A 12-week Study to Evaluate the Efficacy and Safety of Umeclidinium Compared With Tiotropium in Subjects With Chronic Obstructive Pulmonary Disease
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: Umeclidinium; Umeclidinium matching placebo; Tiotropium; Tiotropium matching placebo
Intervention description: Umeclidinium 62.5 mcg once daily in the morning via nDPI; Umeclidinium matching placebo once daily in the morning via nDPI; Tiotropium 18 mcg once daily in the morning via HANDIHALER inhaler; Tiotropium matching placebo once daily in the morning via HANDIHALER inhaler
Intervention MeSH terms: Tiotropium Bromide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 1017.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: COPD; inhaler critical errors; double-dummy; novel dry powder inhaler; inhaler preference; tiotropium; umeclidinium; long-acting muscarinic antagonist

Summary:

      This is a multicentre, randomized, blinded, double dummy, parallel group study to evaluate
      the efficacy and safety of UMEC inhalation powder[ (62.5 microgram (mcg) once daily (QD)]
      when administered via a novel Dry Powder Inhaler compared with tiotropium (18 mcg QD)
      administered via a HANDIHALER® inhaler over a treatment period of 12 weeks (24 weeks in
      Germany) in subjects with chronic obstructive pulmonary disease (COPD). At the end of the
      run-in period, subjects who meet the randomization criteria will be randomized to receive
      UMEC 62.5 mcg administered via novel dry powder inhaler(nDPI) + Placebo administered via
      HANDIHALER inhaler OR Tiotropium 18 mcg administered via HANDIHALER inhaler + Placebo
      administered via nDPI in a 1:1 ratio. There will be up to 8 clinic visits conducted on an
      outpatient basis at Pre-Screening (Visit 0), Screening (Visit 1), a 7 to 14 day run-in
      period, 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). For subjects enrolled in
      Germany, there will be an additional 3 visits at Day 112 (Visit 8), Day 140 (Visit 9) and Day
      168 (Visit 10). The total duration of subject participation in the study will be
      approximately 15 weeks (27 weeks in Germany). The primary endpoint of the study is clinic
      visit trough forced expiratory volume in one second (FEV1) 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 blinded study medication at Visits
      3 to 7.

      HANDIHALER is a registered trademark of Boehringer Ingelheim Pharma GmbH & Co. KG.
    

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 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

          -  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 >=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.

          -  French subjects: In France, a subject will be eligible for inclusion in this study
             only if either affiliated to or a beneficiary of a social security category.

        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.

          -  Moderate to severe Renal Impairment: Patients with moderate to 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
             (LAMAs) 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 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 ; long-acting beta2-agonists/inhaled
             corticosteroids (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 [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 mcg/day of FP or equivalent- 30 days; Initiation or discontinuation of
             ICS use-30 days (Use of ICS is permitted provided the dose does not exceed 1000mcg 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; Inhaled long acting beta2
             agonists (LABAs): salmeterol, formoterol-48 hours, olodaterol, indacaterol,
             vilanterol- 14 days; LAMAs: 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 (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 write would not be able to complete a questionnaire