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
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
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.
This is a Phase IIIb multicentre, randomized, blinded, double-dummy, parallel group study to
 evaluate the efficacy and safety of UMEC/VI Inhalation Powder (62.5/25 mcg) when administered
 once-daily via ELLIPTA dry powder inhaler (DPI) [note: the ELLIPTA DPI may also be referred
 to as the Novel DPI (NDPI) or the DPI] compared with tiotropium (18 mcg) administered
 once-daily via the HandiHaler over a treatment period of 12 weeks in subjects with COPD who
 continue to have symptoms while on tiotropium.

 The target population of the study will include those subjects who continue to have symptoms
 while on tiotropium. The study will screen approximately 650 subjects who continue to have
 symptoms whilst on tiotropium. After a 4 week run-in period on open label tiotropium, those
 subjects who continue to have symptoms and have adhered to the treatment schedule will
 progress into the treatment phase.

 At the end of the run-in phase approximately 490 subjects will be randomised 1:1 to UMEC/VI
 Inhalation Powder (62.5/25 mcg), or tiotropium (18 mcg). During the treatment phase, each
 subject will receive two inhalers, a preloaded ELLIPTA DPI and a HandiHaler dry powder
 inhaler with capsules, for once-daily administration of one active treatment and one placebo
 treatment for 12 weeks.

 There will be a total of 8 study visits. Subjects will sign the informed consent form (ICF)
 at either Visit 0 or Visit 1 and will be assigned a subject identifier. Subjects who meet the
 eligibility criteria at Screening (Visit 1) will enter the open label tiotropium run-in
 phase. After 4 weeks all subjects will be reviewed (Visit 2) and if they satisfy the
 randomisation criteria they will be randomised and enter the treatment phase.

 After Visit 2, there will be a further 6 study clinic visits. Further visits are scheduled at
 Day 2, Week 4, Week 8, Week 12 and Week 12 +1 day (Visits 3 to 7 respectively). Vital signs
 (blood pressure and pulse rate) will be obtained at all clinic visits.

 Trough FEV₁and trough FVC will be performed at Visit 3 and Visit 7. Pre-dose and post dose
 FEV₁and FVC measurement at 5 and 15 mins and 1 and 3 hrs will also be performed at Visit 2,
 Visit 4, Visit 5 and Visit 6.

 At selected study sites, a subset of approximately 200 subjects will perform 24-hour serial
 spirometry at Visit 2 and Visit 6 for evaluation of lung function over the dosing period.

 An assessment of dyspnea will be obtained using the Baseline and Transition Dyspnea Index
 (BDI/TDI). At Visit 2, the severity of dyspnea at baseline will be assessed using the BDI.
 Change from baseline will be assessed using the TDI at Visit 4, Visit 5 and Visit 6.

 In addition to the baseline assessment at Visit 2, health status will be captured using the
 St. George Respiratory Questionnaire for COPD (SGRQ-C) scale at Visit 4 and Visit 6.

 The impact of COPD on the subject's wellbeing and daily life will be measured using the COPD
 Assessment Test (CAT) and the the Euroqol-5D (EQ5D).. In addition to the baseline assessment
 at Visit 2, the CAT and the EQ-5D will also completed at Visit 4 and Visit 6. Furthermore,
 the CAT is also completed during screening.

 The Patient Global Rating of COPD Severity and Change of COPD Severity is a selfreported
 global assessment of severity of illness will be performed at Baseline during Visit 2 and at
 Visit 4 and Visit 6.

 Visits 0/1 through 7 will be clinic visits conducted on an outpatient basis. A safety
 Follow-Up assessment (Visit 8) will be conducted either by phone call or clinic visit where
 required approximately 7 days after the end of the study treatment (Visit 7 or Early
 Withdrawal, if applicable). The total duration of subject participation, including follow-up,
 will be approximately 18 weeks. All subjects will be provided with albuterol/salbutamol for
 use on an "as-needed" basis throughout the run-in and study treatment periods.

 For determination of subject disposition, subjects will be considered to have completed the
 study upon completion of Visit 7 (the last on-treatment clinic visit). There are no plans for
 compassionate use of the study medications.
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.