid ventricular rate >120 beats per minute (bpm); Sustained or
             nonsustained ventricular tachycardia; Second degree heart block Mobitz type II and
             third degree heart block (unless pacemaker or defibrillator had been inserted)

          -  Medication Prior to Spirometry: Unable to withhold albuterol for the 4 hour period
             required prior to spirometry testing at each study visit

          -  Interactions: Concomitant administration with beta-blockers or strong Cytochrome P450
             3A4 (CYP3A4) inhibitors is only permitted if, in the Investigator's opinion, the
             likely benefit outweighs the potential risk

          -  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 (Intra-articular and epidural
             corticosteroid injections are permitted) (6 weeks), antibiotics (for lower respiratory
             tract infection and/or COPD exacerbation) (6 weeks), long-acting beta agonist (LABA)/
             inhaled corticosteroid (ICS) combination products if LABA/ICS therapy is discontinued
             completely (30 days), LABA/ICS combination products only if discontinuing LABA therapy
             and switching to ICS monotherapy (dose of ICS that is switched to must not exceed
             1000mcg of fluticasone propionate or equivalent) (48 hours for the salmeterol or
             formoterol component 14 days for the vilanterol component), use of ICS at a dose >1000
             microgram (mcg)/day of fluticasone propionate or equivalent (Use of ICS is permitted
             provided the dose does not exceed 1000mcg of fluticasone propionate or equivalent; ICS
             use not to be initiated or discontinued within 30 days prior to Visit 1 except for
             participants on LABA/ICS therapy who may discontinue LABA/ICS therapy as indicated and
             switch to ICS monotherapy) (30 days), initiation or discontinuation of ICS use (30
             days), Phosphodiesterase 4 (PDE4) inhibitor (roflumilast) (14 days), Inhaled long
             acting beta2 agonists (LABA): salmeterol, formoterol (48 hours); olodaterol,
             indacaterol (14 days), Long-acting muscarinic antagonists (tiotropium, aclidinium,
             glycopyrronium, umeclidinium) (7 days), LAMA/LABA combination products (whichever mono
             component has the longest washout), theophyllines (48 hours), oral beta2-agonists
             (long-acting [48 hours], short-acting [12 hours]), inhaled short acting beta2-agonists
             (study provided prn albuterol/ is permitted during the study, except in the 4-hour
             period prior to spirometry testing) (4 hours), inhaled short-acting anticholinergics
             (permitted during the run-in period between Visits 1 and 4 and washout period between
             Visits 7 and 9. Participants must discontinue use of short-acting anticholinergics at
             least 4 hours before Visit 4 and Visit 9. Participants should not use short acting
             anticholinergics during the double-blind treatment periods) (4 hours), inhaled
             short-acting anticholinergic/short-acting beta2-agonist combination products (4
             hours), and 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., albuterol) via nebulized therapy

          -  Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary
             rehabilitation program within 4 weeks prior to Visit 1. Participants 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: 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.

          -  Inability to read: In the opinion of the Investigator, any participant who is unable
             to read and/or would not be able to complete a questionnaire

          -  Participation in Previous Exercise Studies: Participants who have previously been
             assigned a participant number (enrolled) in GlaxoSmithKline studies DB2114417 or
             DB2114418.