A Study to Evaluate the Efficacy and Safety of Fluticasone Furoate (FF)/GW642444 Inhalation Powder in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01009463
• Collaborator: (none)
• Enrollment: 1,626
• Locations: 188
• Arms: 4
• Duration (Months): 25.2
• Patients Per Site: 8.6
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The Purpose of this study is to assess the efficacy and safety of three strengths of the FF/GW642444 Inhalation Powder in subject with Chronic Obstructive Pulmonary Disease (COPD)

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: FF/GW642444 Inhalation Powder; Drug: GW642444 Inhalation Powder	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1626 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: HZC102871: A 52-week Efficacy and Safety Study to Compare the Effect of Three Dosage Strengths of Fluticasone Furoate/GW642444 Inhalation Powder With GW642444 on the Annual Rate of Exacerbations in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
• Study Start Date: Sep 25, 2009
• Actual Primary Completion Date: Oct 1, 2011
• Actual Study Completion Date: Oct 31, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FF/GW642444 Inhalation Powder 100/25 mcg QD Inhaled Corticosteroid (ICS)/ Long Acting Beta Agonist(LABA)	Drug: FF/GW642444 Inhalation Powder; Inhaled Corticosteroid (ICS)/ Long Acting Beta Agonist(LABA) delivered within one dry powder inhaler (DPI) device for COPD
Experimental: FF/GW642444 Inhalation Powder 200/25 mcg QD Inhaled Corticosteroid (ICS)/ Long Acting Beta Agonist(LABA)	Drug: FF/GW642444 Inhalation Powder; Inhaled Corticosteroid (ICS)/ Long Acting Beta Agonist(LABA) delivered within one dry powder inhaler (DPI) device for COPD
Experimental: FF/GW642444 Inhalation Powder 50mcg/25mcg QD Inhaled Corticosteroid (ICS)/ Long Acting Beta Agonist(LABA)	Drug: FF/GW642444 Inhalation Powder; Inhaled Corticosteroid (ICS)/ Long Acting Beta Agonist(LABA) delivered within one dry powder inhaler (DPI) device for COPD
Experimental: GW642444 25mcg QD Long Acting Beta Agonist(LABA)	Drug: GW642444 Inhalation Powder; Long Acting Beta Agonist(LABA) Inhalation Powder via DPI

Outcome Measures

Primary Outcome Measures

1. Annual Rate of Moderate and Severe COPD Exacerbations Expressed as Least Square Mean [From the start of the double blinded study medication until Visit 11 (Week 52)/Early Withdrawal]

   The annual rate of moderate and severe chronic obstructive pulmonary disease (COPD) exacerbations during the treatment (trt) period (per participant [par.] per year) was assessed. An exacerbation of COPD, is defined as the worsening of two or more major symptoms (dyspnea, sputum volume, sputum purulence [color]) for at least two consecutive days; or the worsening of any one major symptom together with any one of the minor symptoms (sore throat, cold, fever without other cause, increased cough, increased wheeze) for at least two consecutive days. The COPD exacerbation was categorized as mild, moderate and severe by the investigator. Mild: worsening symptoms of COPD that were self-managed by the par. without the use of oral corticosteroids or antibiotics; Moderate: worsening symptoms of COPD that required treatment with oral corticosteroids and/or antibiotics; Severe: worsening symptoms of COPD that required treatment with in-patient hospitalization.

Secondary Outcome Measures

1. Time to First Occurrence of Moderate or Severe COPD Exacerbation [From the start of the double blind study medication until Visit 11 (Week 52)/Early Withdrawal]

   Time to first occurrence analyzed by using a Cox proportional hazards model with covariates of treatment, smoking status at screening (stratum), baseline disease severity (pre-dose Day 1 % predicted FEV1) and centre grouping. An exacerbation of COPD is defined as the worsening of two or more major symptoms (dyspnea, sputum volume, sputum purulence [color]) for at least two consecutive days; or the worsening of any one major symptom together with any one of the minor symptoms (sore throat, cold, fever without other cause, increased cough, increased wheeze) for at least two consecutive days. A moderate exacerbation is defined as worsening symptoms of COPD that required treatment with oral corticosteroids and/or antibiotics. A severe exacerbation is defined as worsening symptoms of COPD that required treatment with in-patient hospitalization. The number of participants with a moderate or severe COPD exacerbation while on treatment are presented.

2. Annual Rate of Exacerbations Requiring Systemic/Oral Corticosteroids Expressed as Least Square Mean [From the start of the double blind study medication until Visit 11 (Week 52)/Early Withdrawal]

   The annual rate of COPD exacerbations during the treatment period (per participant per year) that required systemic/oral corticosteroids was assessed. An exacerbation of COPD is defined as the worsening of two or more major symptoms (dyspnea, sputum volume, sputum purulence [color]) for at least two consecutive days; or the worsening of any one major symptom together with any one of the minor symptom (sore throat, cold, fever without other cause, increased cough, increased wheeze) for at least two consecutive days. The COPD exacerbation was categorized as mild, moderate, and severe by the investigator. Mild: worsening symptoms of COPD that were self-managed by the participant. Mild exacerbations were not associated with the use of oral corticosteroids or antibiotics. Moderate: worsening symptoms of COPD that required treatment with oral corticosteroids and/or antibiotics. Severe: worsening symptoms of COPD that required treatment with in-patient hospitalization.

3. Change From Baseline in Trough FEV1 at Week 52 (Visit 11) [Baseline to Visit 11 (Week 52)/Early Withdrawal]

   Pulmonary function was measured by forced expiratory volume in one second (FEV1). Trough FEV1 was defined as the 24-hour post-dose FEV1 assessment, which was obtained at each visit. Analysis performed using a repeated measures model with covariates of treatment, smoking status at Screening (stratum), baseline (pre-dose Day 1), centre grouping, Week, Week by Baseline, and Week by treatment interactions.

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: Subjects must give their signed and dated written informed consent to participate.

