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

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01899742
• Collaborator: (none)
• Enrollment: 497
• Locations: 64
• Arms: 2
• Actual Duration (Months): 10.2
• Patients Per Site: 7.8
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: Umeclidinium/Vilanterol 62.5/25 mcg; Drug: Tiotropium 18 mcg	Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 497 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: DB2116960: A Randomized, Double-Dummy, Parallel Group, Multicenter Trial Comparing the Efficacy and Safety of UMEC/VI (a Fixed Combination of Umeclidinium and Vilanterol) With Tiotropium In Subjects With COPD Who Continue To Have Symptoms on Tiotropium
• Actual Study Start Date: Sep 15, 2014
• Actual Primary Completion Date: Jul 22, 2015
• Actual Study Completion Date: Jul 22, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Umeclidinium/Vilanterol Long-acting muscarinic antagonist (LAMA)/Long-acting Beta agonist (LABA)	Drug: Umeclidinium/Vilanterol 62.5/25 mcg; Inhalation Powder
Active Comparator: Tiotropium Long-acting muscarinic antagonist (LAMA)	Drug: Tiotropium 18 mcg; Inhalation Powder

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Day 85 (Visit 8) [Baseline (BL) and Day 85]

   FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in 1 second. BL was the mean of the values measured 23 hour and 24 hour after dosing prior to Day 1 (ie. after the last open label [OL] tiotropium dosing and prior to the randomized dose). Change from BL is defined as the post-BL value minus the BL value. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained at 23 and 24 hours after dosing on Day 84 (at Week 12 + 1 day). Analysis performed using a mixed repeated measures model (MMRM) with covariates of treatment, BL, center group, 24 hour subset flag, Day, Day by BL and Day by treatment interactions. ITT Population is defined as participants who received at least one dose of randomized study medication in the treatment period. Only those participants with data available at the specified time point were included in the analysis.

