The Purpose of the This Study is to Evaluate the Spirometric Effect (Trough FEV1) of Umeclidinium/Vilanterol 62.5/25 mcg Once Daily Compared With Tiotropium 18mcg Once Daily Over a a 12-week Treatment Period in Subjects With COPD Who Continue to Have Symptoms on Tiotropium
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Pulmonary Disease, Chronic Obstructive
Intervention: Umeclidinium/Vilanterol 62.5/25 mcg; Tiotropium 18 mcg
Intervention description: Inhalation Powder; Inhalation Powder
Intervention MeSH terms: Tiotropium Bromide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 497.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No

Summary:

      The primary objective is to compare the efficacy of UMEC/VI Inhalation Powder (62.5/25 mcg)
      once-daily with tiotropium (18 mcg) once-daily over 12 weeks for the treatment of subjects
      with COPD who have received tiotropium and continue to have symptoms while on tiotropium.
    

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 or female subjects. 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 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)

               -  Bronchodilator Treatment: Subjects must have been prescribed tiotropium either
                  via the HandiHaler device or Respimat for at least 3 months prior to screening
                  (Visit 1).

               -  COPD Diagnosis: A diagnosis of COPD in accordance with the definition by the
                  American Thoracic Society/European Respiratory Society [Celli, 2004].

               -  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)]. Previous smokers are defined as those who have
                  stopped smoking for at least 6 months prior to Visit 1.

        Note: Pipe and/or cigar use cannot be used to calculate pack-year history

          -  Severity of Disease: A pre and post-albuterol/salbutamol FEV₁/FVC ratio of <0.70 and
             post-albuterol/salbutamol FEV₁ of ≤70% and ≥50% predicted normal values calculated
             using reference equations at Visit 1 [Quanjer, 2012].

          -  Dyspnoea: A score of ≥1 on the Modified Medical Research Council Dyspnoea 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 α-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. Allergic rhinitis is not exclusionary.

          -  Other Diseases/Abnormalities: Subjects with historical or current evidence of
             clinically significant cardiovascular, neurological, psychiatric, renal, hepatic,
             immunological, endocrine (including uncontrolled diabetes or thyroid disease) or
             hematological abnormalities that are uncontrolled and/or a previous history of cancer
             in remission for <5 years prior to Visit 1 (localized carcinoma of the skin that has
             been resected for cure is not exclusionary). Significant is defined as any disease
             that, in the opinion of the investigator, would put the safety of the subject at risk
             through participation, or which would affect the efficacy or safety analysis if the
             disease/condition exacerbated during the study.

          -  Exacerbations: Has had more than 1 moderate or severe COPD exacerbation in the past 12
             months. Subjects with a moderate exacerbation within 6 weeks or severe exacerbations
             within 10 weeks prior to Visit 1 are excluded from study.

        A moderate COPD exacerbation is defined as worsening symptoms of COPD that require
        treatment with oral/systemic corticosteroids and/or antibiotics. A severe exacerbation is
        defined as worsening symptoms of COPD that require in-patient hospitalization.

          -  Contraindications: A history of allergy or hypersensitivity to any
             anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or
             magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic
             hypertrophy or bladder neck obstruction that, in the opinion of the study physician
             contraindicates study participation or use of an inhaled anticholinergic.

          -  Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior
             to Screening (Visit 1).

          -  12-Lead ECG: An abnormal and significant ECG finding from the 12-lead ECG conducted at
             Visit 1, including the presence of a paced rhythm on a 12-lead ECG which causes the
             underlying rhythm and ECG to be obscured. Investigators will be provided with ECG
             reviews conducted by a centralized independent cardiologist to assist in evaluation of
             subject eligibility. Specific ECG findings that preclude subject eligibility are
             listed in Appendix 3. The study investigator will determine the medical significance
             of any ECG abnormalities not listed in Appendix 3.

        Appendix 3:

          -  Sinus tachycardia ≥120 bpm. *Note: sinus tachycardia ≥120bpm should be confirmed by
             two additional readings at least 5 minutes apart.

          -  Sinus bradycardia <45bpm. *Note: Sinus bradycardia <45bpm should be confirmed by two
             additional readings at least 5 minutes apart.

          -  Multifocal atrial tachycardia.

          -  Supraventricular tachycardia (>100bpm).

          -  Atrial fibrillation with rapid ventricular response (rate >120bpm).

          -  Atrial flutter with rapid ventricular response (rate >120bpm).

          -  Ventricular tachycardias (non sustained, sustained, polymorphic, or monomorphic).

          -  Ventricular flutter.

          -  Ventricular fibrillation.

          -  Torsades de Pointes.

          -  Evidence of Mobitz type II second degree or third degree atrioventricular (AV) block.

          -  AV dissociation.

          -  2:1 AV block.

          -  Trifascicular Block.

          -  For subjects with QRS duration <120 ms: QTc(F) ≥450msec or an ECG that is unsuitable
             for QT measurements (e.g., poor defined termination of the T wave).

          -  For subjects with QRS duration≥120: QTc(F) ≥480msec or an ECG that is unsuitable for
             QT measurements (e.g., poor defined termination of the T wave).

          -  Myocardial infarction (acute or recent) * Note: Evidence of an old (resolved)
             myocardial infarction is not exclusionary

               -  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.

        Use as maintenance treatment in the 3 months prior to Visit 1 is not permitted. Maintenance
        treatment is defined as use for ≥ 14 consecutive days (at any time in the 3 months prior to
        Visit 1).

          -  Inhaled Corticosteroid (ICS)/Inhaled long acting beta2-agonists combinations

          -  Phosphodiesterase 4 (PDE4) inhibitors

          -  LABA

          -  Other Long acting muscarinic antagonists (does not include tiotropium)

          -  LAMA/LABA combinations

          -  Theophyllines

          -  Oral beta2-agonists (long-acting and short-acting) Use within 12 weeks is not
             permitted.

          -  Depot corticosteroids Use within 6 weeks is not permitted.

          -  Systemic, oral or parenteral corticosteroids

          -  Antibiotics (for lower respiratory tract infection)

          -  Cytochrome P450 3A4 strong inhibitors Use within 4 hours is not permitted.

          -  Inhaled short acting beta2-agonists, short-acting anticholinergics, and short-acting
             anticholinergic/short- acting beta2-agonist combination products (Use of study
             provided prn albuterol/salbutamol is permitted during the study, except in the 4-hour
             period prior to spirometry testing. Subjects who are taking short acting
             bronchodilators (beta-agonists or muscarinic antagonists) as their only form of
             bronchodilation at screening may NOT be recruited into the study).

        Any other investigational medication use within 30 days or within 5 drug half-lives
        (whichever is longer) is not permitted

        Note: if a LABA, LAMA (non-tiotropium), ICS/LABA, LAMA/LABA, theophylline, oral
        beta-agonist,or PDE4 inhibitor was taken on a non-maintenance basis (i.e., < 14 consecutive
        days over the 3 months prior to screening) the following minimum washouts must be observed
        prior to visit 1: twice-daily LABAs and ICS/LABAs = 48 hours; once-daily LABAs and
        ICS/LABAs= 14 days; LAMAs (excluding tiotropium) = 7 days; once-daily LAMA/LABA = 14 days,
        twice-daily LAMA/LABA = 7days; theophyllines = 48 hours; oral beta2 agonists = 48 hours;
        PDE4 inhibitor = 14 days.

          -  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 12 weeks prior to Visit 1 or are in the maintenance
             phase of a pulmonary rehabilitation program are 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.