• 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, history of vasomotor symptoms. However in questionable cases, a blood sample with FSH > 40MIU/ml and estradiol <40pg/ml (<140 pmol/L) is confirmatory. 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):

• Complete abstinence from intercourse from screening until the Follow-Up Phone Contact; or

• Male partner is sterile (vasectomy with documentation of azoospermia) prior to female subject entry into the study, and this male partner is the sole partner for that subject; or

• Implants of levonorgestral inserted for at least 1 month prior to the study medication administration but not beyond the third successive year following insertion; or

• Injectable progestogen administered for at least 1 month prior to study medication administration and administered until the Follow-Up Phone Contact; or

• Oral contraceptive (combined or progestogen only) administered for at least one monthly cycle prior to study medication administration; or

• Double barrier method: condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository); or

• An intrauterine device (IUD), inserted by a qualified physician, with published data showing that the highest expected failure rate is less than 1% per year; or

• Estrogenic vaginal ring; or

• Percutaneous contraceptive patches

• Age: ≥40 years of age at Screening (Visit 1)

• COPD diagnosis: Subjects with a clinical history of COPD in accordance with the following definition by the American Thoracic Society/European Respiratory Society [Celli, 2004]: COPD is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences.

• Tobacco use: Subjects with a current or prior history of ≥10 pack-years of cigarette smoking at Screening (Visit 1). Former 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. Number of pack years = (number of cigarettes per day/20) x number of years smoked

• Severity of Disease:

• Subject with a measured post-albuterol/salbutamol FEV1/FVC ratio of ≤0.70 at Screening (Visit 1)

• Subjects with a measured post-albuterol/salbutamol FEV1 <70% of predicted normal values calculated (via centralized vendor equipment) using NHANES III reference equations [Hankinson, 1999] at Screening (Visit 1). Post-bronchodilator spirometry will be performed approximately 10-15 minutes after the subject has self-administered 4 inhalations (i.e., total 400mcg) of albuterol/salbutamol via an MDI with a valved-holding chamber. The study provided central spirometry equipment will calculate the FEV1/FVC ratio and FEV1 percent predicted values.

• History of Exacerbations: A documented history (e.g., medical record verification) of at least one COPD exacerbation in the 12 months prior to Visit 1 that required either oral corticosteroids, antibiotics and/or hospitalization. Prior use of antibiotics alone does not qualify as an exacerbation history unless the use was associated with treatment of worsening symptoms of COPD, such as increased dyspnea, sputum volume, or sputum purulence (color). Subject verbal reports are not acceptable.

Exclusion Criteria:

Subjects meeting any of the following criteria must not be enrolled in the study:

• Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.

• Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD)

• α1-antitrypsin deficiency: Subjects with α1-antitrypsin deficiency as the underlying cause of COPD

• Other respiratory disorders: Subjects with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases

• Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1)

• Chest X-ray (or CT scan): Subjects with a chest X-ray (or CT scan) that reveals evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest X-ray must be taken at Screening (Visit 1) if a chest X-ray or CT scan is not available within 6 months prior to Visit 1. For sites in Germany, if a chest X-ray (or CT scan) is not available in the 6 months preceding Screening (Visit 1), the subject will not be eligible for the study.

• Risk Factors for Pneumonia: immune suppression (HIV, Lupus, etc) or other risk for pneumonia (e.g. neurological disorders affecting control of the upper airway, such as Parkinson's, Myasthenia Gravis, etc).

• A moderate and severe COPD exacerbation that has not resolved at least 14 days prior to Visit 1 and at least 30 days following the last dose of oral corticosteroids (if applicable).

• Pneumonia and/or moderate and severe COPD exacerbation at Visit 1 Note: Subjects who experience a pneumonia and/or exacerbation at Screening (Visit 1) must be not continue in the study, but may be re-screened at a later time provided the pneumonia and/or COPD exacerbation has resolved prior to the re-screening visit. At the Re-screening Visit, the chest x-ray should confirm resolution of pneumonia. The Re-screening Visit must be conducted at least ≥ 14 days following the resolution date of the exacerbation and/or pneumonia and at least 30 days following the last dose of oral corticosteroids (if applicable).

• Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular (i.e., pacemaker), neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or haematological abnormalities that are uncontrolled. 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.

• Peptic Ulcer disease: Subjects with clinically significant peptic ulcer disease that is uncontrolled.

• Hypertension: Subjects with clinically significant hypertension that is uncontrolled.

• Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years. Carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded if the subject has been considered cured within 5 years since diagnosis.

• Drug/food allergy: Subjects with a history of hypersensitivity to any of the study medications (e.g., beta-agonists, corticosteroid) or components of the inhalation powder (e.g., lactose, magnesium stearate). In addition, subjects with a history of severe milk protein allergy that, in the opinion of the study physician, contraindicates the subject's participation will also be excluded.

• Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years

• Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol/salbutamol and/or their ipratropium for the 4-hour period required prior to spirometry testing at each study visit.

• Additional medication: Unable to stop using certain medications such as bronchodilators and corticosteroids for the protocol-specified times prior to Visit 1 (the Investigator will discuss the specific medications)

• Oxygen therapy: Subjects receiving treatment with long-term oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day. Oxygen prn use (i.e., ≤12 hours per day) is not exclusionary.

• Sleep apnea: Subjects with clinically significant sleep apnea who require use of continuous positive airway pressure (CPAP) device or non-invasive positive pressure ventilation (NIPPV) device.

• Pulmonary rehabilitation: Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Program within 4 weeks prior to Screening (Visit 1) or who will enter the acute phase of a Pulmonary Rehabilitation Program during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation Program are not excluded.

• Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits.

• Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study.

• Prior use of study medication/other investigational drugs: Subjects who have previously been randomized to treatment with GW642444 Inhalation Powder in the B2C111045 study, randomized to treatment in the HZC111348 study or have participated in the HZC112207, HZC102871, HZC102970, or HZC110946 studies. Subjects who have received an investigational drug within 30 days of entry into this study (Screening), or within 5 drug half-lives of the investigational drug, whichever is longer.