Secondary Outcome Measures

1. Change From BL in FEV1 at 3 Hours Postdose on Day 84 [Baseline and Day 84]

   FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in 1 second. FEV1 assessments taken on 0 to 3 hour on Day 84 (pre-dose, 5 minutes (min), 15 min, 30 min, 1 hour, and 3 hour post-dose). Pre-dose was the reading obtained at 24 hours after the previous day's dose (Day 83 dose). BL is defined as mean of the values measured 23 hour and 24 hour after dosing prior to Day 1 (ie. after the last OL tiotropium dosing and prior to the randomized dose). Change from BL is defined as the post-BL value minus the BL value. Analysis performed using mixed model repeated measures with covariates of treatment, BL FEV1, center group, 24 hour subset flag, time, time by treatment interaction and time by BL interaction. Only those participants with data available at the specified time point were included in the analysis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Medford	Oregon	United States	97504
2	GSK Investigational Site	Greenville	South Carolina	United States	29615
3	GSK Investigational Site	Spartanburg	South Carolina	United States	29303
4	GSK Investigational Site	La Plata	Buenos Aires	Argentina	1900
5	GSK Investigational Site	San Rafael	Mendoza	Argentina	5600
6	GSK Investigational Site	Buenos Aires		Argentina	C1425BEN
7	GSK Investigational Site	Ciudad Autónoma de Buenos Aires		Argentina	C1426ABP
8	GSK Investigational Site	Mendoza		Argentina	5500
9	GSK Investigational Site	Mendoza		Argentina	M5500CCG
10	GSK Investigational Site	San Miguel de Tucumán		Argentina	4000
11	GSK Investigational Site	Tallinn		Estonia	10117
12	GSK Investigational Site	Tallinn		Estonia	10138
13	GSK Investigational Site	Tallinn		Estonia	13419
14	GSK Investigational Site	Tallinn		Estonia	13619
15	GSK Investigational Site	Tartu		Estonia	51014
16	GSK Investigational Site	Potsdam	Brandenburg	Germany	14467
17	GSK Investigational Site	Potsdam	Brandenburg	Germany	14469
18	GSK Investigational Site	Frankfurt	Hessen	Germany	60389
19	GSK Investigational Site	Frankfurt	Hessen	Germany	60596
20	GSK Investigational Site	Hannover	Niedersachsen	Germany	30159
21	GSK Investigational Site	Hannover	Niedersachsen	Germany	30173
22	GSK Investigational Site	Dortmund	Nordrhein-Westfalen	Germany	44263
23	GSK Investigational Site	Dueren	Nordrhein-Westfalen	Germany	52349
24	GSK Investigational Site	Witten	Nordrhein-Westfalen	Germany	58452
25	GSK Investigational Site	Berlin		Germany	10367
26	GSK Investigational Site	Berlin		Germany	12157
27	GSK Investigational Site	Berlin		Germany	13086
28	GSK Investigational Site	Berlin		Germany	13581
29	GSK Investigational Site	Gyeonggi-do		Korea, Republic of	410-719
30	GSK Investigational Site	Bodø		Norway	8005
31	GSK Investigational Site	Hamar		Norway	2317
32	GSK Investigational Site	Haugesund		Norway	5528
33	GSK Investigational Site	Kløfta		Norway	2040
34	GSK Investigational Site	Stavanger		Norway	4005
35	GSK Investigational Site	Tønsberg		Norway	3116
36	GSK Investigational Site	Blagoveshchensk		Russian Federation	675000
37	GSK Investigational Site	Chelyabinsk		Russian Federation	454021
38	GSK Investigational Site	Irkutsk		Russian Federation	664005
39	GSK Investigational Site	Kemerovo		Russian Federation	650000
40	GSK Investigational Site	Kemerovo		Russian Federation	650002
41	GSK Investigational Site	Moscow		Russian Federation	125315
42	GSK Investigational Site	Novosibirsk		Russian Federation	630102
43	GSK Investigational Site	Saint-Petersburg		Russian Federation	194356
44	GSK Investigational Site	Bellville		South Africa	7530
45	GSK Investigational Site	Bloemfontein		South Africa	9301
46	GSK Investigational Site	Durban		South Africa	4001
47	GSK Investigational Site	Gatesville		South Africa	7764
48	GSK Investigational Site	Middelburg		South Africa	1501
49	GSK Investigational Site	Mowbray		South Africa	7700
50	GSK Investigational Site	Somerset West		South Africa	7130
51	GSK Investigational Site	Borås		Sweden	SE-506 30
52	GSK Investigational Site	Göteborg		Sweden	SE-413 90
53	GSK Investigational Site	Luleå		Sweden	SE-971 89
54	GSK Investigational Site	Lund		Sweden	SE-221 85
55	GSK Investigational Site	Stockholm		Sweden	SE-111 57
56	GSK Investigational Site	Örebro		Sweden	SE-703 62
57	GSK Investigational Site	Kharkiv		Ukraine	61124
58	GSK Investigational Site	Kiev		Ukraine	03680
59	GSK Investigational Site	Kyiv		Ukraine	03038
60	GSK Investigational Site	Kyiv		Ukraine	03049
61	GSK Investigational Site	Kyiv		Ukraine	03680
62	GSK Investigational Site	Kyiv		Ukraine
63	GSK Investigational Site	Mykolayiv		Ukraine	54003
64	GSK Investigational Site	Vinnytsya		Ukraine	21001

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01899742
• Other Study ID Numbers: 116960
• First Posted: Jul 15, 2013
• Last Update Posted: Jan 24, 2018
• Last Verified: Jan 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Study Results

Participant Flow

Recruitment Details	Eligible participants (par) completed a 4-week open label tiotropium run-in phase, and were randomized to blinded study medication for 12 weeks. Supplemental albuterol/salbutamol was provided to all par, to be used on an as-needed basis during the run-in phase and up to Day 85.
Pre-assignment Detail	A total of 739 par were enrolled; 496 par randomized and 494 par were included in the Intent-to-Treat (ITT) Population (Pop), comprised of all par randomized to treatment (trt) who received at least 1 dose of randomized study medication in the trt period.

