A Phase IIIb Study to Evaluate the Efficacy of Umeclidinium/Vilanterol (UMEC/VI) in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive
Intervention: UMEC/VI; Placebo
Intervention description: Dry white powder delivered via DPI (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; Dry white powder delivered via DPI (2 strips with 30 blisters each, both containing lactose with magnesium stearate), administered as one inhalation of placebo
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 498.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: SGRQ; vilanterol; long-acting beta2-agonist; long-acting muscarinic antagonist; COPD; umeclidinium

Summary:

      This study is a 12-week, multicenter, randomized, double blind, parallel group,
      placebo-controlled study.

      The purpose of this study is to replicate the therapeutic benefit of UMEC/VI 62.5/25
      microgram (mcg) on health-related quality of life as reflected by St. George's Respiratory
      Questionnaire (SGRQ) scores and symptoms as reflected by rescue medication use observed in
      the 6 month placebo controlled study (DB2113373). Lung function will be assessed as it
      provides an objective measure to support the subjective patient reported outcomes of SGRQ and
      rescue medication use. The study is intended to provide additional evidence to support the
      use of UMEC/VI for the maintenance treatment of COPD Approximately 496 subjects will be
      randomized from approximately 62 centers in order to ensure 422 subjects complete 12 weeks of
      treatment. Eligible subjects will be randomized to UMEC/VI 62.5/25mcg or placebo in a 1:1
      ratio. All treatments will be administered once-daily in the morning via a Dry Powder Inhaler
      (DPI).

      There will be a total of 5 clinic visits. The total duration of study participation will be
      approximately 15 weeks. All subjects will be provided with albuterol/salbutamol to use as
      needed for the relief of COPD symptoms throughout the run-in and double-blind treatment
      periods.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Type of subject: 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 and female subjects are eligible to participate in the study.

          -  A female subject 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 (For example
             [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, if appropriate, 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 SOP effectiveness criteria as stated in the product label; male
             partner sterilization (vasectomy with documentation of azoospermia) prior to the
             female subject's entry into the study (this male is the sole partner for that
             subject); and double barrier method: condom and an occlusive cap (diaphragm or
             cervical/vault caps) with a vaginal spermicidal agent
             (foam/gel/film/cream/suppository).

          -  Diagnosis: An established clinical history 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 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.

          -  Severity of Disease: A pre and post-albuterol/salbutamol FEV1/ Forced Vital Capacity
             (FVC) ratio of <0.70 and a post-albuterol/salbutamol FEV1 of <=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 (mMRC) Dyspnea Scale
             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 conditions in addition to COPD should be excluded. Examples
             may include clinically significant bronchiectasis, pulmonary hypertension,
             sarcoidosis, or interstitial lung disease.

          -  Other Diseases/Abnormalities: 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 condition
             (e.g. neurological condition) that is likely to affect respiratory function 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: UMEC/VI should be used with caution in
             subjects 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: Subjects 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: Lung volume reduction surgery within the 12 months prior to Visit 1.

          -  12-Lead Electrocardiogram (ECG): Investigators will be provided with ECG reviews
             conducted by a centralized independent cardiologist to assist in evaluation of subject
             eligibility. The Investigator will determine the clinical significance of each
             abnormal 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 and third degree
             heart block (unless pacemaker or defibrillator had been inserted).

          -  Medication Prior to Spirometry: Unable to withhold albuterol/salbutamol for the 4 hour
             period required prior to spirometry testing at each study visit.

          -  Interactions: Concomitant administration with beta-blockers and 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 (6 weeks), antibiotics (for lower
             respiratory tract infection) (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/ICS
             therapy and switching to ICS monotherapy (48 hours for salmeterol or formoterol
             component and 14 days for vilanterol component), ICS (dose >1000 mcg/day of
             fluticasone propionate or equivalent) (30 days), Initiation or discontinuation of ICS
             use (30 days), Phosphodiesterase 4 (PDE4) Inhibitor (roflumilast) (14 days), Inhaled
             long acting beta2 agonists (48 hours for salmeterol, formoterol, 14 days for
             olodaterol, indacaterol), Long-acting muscarinic antagonists (tiotropium, aclidinium,
             glycopyrronium, umeclidinium) (7 days), LAMA/LABA combination products if LAMA/LABA
             therapy is discontinued completely (Apply 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 (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.

          -  Nebulised Therapy: Regular use (prescribed for use every day, not for as-needed use)
             of short-acting bronchodilators (e.g., albuterol/salbutamol) via nebulised 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: 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 subject who is unable to
             read and/or would not be able to complete a questionnaire.

          -  Previous participation in DB2113373 study: Subjects who have previously been assigned
             a subject number (enrolled) in GlaxoSmithKline study DB2113373.