• Affiliation with investigator site: Study investigators, sub-investigators, study coordinators, employees of a participating investigator or immediate family members of the aforementioned are excluded from participating in this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Birmingham	Alabama	United States	35235
2	GSK Investigational Site	Birmingham	Alabama	United States	35294
3	GSK Investigational Site	Jasper	Alabama	United States	35501
4	GSK Investigational Site	Peoria	Arizona	United States	85381
5	GSK Investigational Site	Phoenix	Arizona	United States	85012
6	GSK Investigational Site	Phoenix	Arizona	United States	85050
7	GSK Investigational Site	Scottsdale	Arizona	United States	85258
8	GSK Investigational Site	Chula Vista	California	United States	91911
9	GSK Investigational Site	Lincoln	California	United States	95648
10	GSK Investigational Site	Long Beach	California	United States	90822
11	GSK Investigational Site	Los Angeles	California	United States	90048
12	GSK Investigational Site	Mission Viejo	California	United States	92691
13	GSK Investigational Site	Palo Alto	California	United States	94304
14	GSK Investigational Site	Poway	California	United States	92064
15	GSK Investigational Site	Rancho Mirage	California	United States	92270
16	GSK Investigational Site	Riverside	California	United States	92506
17	GSK Investigational Site	Rolling Hills Estates	California	United States	90274
18	GSK Investigational Site	Santa Monica	California	United States	90404
19	GSK Investigational Site	Sepulveda	California	United States	91343
20	GSK Investigational Site	Torrance	California	United States	90503
21	GSK Investigational Site	Stamford	Connecticut	United States	06902
22	GSK Investigational Site	Bay Pines	Florida	United States	33744
23	GSK Investigational Site	Clearwater	Florida	United States	33755
24	GSK Investigational Site	Clearwater	Florida	United States	33756
25	GSK Investigational Site	Fort Myers	Florida	United States	33916
26	GSK Investigational Site	Gainesville	Florida	United States	32608
27	GSK Investigational Site	Miami	Florida	United States	33136
28	GSK Investigational Site	Orlando	Florida	United States	32822
29	GSK Investigational Site	Ormond Beach	Florida	United States	32174
30	GSK Investigational Site	Tamarac	Florida	United States	33321
31	GSK Investigational Site	Winter Park	Florida	United States	32792
32	GSK Investigational Site	Austell	Georgia	United States	30106
33	GSK Investigational Site	Decatur	Georgia	United States
34	GSK Investigational Site	Lawrenceville	Georgia	United States	30046
35	GSK Investigational Site	Belleville	Illinois	United States	62220
36	GSK Investigational Site	River Forest	Illinois	United States	60305
37	GSK Investigational Site	Avon	Indiana	United States	46123
38	GSK Investigational Site	Lafayette	Indiana	United States	47904
39	GSK Investigational Site	Muncie	Indiana	United States	47304-5547
40	GSK Investigational Site	Newburgh	Indiana	United States	47630
41	GSK Investigational Site	Iowa City	Iowa	United States	52242
42	GSK Investigational Site	Lenexa	Kansas	United States	66215
43	GSK Investigational Site	Wichita	Kansas	United States	67205
44	GSK Investigational Site	Munfordville	Kentucky	United States	42765
45	GSK Investigational Site	Owensboro	Kentucky	United States	42301
46	GSK Investigational Site	New Orleans	Louisiana	United States	70115
47	GSK Investigational Site	Sunset	Louisiana	United States	70584
48	GSK Investigational Site	Columbia	Maryland	United States	21044
49	GSK Investigational Site	Saint Joseph	Michigan	United States	49085
50	GSK Investigational Site	Southfield	Michigan	United States	48034
51	GSK Investigational Site	Minneapolis	Minnesota	United States	55402
52	GSK Investigational Site	Minneapolis	Minnesota	United States	55407
53	GSK Investigational Site	Plymouth	Minnesota	United States	55441
54	GSK Investigational Site	Saint Charles	Missouri	United States	63301
55	GSK Investigational Site	Billings	Montana	United States	59102
56	GSK Investigational Site	Lebanon	New Hampshire	United States	03756
57	GSK Investigational Site	Ocean City	New Jersey	United States	7712
58	GSK Investigational Site	New York	New York	United States	10004
59	GSK Investigational Site	New York	New York	United States	10029
60	GSK Investigational Site	Elizabeth City	North Carolina	United States	27909
61	GSK Investigational Site	Salisbury	North Carolina	United States	28144
62	GSK Investigational Site	Dayton	Ohio	United States	45406
63	GSK Investigational Site	Oklahoma City	Oklahoma	United States	73103
64	GSK Investigational Site	Oklahoma City	Oklahoma	United States	73120
65	GSK Investigational Site	Tulsa	Oklahoma	United States	74136-8303
66	GSK Investigational Site	Medford	Oregon	United States	97504
67	GSK Investigational Site	Sellersville	Pennsylvania	United States	18960
68	GSK Investigational Site	Johnston	Rhode Island	United States	02919
69	GSK Investigational Site	Anderson	South Carolina	United States	29621
70	GSK Investigational Site	Charleston	South Carolina	United States	29406-7108
71	GSK Investigational Site	Chester	South Carolina	United States	29706
72	GSK Investigational Site	Gaffney	South Carolina	United States	29340
73	GSK Investigational Site	Greenwood	South Carolina	United States	29646
74	GSK Investigational Site	Greer	South Carolina	United States	29651
75	GSK Investigational Site	Seneca	South Carolina	United States	29678
76	GSK Investigational Site	Chattanooga	Tennessee	United States	37421
77	GSK Investigational Site	New Tazewell	Tennessee	United States	37824-1409
78	GSK Investigational Site	Austin	Texas	United States	78705
79	GSK Investigational Site	Boerne	Texas	United States	78006
80	GSK Investigational Site	Fort Worth	Texas	United States	76109
81	GSK Investigational Site	Kingwood	Texas	United States	77339
82	GSK Investigational Site	Lake Jackson	Texas	United States	77566
83	GSK Investigational Site	San Antonio	Texas	United States	78229
84	GSK Investigational Site	Temple	Texas	United States	76508
85	GSK Investigational Site	South Burlington	Vermont	United States	05403
86	GSK Investigational Site	Abingdon	Virginia	United States	24210
87	GSK Investigational Site	Charlottesville	Virginia	United States	22911