Arm/Group Title	Umeclidinium/Vilanterol 62.5/25 µg	Tiotropium Bromide 18 µg
Arm/Group Description	Participants self-administered one dose of umeclidinium/vilanterol inhalation powder 62.5/25 micrograms (µg) once daily via an ELLIPTA dry powder inhaler and placebo once daily via a HANDIHALER each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Participants self-administered one dose of tiotropium bromide 18 µg once daily via a HANDIHALER and placebo once daily via an ELLIPTA dry powder inhaler each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.
Period Title: Overall Study
STARTED	247	247
COMPLETED	230	231
NOT COMPLETED	17	16

Baseline Characteristics

Arm/Group Title	Umeclidinium/Vilanterol 62.5/25 µg	Tiotropium Bromide 18 µg	Total
Arm/Group Description	Participants self-administered one dose of umeclidinium/vilanterol inhalation powder 62.5/25 µg once daily via an ELLIPTA dry powder inhaler and placebo once daily via a HANDIHALER each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Participants self-administered one dose of tiotropium bromide 18 µg once daily via a HANDIHALER and placebo once daily via an ELLIPTA dry powder inhaler each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Total of all reporting groups
Overall Participants	247	247	494
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.5 (8.71)	64.3 (8.74)	64.4 (8.71)
Sex: Female, Male (Count of Participants)
Female	84 34%	87 35.2%	171 34.6%
Male	163 66%	160 64.8%	323 65.4%
Race/Ethnicity, Customized (Number) [Number]
African American/African Heritage	2 0.8%	4 1.6%	6 1.2%
Asian - Central/South Asian Heritage	1 0.4%	1 0.4%	2 0.4%
White - Arabic/North African Heritage	4 1.6%	4 1.6%	8 1.6%
White - White/Caucasian/European Heritage	239 96.8%	237 96%	476 96.4%
White - Mixed Race	1 0.4%	1 0.4%	2 0.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Day 85 (Visit 8)
Description	FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in 1 second. BL was the mean of the values measured 23 hour and 24 hour after dosing prior to Day 1 (ie. after the last open label [OL] tiotropium dosing and prior to the randomized dose). Change from BL is defined as the post-BL value minus the BL value. Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained at 23 and 24 hours after dosing on Day 84 (at Week 12 + 1 day). Analysis performed using a mixed repeated measures model (MMRM) with covariates of treatment, BL, center group, 24 hour subset flag, Day, Day by BL and Day by treatment interactions. ITT Population is defined as participants who received at least one dose of randomized study medication in the treatment period. Only those participants with data available at the specified time point were included in the analysis.
Time Frame	Baseline (BL) and Day 85

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Umeclidinium/Vilanterol 62.5/25 µg	Tiotropium Bromide 18 µg
Arm/Group Description	Participants self-administered one dose of umeclidinium/vilanterol inhalation powder 62.5/25 µg once daily via an ELLIPTA dry powder inhaler and placebo once daily via a HANDIHALER each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Participants self-administered one dose of tiotropium bromide 18 µg once daily via a HANDIHALER and placebo once daily via an ELLIPTA dry powder inhaler each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.
Measure Participants	224	225
Least Squares Mean (Standard Error) [Liters]	0.074 (0.0155)	-0.014 (0.0155)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Umeclidinium/Vilanterol 62.5/25 µg, Tiotropium Bromide 18 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.088
	Confidence Interval	(2-Sided) 95%; 0.045 to 0.131
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From BL in FEV1 at 3 Hours Postdose on Day 84
Description	FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in 1 second. FEV1 assessments taken on 0 to 3 hour on Day 84 (pre-dose, 5 minutes (min), 15 min, 30 min, 1 hour, and 3 hour post-dose). Pre-dose was the reading obtained at 24 hours after the previous day's dose (Day 83 dose). BL is defined as mean of the values measured 23 hour and 24 hour after dosing prior to Day 1 (ie. after the last OL tiotropium dosing and prior to the randomized dose). Change from BL is defined as the post-BL value minus the BL value. Analysis performed using mixed model repeated measures with covariates of treatment, BL FEV1, center group, 24 hour subset flag, time, time by treatment interaction and time by BL interaction. Only those participants with data available at the specified time point were included in the analysis.
Time Frame	Baseline and Day 84

