A 12-week Study to Evaluate the Efficacy and Safety of Umeclidinium 62.5 Microgram (mcg) Compared With Glycopyrronium 44 mcg 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: Umeclidinium; Glycopyrronium
Intervention description: Umeclidinium 62.5 mcg will be available as dry inhalation powder to be taken using a nDPI; Glycopyrronium bromide will be available as inhalation capsules, 44 mcg per capsule, taken using BREEZHALER inhalers
Intervention MeSH terms: Glycopyrrolate
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 1036.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: COPD; inhaler ease of use; glycopyrronium; umeclidinium; novel dry powder inhaler; long-acting muscarinic antagonist; inhaler errors

Summary:

      This is a 12-week, multicentre, randomized, open-label, 2-arm, parallel-group study designed
      to compare the efficacy and safety of umeclidinium inhalation powder (62.5 mcg once daily
      [QD]) administered via a novel Dry Powder Inhaler (nDPI) with glycopyrronium (44 mcg QD)
      administered via a Breezhaler® inhaler in subjects with COPD over 12 weeks of treatment. At
      the end of the run-in period, eligible subjects will be randomized in a 1:1 ratio to receive
      umeclidinium 62.5 mcg administered via nDPI or glycopyrronium 44 mcg administered via
      BREEZHALER inhaler. There will be up to 8 clinic visits conducted on an outpatient basis at
      Pre-Screening (Visit 0), Screening (Visit 1), Randomization at Day 1 (Visit 2), and after
      Randomization at Day 2 (Visit 3), Day 28 (Visit 4), Day 56 (Visit 5), Day 84 (Visit 6) and
      Day 85 (Visit 7). The total duration of subject participation in the study will be
      approximately 15 weeks. The primary endpoint of the study is clinic visit trough FEV1 (forced
      expiratory volume in one second) on treatment Day 85. All subjects will have spirometry
      performed at clinic Visits 1 though 7. Trough spirometry will be obtained 23 and 24 hours
      after the previous day's dose of open-label study medication at Visits 3 to 7.

      BREEZHALER is a registered trademark of Novartis AG.
    

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, eg, 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 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.

          -  Diagnosis: an established clinical history of COPD in accordance with the definition
             by the American Thoracic Society/European Respiratory Society (ERS)

          -  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 (eg. 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 forced expiratory volume in
             one second/ forced vital capacity (FEV1/FVC ratio of <0.70 and a
             post-albuterol/salbutamol FEV1 of >=30% and =<70% of predicted normal values at Visit
             1. Predicted values will be based upon the ERS Global Lung Function Initiative

          -  Dyspnea: A score of >=2 on the modified medical research council dyspnea scale (mMRC)
             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.

          -  Severe renal impairment: patients with severe renal impairment (e.g., end-stage renal
             disease requiring dialysis) should be excluded, unless in the opinion of the
             investigator, the benefit is likely to outweigh the risk.

          -  Unstable or life threatening cardiac disease: long-acting muscarinic antagonists
             (LAMA) 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, 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; sustained or nonsustained ventricular
             tachycardia; second degree heart block Mobitz type II or 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.

          -  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, inhaled long acting beta2 agonists/ inhaled
             corticosteroid (LABA/ICS) combination products if LABA/ICS therapy is discontinued
             completely 30 days; LABA/ICS combination products only If discontinuing ICS/ LABA
             therapy and switching to ICS monotherapy 48 hours for the salmeterol or formoterol
             component 14 days for the vilanterol component (note: the dose of ICS must be a dose
             of fluticasone propionate (FP) or equivalent but not to exceed 1000 mcg/day), use of
             ICS at a dose >1000 microgram (mcg)/day of FP or equivalent 30 days (note: use of ICS
             is permitted provided the dose does not exceed 1000 mcg of FP or equivalent; ICS use
             not to be initiated or discontinued within 30 days prior to Visit 1, except for
             subjects on LABA/ICS therapy who may discontinue the ICS/LABA product as indicated in
             the table above and switch to ICS monotherapy); initiation or discontinuation of ICS
             use 30 days (note: use of ICS is permitted provided the dose does not exceed 1000 mcg
             of FP or equivalent; ICS use not to be initiated or discontinued within 30 days prior
             to Visit 1, except for subjects on LABA/ICS therapy who may discontinue the ICS/LABA
             product as indicated in the table above and switch to ICS monotherapy);
             phosphodiesterase 4 (PDE4) Inhibitor (roflumilast) 14 days; LABA: salmeterol and
             formoterol 48 hours; olodaterol, indacaterol, and vilanterol 14 days; LAMA:
             tiotropium, aclidinium, glycopyrronium, umeclidinium 7 days; LAMA/LABA combination
             products if LAMA/LABA therapy is discontinued completely then 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 (note: use of study provided albuterol/salbutamol is permitted during the study,
             except in the 4-hour period prior to spirometry testing); 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. 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. 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