88	GSK Investigational Site	Fredericksburg	Virginia	United States	22401
89	GSK Investigational Site	Richmond	Virginia	United States	23225
90	GSK Investigational Site	Virginia Beach	Virginia	United States	23455
91	GSK Investigational Site	Lakewood	Washington	United States	98499
92	GSK Investigational Site	Spokane	Washington	United States	99204
93	GSK Investigational Site	Tacoma	Washington	United States	98405
94	GSK Investigational Site	Wenatchee	Washington	United States	98801
95	GSK Investigational Site	Cipolletti	Río Negro	Argentina	R8324EMB
96	GSK Investigational Site	Buenos Aires		Argentina	C1424BSF
97	GSK Investigational Site	Buenos Aires		Argentina	C1425BEN
98	GSK Investigational Site	Ciudad Autónoma de Buenos Aires		Argentina	C1426ABP
99	GSK Investigational Site	Ciudad Autónoma de Buenos Aires		Argentina	C1428DDE
100	GSK Investigational Site	Mendoza		Argentina	M5500CCG
101	GSK Investigational Site	Garran	Australian Capital Territory	Australia	2606
102	GSK Investigational Site	Cairns	Queensland	Australia	4870
103	GSK Investigational Site	Kippa Ring	Queensland	Australia	4021
104	GSK Investigational Site	Daw Park	South Australia	Australia	5041
105	GSK Investigational Site	Frankston	Victoria	Australia	3199
106	GSK Investigational Site	Geelong	Victoria	Australia	3220
107	GSK Investigational Site	Heidelberg	Victoria	Australia	3084
108	GSK Investigational Site	Nedlands	Western Australia	Australia	6009
109	GSK Investigational Site	Vancouver	British Columbia	Canada	V5Z 4E1
110	GSK Investigational Site	St. John's	Newfoundland and Labrador	Canada	A1E 2E2
111	GSK Investigational Site	Burlington	Ontario	Canada	L7N 3V2
112	GSK Investigational Site	Corunna	Ontario	Canada	N0N 1G0
113	GSK Investigational Site	Sudbury	Ontario	Canada	P3E 1H5
114	GSK Investigational Site	Toronto	Ontario	Canada	M3H 5S4
115	GSK Investigational Site	Toronto	Ontario	Canada	M4P 1P2
116	GSK Investigational Site	Toronto	Ontario	Canada	M9W 4L6
117	GSK Investigational Site	Montreal	Quebec	Canada	H2R 1V6
118	GSK Investigational Site	Quebec		Canada	G1V 4G5
119	GSK Investigational Site	Temuco	Región De La Araucania	Chile	4800798
120	GSK Investigational Site	Valparaiso	Valparaíso	Chile	2341131
121	GSK Investigational Site	Santiago		Chile	8380453
122	GSK Investigational Site	Rakvere		Estonia	44316
123	GSK Investigational Site	Tallinn		Estonia	10117
124	GSK Investigational Site	Tallinn		Estonia	10611
125	GSK Investigational Site	Tartu		Estonia	51014
126	GSK Investigational Site	Geesthacht	Schleswig-Holstein	Germany	21502
127	GSK Investigational Site	Berlin		Germany	10367
128	GSK Investigational Site	Berlin		Germany	10717
129	GSK Investigational Site	Berlin		Germany	12203
130	GSK Investigational Site	Eboli (SA)	Campania	Italy	84025
131	GSK Investigational Site	Telese Terme (BN)	Campania	Italy	82037
132	GSK Investigational Site	Ferrara	Emilia-Romagna	Italy	44100
133	GSK Investigational Site	Roma	Lazio	Italy	00135
134	GSK Investigational Site	Roma	Lazio	Italy	00163
135	GSK Investigational Site	Genova	Liguria	Italy	16132
136	GSK Investigational Site	Milano	Lombardia	Italy	20142
137	GSK Investigational Site	Tradate (VA)	Lombardia	Italy	21049
138	GSK Investigational Site	Torrette (AN)	Marche	Italy	60126
139	GSK Investigational Site	Cassano Murge (BA)	Puglia	Italy	70020
140	GSK Investigational Site	Tijuana	Baja California Norte	Mexico	22320
141	GSK Investigational Site	Guadalajara	Jalisco	Mexico	44100
142	GSK Investigational Site	Zapopan	Jalisco	Mexico	45040
143	GSK Investigational Site	Monterrey	Nuevo León	Mexico	64060
144	GSK Investigational Site	Bunnik		Netherlands	3981 LB
145	GSK Investigational Site	Enschede		Netherlands	7513 ER
146	GSK Investigational Site	Etten-leur		Netherlands	4872 LA
147	GSK Investigational Site	Harderwijk		Netherlands	3844 DG
148	GSK Investigational Site	Heerlen		Netherlands	6419 PC
149	GSK Investigational Site	Helmond		Netherlands	5707 HA
150	GSK Investigational Site	Nijverdal		Netherlands	7442 LS
151	GSK Investigational Site	Rotterdam		Netherlands	3078 HT
152	GSK Investigational Site	Sneek		Netherlands	8601 ZK
153	GSK Investigational Site	Spijkenisse		Netherlands	3207 NB
154	GSK Investigational Site	Veldhoven		Netherlands	5504 DB
155	GSK Investigational Site	Voerendaal		Netherlands	6367 ED
156	GSK Investigational Site	Jesus Maria	Lima	Peru	Lima 11
157	GSK Investigational Site	San Martin de Porres	Lima	Peru	Lima 31
158	GSK Investigational Site	Lima		Peru	Lima 27
159	GSK Investigational Site	Lima		Peru	Lima 41
160	GSK Investigational Site	Dagupan City		Philippines	2400
161	GSK Investigational Site	Quezon City		Philippines	1100
162	GSK Investigational Site	Quezon City		Philippines	1101
163	GSK Investigational Site	Quezon City		Philippines	1109
164	GSK Investigational Site	Cape Town	Gauteng	South Africa	7505
165	GSK Investigational Site	Mueckelneck	Gauteng	South Africa	0001
166	GSK Investigational Site	Boksburg North		South Africa	1459
167	GSK Investigational Site	Cape Town		South Africa	8001
168	GSK Investigational Site	Durban		South Africa	4001
169	GSK Investigational Site	Durban		South Africa	4091
170	GSK Investigational Site	Groenkloof		South Africa	0181
171	GSK Investigational Site	Lynnwood Manor		South Africa	0081
172	GSK Investigational Site	Lyttleton		South Africa	0140
173	GSK Investigational Site	Paarl		South Africa	7646
174	GSK Investigational Site	Panorama		South Africa	7500
175	GSK Investigational Site	Reiger Park		South Africa	1459
176	GSK Investigational Site	Somerset West		South Africa	7130
177	GSK Investigational Site	Witbank		South Africa	1034
178	GSK Investigational Site	Göteborg		Sweden	SE-412 63
179	GSK Investigational Site	Göteborg		Sweden	SE-413 45
180	GSK Investigational Site	Höllviken		Sweden	SE-236 51
181	GSK Investigational Site	KIL		Sweden	SE-665 30
182	GSK Investigational Site	Örebro		Sweden	SE-703 62
183	GSK Investigational Site	High Heaton, Newcastle upon Tyne	Tyne & Wear	United Kingdom	NE7 7DN
184	GSK Investigational Site	Doncaster		United Kingdom	DN9 2HY
185	GSK Investigational Site	Liverpool		United Kingdom	L9 7AL
186	GSK Investigational Site	London		United Kingdom	E7 8QP
187	GSK Investigational Site	London		United Kingdom	NW3 2PF
188	GSK Investigational Site	London		United Kingdom	SW17 0RE