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Umeclidinium/Vilanterol 62.5/25 µg	Tiotropium Bromide 18 µg
Arm/Group Description	Participants self-administered one dose of umeclidinium/vilanterol inhalation powder 62.5/25 µg once daily via an ELLIPTA dry powder inhaler and placebo once daily via a HANDIHALER each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.	Participants self-administered one dose of tiotropium bromide 18 µg once daily via a HANDIHALER and placebo once daily via an ELLIPTA dry powder inhaler each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.
Measure Participants	225	228
Least Squares Mean (Standard Error) [Liters]	0.164 (0.0178)	0.091 (0.0177)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Umeclidinium/Vilanterol 62.5/25 µg, Tiotropium Bromide 18 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.073
	Confidence Interval	(2-Sided) 95%; 0.024 to 0.122
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected over a period of a maximum of 94 days starting from Day 1 of treatment until the follow-up contact.
Adverse Event Reporting Description	On-treatment SAEs and non-serious AEs were reported for members of the ITT Population, comprised of all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period.
Arm/Group Title	Umeclidinium/Vilanterol 62.5/25 µg		Tiotropium Bromide 18 µg
Arm/Group Description	Participants self-administered one dose of umeclidinium/vilanterol inhalation powder 62.5/25 µg once daily via an ELLIPTA dry powder inhaler and placebo once daily via a HANDIHALER each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.		Participants self-administered one dose of tiotropium bromide 18 µg once daily via a HANDIHALER and placebo once daily via an ELLIPTA dry powder inhaler each morning for 12 weeks. Each inhaler containing placebo was identical in appearance to its corresponding inhaler containing active study medication.
All Cause Mortality
	Umeclidinium/Vilanterol 62.5/25 µg		Tiotropium Bromide 18 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Umeclidinium/Vilanterol 62.5/25 µg		Tiotropium Bromide 18 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/247 (2.8%)		6/247 (2.4%)
Cardiac disorders
Myocardial infarction	1/247 (0.4%)		0/247 (0%)
Atrial flutter	1/247 (0.4%)		0/247 (0%)
Infections and infestations
Pneumonia	1/247 (0.4%)		0/247 (0%)
Appendicitis	1/247 (0.4%)		0/247 (0%)
Injury, poisoning and procedural complications
Cervical vertebral fracture	0/247 (0%)		1/247 (0.4%)
Metabolism and nutrition disorders
Dehydration	0/247 (0%)		1/247 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pancreatic carcinoma	0/247 (0%)		1/247 (0.4%)
Nervous system disorders
Cerebrovascular accident	1/247 (0.4%)		0/247 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/247 (0.4%)		1/247 (0.4%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/247 (0%)		2/247 (0.8%)
Pneumothorax	1/247 (0.4%)		0/247 (0%)
Vascular disorders
Hypotension	0/247 (0%)		1/247 (0.4%)
Other (Not Including Serious) Adverse Events
	Umeclidinium/Vilanterol 62.5/25 µg		Tiotropium Bromide 18 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/247 (13.8%)		34/247 (13.8%)
Infections and infestations
Nasopharyngitis	18/247 (7.3%)		17/247 (6.9%)
Nervous system disorders
Headache	16/247 (6.5%)		18/247 (7.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.