A Study to Evaluate the Effect of Umeclidinium (UMEC) as Combination Therapy 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 DPI; Placebo DPI; ICS/LABA medication; Albuterol/salbutamol Metered Dose Inhaler (MDI)
Intervention description: The UMEC DPI will contain one blister strip which will have 30 blisters of UMEC as dry powder blended with lactose and magnesium stearate, with no companion strip. Each actuation of the DPI will deliver the contents of one blister from each strip simultaneously.; The matching 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.; Participants will use ICS/LABA combinations that are approved for the treatment of COPD at approved doses and frequency including SERETIDE 500/50mcg twice daily, FSC 500/50 mcg twice daily generic products such as AIRFLUSAL FORSPIRO inhaler 500/50mcg twice daily or ROLENIUM ELPENHALER inhaler 500/50mcg twice daily and SYMBICORT TURBUHALER inhaler at doses of 200/6mcg twice daily and 400/12mcg twice daily. The ICS/LABA will be sourced from local commercial stock while on the study; Albuterol/salbutamol MDI or nebules will be issued throughout the study as rescue medication, for use as-needed. Albuterol/salbutamol will be sourced from local commercial stock or provided centrally from GlaxoSmithKline.
Intervention MeSH terms: Albuterol
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 236.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: FEV1; DPI; ICS/LABA; UMEC; COPD

Summary:

      This is a multicenter, randomized, double-blind, parallel-group study to evaluate the
      efficacy and safety of the addition of UMEC (62.5 microgram[mcg]) when administered
      once-daily via dry powder inhaler (DPI) to Inhaled corticosteroid/ Long-acting beta2-agonist
      (ICS/LABA) twice-daily compared with placebo via DPI added to the ICS/LABA therapy over a
      treatment period of 12 weeks in subjects with COPD. This study is designed to investigate the
      addition of UMEC to ICS/LABA combinations at approved doses and frequencies for the treatment
      of COPD including SERETIDE™ 500/50 mcg twice daily, Fluticasone Propionate/Salmeterol
      Combination (FSC) 500/50 twice daily generic products such as AIRFLUSAL FORSPIRO inhaler
      500/50 mcg twice daily or ROLENIUM ELPENHALER inhaler 500/50 mcg twice daily and SYMBICORT
      TURBUHALER inhaler at doses of 200/6 mcg twice daily and 400/12 mcg twice daily, over 12
      weeks in subjects with COPD. Albuterol/salbutamol metered-dose-inhaler (MDI) or nebules will
      be issued throughout the study for use as-needed (prn).

      Subjects who meet the eligibility criteria will be randomly assigned to one of the following
      blinded study treatment regimens in equal proportion (1:1): UMEC 62.5 mcg once-daily and
      Placebo once-daily. Approximately 230 subjects (115 subjects per treatment) will be
      randomized in order to complete at least 206 evaluable subjects. The total duration of the
      study will be approximately 14 weeks for each subject.

      UMEC is a Long-acting Muscarinic Antagonist (LAMA) currently under development as a
      monotherapy, as a combination product with a LABA, vilanterol (VI), for the treatment of
      COPD, and as a combination product with an ICS, fluticasone furoate (FF), for the treatment
      of asthma. The UMEC/VI combination 62.5/25 .mcg once-daily has been approved in the United
      States (U.S.) and Canada for COPD under the trade name ANORO™ ELLIPTA™ and is under
      regulatory review in other countries.

      SERETIDE, ANORO, and ELLIPTA are trade marks of the GlaxoSmithKline Group of Companies. Other
      company or product names mentioned herein may be the property of their respective owners.
    

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 and female subjects are eligible to participate in the study. 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 Procedure (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, 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 subject or review of the subject's medical history for study
             eligibility, as obtained via a verbal interview with the subject or from the subject'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: 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)]. 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 Forced Expiratory Volume in
             One Second /Forced Vital Capacity (FEV1/FVC) ratio of <0.70 and
             post-albuterol/salbutamol FEV1 of <=70% of predicted normal values at Visit 1
             (Screening) calculated using reference values provided by Quanjer.

          -  Current clinically prescribed medication: The subject must be on the dose and
             frequency of one of the following ICS/LABA combinations approved for COPD at least 30
             days prior screening : FSC at a dose of 500/50 mcg twice-daily (i.e. SERETIDE DISKUS™
             inhaler or approved generic product such as AIRFLUSAL FORSPIRO inhaler 500/50 mcg
             twice daily or ROLENIUM ELPENHALER inhaler 500/50 mcg twice daily) ; The combination
             of budesonide/formoterol (i.e., SYMBICORT TURBUHALER inhaler) at doses of 200/6 mcg
             twice-daily or 400/12 mcg twice-daily .

          -  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: The subject is considered unlikely to survive the
             duration of the study period or has any rapidly progressing disease or immediately
             life-threatening illness e.g. cancer.

          -  Contraindications: Any history of allergy or hypersensitivity to any
             anticholinergic/muscarinic receptor antagonist, beta2-agonist, sympathomimetic,
             corticosteroid (intranasal, inhaled or systemic) lactose/milk protein or magnesium
             stearate.

          -  Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior to Visit
             1.

          -  Lower respiratory tract infection: Subjects with lower respiratory tract infection
             that required the use of antibiotics within 6 weeks prior to Visit 1.

          -  Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior
             to Visit 1.

          -  Unstable or life threatening cardiac disease: UMEC 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

          -  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 Principle 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
             nonsustained ventricular tachycardia; Second degree heart block Mobitz type II and
             third degree heart block (unless pacemaker or defibrillator had been inserted)

          -  Antimuscarinic effects: Subjects with medical conditions such as narrow-angle
             glaucoma, prostatic hypertrophy, or bladder neck obstruction should only be included
             if, in the opinion of the study physician, the benefit outweighs the risk.

          -  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.

          -  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.

          -  Medication Prior to Spirometry: Unable to withhold albuterol/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); CYP3A4 strong inhibitors (6 weeks) ; ICS /LABA
             combination products except SERETIDE and approved FSC 500/50 generic products and
             SYMBICORT at approved doses and frequencies for COPD (30 days) ; SERETIDE, approved
             FSC 500/50 generic products, and SYMBICORT at approved doses and frequencies for COPD
             (12 hours prior to screening); Phosphodiesterase 4 (PDE4) Inhibitor (roflumilast) (14
             days); Long-acting muscarinic antagonists (tiotropium, aclidinium, glycopyrronium,
             UMEC) (7 days); Inhaled long acting beta2 agonists (LABA) (salmeterol, formoterol: 48
             hrs) olodaterol, indacaterol (14 days); LAMA/LABA combination products (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). Note: Use of study provided albuterol/salbutamol is permitted
             during the study, except in the 4-hour period prior to spirometry testing.
             Intra-articular and epidural corticosteroid injections are permitted. Corticosteroids
             for short term treatment of COPD exacerbations is allowed

          -  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/salbutamol) via nebulized therapy.

          -  Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary
             rehabilitation program within 4 weeks prior to Visit 1, or who will enter the acute
             phase of a pulmonary rehabilitation program during the study. 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,
             subinvestigator, study coordinator, or employee of the participating investigator.

          -  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.

        DISKUS is a trade mark of the GlaxoSmithKline Group of Companies. Other company or product
        names mentioned herein may be the property of their respective owners.