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

• Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J, Wachtel A, Martinez FJ, Barnhart F, Sanford L, Lettis S, Crim C, Calverley PM. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med. 2013 May;1(3):210-23. doi: 10.1016/S2213-2600(13)70040-7. Epub 2013 Apr 12. Erratum in: Lancet Respir Med. 2013 May;1(3):186.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01009463
• Other Study ID Numbers: 102871
• First Posted: Nov 6, 2009
• Last Update Posted: Nov 9, 2017
• Last Verified: Oct 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by GlaxoSmithKline: COPD; Safety; FEV1; Efficacy
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive

Study Results

Participant Flow

Pre-assignment Detail	At Visit (V) 1, eligible participants (par.) entered a 4-week, open-label Run-In Period (RIP) to establish a stable Baseline. At V 2, eligible par. were randomized to a 52 week, double-blind Treatment Period. 2631 par. were screened, 2071 par. entered the RIP, and 1626 par. were randomized, out of which 1622 received at >= 1 study treatment dose.

Arm/Group Title	FP/SAL 250/50 µg BID	VI 25 µg QD	FF/VI 50/25 µg QD	FF/VI 100/25 µg QD	FF/VI 200/25 µg QD
Arm/Group Description	Participants (Par.) were instructed to take open label Fluticasone Propionate and Salmeterol (FP/SAL) 250/50 microgram (µg) twice daily (BID) from the ACCUHALER/DISKUS, one inhalation each morning and evening with approximately 12 hours between doses. In addition, all par. were provided supplemental albuterol/salbutamol (metered dose inhaler [MDI] and/or nebules) to be used as needed throughout the study.	Participants received a Vilanterol (VI) 25 µg dry inhalation powder once daily (QD) in the morning from the Dry Powder Inhaler (DPI) for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a Fluticasone Furoate/Vilanterol (FF/VI) 50/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a FF/VI 100/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a FF/VI 200/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
Period Title: 4-week, Open-label Run-In Period
STARTED	2071	0	0	0	0
COMPLETED	1622	0	0	0	0
NOT COMPLETED	449	0	0	0	0
Period Title: 4-week, Open-label Run-In Period
STARTED	0	409	408	403	402
Completed the Treatment Period	0	295	318	314	303
COMPLETED	0	294	315	312	301
NOT COMPLETED	0	115	93	91	101

Baseline Characteristics

Arm/Group Title	VI 25 µg QD	FF/VI 50/25 µg QD	FF/VI 100/25 µg QD	FF/VI 200/25 µg QD	Total
Arm/Group Description	Participants received a Vilanterol (VI) 25 µg dry inhalation powder once daily (QD) in the morning from the Dry Powder Inhaler (DPI) for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a Fluticasone Furoate/Vilanterol (FF/VI) 50/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a FF/VI 100/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a FF/VI 200/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Total of all reporting groups
Overall Participants	409	408	403	402	1622
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.6 (9.43)	63.6 (9.06)	63.6 (9.06)	63.8 (9.30)	63.6 (9.21)
Sex: Female, Male (Count of Participants)
Female	170 41.6%	163 40%	172 42.7%	153 38.1%	658 40.6%
Male	239 58.4%	245 60%	231 57.3%	249 61.9%	964 59.4%
Race/Ethnicity, Customized (participants) [Number]
White	331 80.9%	334 81.9%	332 82.4%	324 80.6%	1321 81.4%
African American/ African Heritage	9 2.2%	8 2%	6 1.5%	9 2.2%	32 2%
Asian	39 9.5%	37 9.1%	37 9.2%	41 10.2%	154 9.5%
American Indian or Alaska Native & White	19 4.6%	16 3.9%	19 4.7%	15 3.7%	69 4.3%
Asian & White	0 0%	1 0.2%	0 0%	0 0%	1 0.1%
American Indian or Alaska Native	10 2.4%	12 2.9%	9 2.2%	12 3%	43 2.7%
Unknown	1 0.2%	0 0%	0 0%	1 0.2%	2 0.1%

Outcome Measures

1. Primary Outcome

Title	Annual Rate of Moderate and Severe COPD Exacerbations Expressed as Least Square Mean
Description	The annual rate of moderate and severe chronic obstructive pulmonary disease (COPD) exacerbations during the treatment (trt) period (per participant [par.] per year) was assessed. An exacerbation of COPD, is defined as the worsening of two or more major symptoms (dyspnea, sputum volume, sputum purulence [color]) for at least two consecutive days; or the worsening of any one major symptom together with any one of the minor symptoms (sore throat, cold, fever without other cause, increased cough, increased wheeze) for at least two consecutive days. The COPD exacerbation was categorized as mild, moderate and severe by the investigator. Mild: worsening symptoms of COPD that were self-managed by the par. without the use of oral corticosteroids or antibiotics; Moderate: worsening symptoms of COPD that required treatment with oral corticosteroids and/or antibiotics; Severe: worsening symptoms of COPD that required treatment with in-patient hospitalization.
Time Frame	From the start of the double blinded study medication until Visit 11 (Week 52)/Early Withdrawal

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all par. randomized who received at least 1 dose of study drug and with available data for analysis. Analysis used a negative binomial regression model with covariates of trt, smoking status at Screening, Baseline pre-dose Day 1 % predicted FEV1 and region and with logarithm of time on trt as an offset variable.

Arm/Group Title	VI 25 µg QD	FF/VI 50/25 µg QD	FF/VI 100/25 µg QD	FF/VI 200/25 µg QD
Arm/Group Description	Participants received a Vilanterol (VI) 25 µg dry inhalation powder once daily (QD) in the morning from the Dry Powder Inhaler (DPI) for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a Fluticasone Furoate/Vilanterol (FF/VI) 50/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a FF/VI 100/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a FF/VI 200/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
Measure Participants	409	408	403	402
Least Squares Mean (95% Confidence Interval) [Exacerbations per participant per year]	1.05	0.92	0.70	0.90

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VI 25 µg QD, FF/VI 50/25 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.181
	Comments
	Method	Generalized Linear Model
	Comments	Assuming Negative Binomial distribution with logarithm of time on treatment as an offset variable.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	VI 25 µg QD, FF/VI 100/25 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Nominal p-value
	Method	Generalized Linear Model
	Comments	Assuming Negative Binomial distribution with logarithm of time on treatment as an offset variable.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.54 to 0.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	VI 25 µg QD, FF/VI 200/25 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.109
	Comments
	Method	Generalized Linear Model
	Comments	Assuming Negative Binomial distribution with logarithm of time on treatment as an offset variable.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.70 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Time to First Occurrence of Moderate or Severe COPD Exacerbation
Description	Time to first occurrence analyzed by using a Cox proportional hazards model with covariates of treatment, smoking status at screening (stratum), baseline disease severity (pre-dose Day 1 % predicted FEV1) and centre grouping. An exacerbation of COPD is defined as the worsening of two or more major symptoms (dyspnea, sputum volume, sputum purulence [color]) for at least two consecutive days; or the worsening of any one major symptom together with any one of the minor symptoms (sore throat, cold, fever without other cause, increased cough, increased wheeze) for at least two consecutive days. A moderate exacerbation is defined as worsening symptoms of COPD that required treatment with oral corticosteroids and/or antibiotics. A severe exacerbation is defined as worsening symptoms of COPD that required treatment with in-patient hospitalization. The number of participants with a moderate or severe COPD exacerbation while on treatment are presented.
Time Frame	From the start of the double blind study medication until Visit 11 (Week 52)/Early Withdrawal

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	VI 25 µg QD	FF/VI 50/25 µg QD	FF/VI 100/25 µg QD	FF/VI 200/25 µg QD
Arm/Group Description	Participants received a Vilanterol (VI) 25 µg dry inhalation powder once daily (QD) in the morning from the Dry Powder Inhaler (DPI) for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study. )	Participants received a Fluticasone Furoate/Vilanterol (FF/VI) 50/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a FF/VI 100/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a FF/VI 200/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
Measure Participants	409	408	403	402
Number [Participants]	202 49.4%	190 46.6%	160 39.7%	178 44.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VI 25 µg QD, FF/VI 50/25 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.430
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	VI 25 µg QD, FF/VI 100/25 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	Nominal p-value
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.59 to 0.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	VI 25 µg QD, FF/VI 200/25 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.114
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Annual Rate of Exacerbations Requiring Systemic/Oral Corticosteroids Expressed as Least Square Mean
Description	The annual rate of COPD exacerbations during the treatment period (per participant per year) that required systemic/oral corticosteroids was assessed. An exacerbation of COPD is defined as the worsening of two or more major symptoms (dyspnea, sputum volume, sputum purulence [color]) for at least two consecutive days; or the worsening of any one major symptom together with any one of the minor symptom (sore throat, cold, fever without other cause, increased cough, increased wheeze) for at least two consecutive days. The COPD exacerbation was categorized as mild, moderate, and severe by the investigator. Mild: worsening symptoms of COPD that were self-managed by the participant. Mild exacerbations were not associated with the use of oral corticosteroids or antibiotics. Moderate: worsening symptoms of COPD that required treatment with oral corticosteroids and/or antibiotics. Severe: worsening symptoms of COPD that required treatment with in-patient hospitalization.
Time Frame	From the start of the double blind study medication until Visit 11 (Week 52)/Early Withdrawal

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all par. randomized who received at least 1 dose of study drug and with available data for analysis. Analysis used a negative binomial regression model with covariates of trt, smoking status at Screening, Baseline pre-dose Day 1 % predicted FEV1 and region and with logarithm of time on trt as an offset variable.

Arm/Group Title	VI 25 µg QD	FF/VI 50/25 µg QD	FF/VI 100/25 µg QD	FF/VI 200/25 µg QD
Arm/Group Description	Participants received a Vilanterol (VI) 25 µg dry inhalation powder once daily (QD) in the morning from the Dry Powder Inhaler (DPI) for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a Fluticasone Furoate/Vilanterol (FF/VI) 50/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a FF/VI 100/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a FF/VI 200/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
Measure Participants	409	408	403	402
Least Squares Mean (95% Confidence Interval) [Exacerbations per participant per year]	0.84	0.71	0.52	0.68

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VI 25 µg QD, FF/VI 50/25 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.125
	Comments
	Method	Generalized Linear Model
	Comments	Assuming Negative Binomial distribution with logarithm of time on treatment as an offset variable.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.67 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	VI 25 µg QD, FF/VI 100/25 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Nominal p-value
	Method	Generalized Linear Model
	Comments	Assuming Negative Binomial distribution with logarithm of time on treatment as an offset variable
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	VI 25 µg QD, FF/VI 200/25 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.064
	Comments
	Method	Generalized Linear Model
	Comments	Assuming Negative Binomial distribution with logarithm of time on treatment as an offset variable
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.64 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Trough FEV1 at Week 52 (Visit 11)
Description	Pulmonary function was measured by forced expiratory volume in one second (FEV1). Trough FEV1 was defined as the 24-hour post-dose FEV1 assessment, which was obtained at each visit. Analysis performed using a repeated measures model with covariates of treatment, smoking status at Screening (stratum), baseline (pre-dose Day 1), centre grouping, Week, Week by Baseline, and Week by treatment interactions.
Time Frame	Baseline to Visit 11 (Week 52)/Early Withdrawal

Outcome Measure Data

Analysis Population Description

ITT Population. Number of participants presented represent those with data available at the time point being presented, however all participants in the ITT population without missing covariate information and with at least one post Baseline measurement are included in the analysis.

Arm/Group Title	VI 25 µg QD	FF/VI 50/25 µg QD	FF/VI 100/25 µg QD	FF/VI 200/25 µg QD
Arm/Group Description	Participants received a Vilanterol (VI) 25 µg dry inhalation powder once daily (QD) in the morning from the Dry Powder Inhaler (DPI) for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a Fluticasone Furoate/Vilanterol (FF/VI) 50/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a FF/VI 100/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.	Participants received a FF/VI 200/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
Measure Participants	291	308	310	289
Least Squares Mean (Standard Error) [Liters]	-0.040 (0.0114)	0.000 (0.0112)	0.018 (0.0112)	0.024 (0.0114)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VI 25 µg QD, FF/VI 50/25 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments	Nominal p-value
	Method	Mixed Models Analysis
	Comments	Restricted maximum likelihood (REML)-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.041
	Confidence Interval	(2-Sided) 95%; 0.009 to 0.072
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	VI 25 µg QD, FF/VI 100/25 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Nominal p-value
	Method	Mixed Models Analysis
	Comments	Restricted maximum likelihood (REML)-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.058
	Confidence Interval	(2-Sided) 95%; 0.027 to 0.090
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	VI 25 µg QD, FF/VI 200/25 µg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Nominal p-value
	Method	Mixed Models Analysis
	Comments	Restricted maximum likelihood (REML)-based repeated measures approach (MMRM).
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	0.064
	Confidence Interval	(2-Sided) 95%; 0.033 to 0.096
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Serious adverse events (SAEs) and non-serious AEs will be collected from Baseline to the end of the treatment period (up to 52 weeks).
Adverse Event Reporting Description	SAEs and non-serious adverse events are reported for members of the Intent-to-Treat Population, comprised of all randomized participants who received at least one dose of study medication during the treatment period.
Arm/Group Title	VI 25 µg QD		FF/VI 50/25 µg QD		FF/VI 100/25 µg QD		FF/VI 200/25 µg QD
Arm/Group Description	Participants received a Vilanterol (VI) 25 µg dry inhalation powder once daily (QD) in the morning from the Dry Powder Inhaler (DPI) for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.		Participants received a Fluticasone Furoate/Vilanterol (FF/VI) 50/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.		Participants received a FF/VI 100/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.		Participants received a FF/VI 200/25 µg inhalation powder QD in the morning from the DPI for the duration of the 52 weeks. In addition, all participants were provided supplemental albuterol/salbutamol (MDI and/or nebules) to be used as needed throughout the study.
All Cause Mortality
	VI 25 µg QD		FF/VI 50/25 µg QD		FF/VI 100/25 µg QD		FF/VI 200/25 µg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	VI 25 µg QD		FF/VI 50/25 µg QD		FF/VI 100/25 µg QD		FF/VI 200/25 µg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	60/409 (14.7%)		65/408 (15.9%)		56/403 (13.9%)		63/402 (15.7%)
Blood and lymphatic system disorders
Anaemia	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		1/402 (0.2%)
Cardiac disorders
Myocardial infarction	1/409 (0.2%)		2/408 (0.5%)		2/403 (0.5%)		2/402 (0.5%)
Acute coronary syndrome	1/409 (0.2%)		1/408 (0.2%)		1/403 (0.2%)		0/402 (0%)
Angina pectoris	1/409 (0.2%)		2/408 (0.5%)		0/403 (0%)		0/402 (0%)
Angina unstable	2/409 (0.5%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Acute myocardial infarction	1/409 (0.2%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Atrial fibrillation	1/409 (0.2%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Cardiac failure congestive	1/409 (0.2%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Cardio-respiratory arrest	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Coronary artery stenosis	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Coronary artery thrombosis	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Palpitations	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Supraventricular tachycardia	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Arrhythmia	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Cardiac arrest	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Cardiac failure	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Eye disorders
Diplopia	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Gastrointestinal disorders
Rectal haemorrhage	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Upper gastrointestinal haemorrhage	1/409 (0.2%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Abdominal pain	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Abdominal pain lower	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Abdominal strangulated hernia	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Constipation	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Diverticulum intestinal	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Gastric ulcer haemorrhage	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Gastritis	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Gastritis erosive	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Gastrointestinal haemorrhage	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Gastrooesophageal reflux disease	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Haemorrhoids	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Hiatus hernia	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Ileus	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Melaena	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
AE Term: Salivary gland enlargement	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Small intestinal obstruction	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
General disorders
Chest pain	1/409 (0.2%)		2/408 (0.5%)		0/403 (0%)		0/402 (0%)
Death	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Non-cardiac chest pain	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Hepatobiliary disorders
Bile duct stone	1/409 (0.2%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Bile duct obstruction	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Cholecystitis	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Immune system disorders
Anaphylactic shock	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Infections and infestations
Pneumonia	2/409 (0.5%)		12/408 (2.9%)		9/403 (2.2%)		12/402 (3%)
Cellulitis	2/409 (0.5%)		0/408 (0%)		4/403 (1%)		0/402 (0%)
Infective exacerbation of chronic obstructive airway disease	2/409 (0.5%)		0/408 (0%)		2/403 (0.5%)		0/402 (0%)
Bronchitis	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		2/402 (0.5%)
Upper respiratory tract infection	2/409 (0.5%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Bronchopneumonia	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		1/402 (0.2%)
Lobar pneumonia	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		1/402 (0.2%)
Lung abscess	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		1/402 (0.2%)
Arthritis bacterial	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Bone tuberculosis	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Clostridium difficile colitis	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Escherichia sepsis	0/409 (0%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Gastroenteritis viral	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
H1N1 influenza	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Lower respiratory tract infection	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Mycobacterium avium complex infection	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Pulmonary tuberculosis	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Pyelonephritis acute	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Respiratory tract infection	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Septic shock	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Tuberculosis	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Urinary tract infection	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Urinary tract infection bacterial	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Injury, poisoning and procedural complications
Fall	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Foot fracture	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Head injury	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Hip fracture	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Laceration	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Operative haemorrhage	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Pneumothorax traumatic	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Spinal compression fracture	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Toxicity to various agents	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Wrist fracture	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Metabolism and nutrition disorders
Hypokalaemia	2/409 (0.5%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Hyperglycaemia	0/409 (0%)		0/408 (0%)		2/403 (0.5%)		0/402 (0%)
Diabetes mellitus inadequate control	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Hyponatraemia	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Hypovolaemia	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Ketoacidosis	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	2/409 (0.5%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Arthritis reactive	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Back pain	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Bursitis	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Costochondritis	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Intervertebral disc protrusion	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Joint stiffness	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Osteoarthritis	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pancreatic carcinoma metastatic	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		1/402 (0.2%)
Squamous cell carcinoma	0/409 (0%)		0/408 (0%)		0/403 (0%)		2/402 (0.5%)
Acute lymphocytic leukaemia	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Brain cancer metastatic	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Breast cancer	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Colon cancer	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Laryngeal cancer	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Lung cancer metastatic	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Lung neoplasm malignant	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Malignant hepatobiliary neoplasm	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Malignant melanoma	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Metastases to bone	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Metastases to liver	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Metastases to lung	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Metastatic carcinoma of the bladder	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Non-Hodgkin's lymphoma	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Small cell carcinoma	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Nervous system disorders
Cerebrovascular accident	0/409 (0%)		0/408 (0%)		2/403 (0.5%)		3/402 (0.7%)
Syncope	2/409 (0.5%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Carotid artery aneurysm	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Carotid artery stenosis	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Convulsion	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Dizziness	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Loss of consciousness	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Metabolic encephalopathy	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Psychiatric disorders
Depression	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Depression suicidal	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Renal and urinary disorders
Renal failure acute	0/409 (0%)		3/408 (0.7%)		0/403 (0%)		0/402 (0%)
Calculus urinary	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Haematuria	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Urethral stenosis	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	2/409 (0.5%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	28/409 (6.8%)		27/408 (6.6%)		26/403 (6.5%)		30/402 (7.5%)
Acute respiratory failure	0/409 (0%)		3/408 (0.7%)		3/403 (0.7%)		2/402 (0.5%)
Pleural effusion	0/409 (0%)		0/408 (0%)		2/403 (0.5%)		0/402 (0%)
Pneumothorax	0/409 (0%)		0/408 (0%)		0/403 (0%)		2/402 (0.5%)
Respiratory failure	0/409 (0%)		2/408 (0.5%)		0/403 (0%)		0/402 (0%)
Acute pulmonary oedema	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Asthma	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Bronchitis chronic	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Bronchopleural fistula	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Hypoxia	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Pulmonary embolism	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Pulmonary oedema	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Vocal cord disorder	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Vascular disorders
Hypertension	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		1/402 (0.2%)
Aortic aneurysm rupture	0/409 (0%)		0/408 (0%)		0/403 (0%)		1/402 (0.2%)
Haematoma	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Hypertensive crisis	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Peripheral arterial occlusive disease	0/409 (0%)		0/408 (0%)		1/403 (0.2%)		0/402 (0%)
Shock	1/409 (0.2%)		0/408 (0%)		0/403 (0%)		0/402 (0%)
Shock haemorrhagic	0/409 (0%)		1/408 (0.2%)		0/403 (0%)		0/402 (0%)
Other (Not Including Serious) Adverse Events
	VI 25 µg QD		FF/VI 50/25 µg QD		FF/VI 100/25 µg QD		FF/VI 200/25 µg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	197/409 (48.2%)		227/408 (55.6%)		221/403 (54.8%)		225/402 (56%)
Gastrointestinal disorders
Diarrhoea	15/409 (3.7%)		12/408 (2.9%)		8/403 (2%)		15/402 (3.7%)
Nausea	10/409 (2.4%)		24/408 (5.9%)		7/403 (1.7%)		10/402 (2.5%)
General disorders
Pyrexia	5/409 (1.2%)		17/408 (4.2%)		10/403 (2.5%)		8/402 (2%)
Infections and infestations
Nasopharyngitis	54/409 (13.2%)		58/408 (14.2%)		60/403 (14.9%)		76/402 (18.9%)
Upper respiratory tract infection	45/409 (11%)		47/408 (11.5%)		51/403 (12.7%)		39/402 (9.7%)
Oral candidiasis	21/409 (5.1%)		39/408 (9.6%)		34/403 (8.4%)		36/402 (9%)
Bronchitis	20/409 (4.9%)		13/408 (3.2%)		21/403 (5.2%)		23/402 (5.7%)
Sinusitis	17/409 (4.2%)		21/408 (5.1%)		22/403 (5.5%)		13/402 (3.2%)
Pneumonia	10/409 (2.4%)		17/408 (4.2%)		16/403 (4%)		16/402 (4%)
Influenza	21/409 (5.1%)		10/408 (2.5%)		13/403 (3.2%)		13/402 (3.2%)
Pharyngitis	14/409 (3.4%)		8/408 (2%)		14/403 (3.5%)		16/402 (4%)
Urinary tract infection	7/409 (1.7%)		16/408 (3.9%)		10/403 (2.5%)		17/402 (4.2%)
Rhinitis	6/409 (1.5%)		9/408 (2.2%)		10/403 (2.5%)		15/402 (3.7%)
Oropharyngeal candidiasis	2/409 (0.5%)		14/408 (3.4%)		7/403 (1.7%)		6/402 (1.5%)
Musculoskeletal and connective tissue disorders
Back pain	30/409 (7.3%)		21/408 (5.1%)		24/403 (6%)		20/402 (5%)
Arthralgia	13/409 (3.2%)		13/408 (3.2%)		16/403 (4%)		13/402 (3.2%)
Nervous system disorders
Headache	30/409 (7.3%)		27/408 (6.6%)		25/403 (6.2%)		34/402 (8.5%)
Dizziness	8/409 (2%)		13/408 (3.2%)		5/403 (1.2%)		3/402 (0.7%)
Respiratory, thoracic and mediastinal disorders
Cough	14/409 (3.4%)		21/408 (5.1%)		16/403 (4%)		13/402 (3.2%)
Oropharyngeal pain	13/409 (3.2%)		7/408 (1.7%)		14/403 (3.5%)		13/402 (3.2%)
Dyspnoea	10/409 (2.4%)		13/408 (3.2%)		6/403 (1.5%)		4/402 (1%)
Vascular disorders
Hypertension	6/409 (1.5%)		15/408 (3.7%)		19/403 (4.7%)		12/402 (3%)

Limitations/Caveats

[Not Specified]

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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.