Safety and Efficacy Study of Fluticasone Furoate/Vilanterol (FF/VI) Fixed Dose Combination (FDC) Compared to FF Alone in Subjects With Asthma

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Completed

CT.gov ID

NCT03248128

Collaborator

(none)

908

Enrollment

184

Locations

Arms

53.3

Actual Duration (Months)

4.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The goal of asthma treatment is to achieve and maintain asthma control and to reduce the future risk of exacerbations. Inhaled corticosteroids (ICS) are considered as the most effective anti- inflammatory treatment for all severities of persistent asthma. For children

=5 years of age and adolescents whose asthma is uncontrolled, low-dose ICS plus adjunctive therapy with long-acting beta agonist (LABA) is considered as effective. Thus, this study is designed to evaluate the efficacy and safety of FF (ICS component)/VI (LABA component) compared to FF alone for the treatment of asthma, in subjects aged 5 to 17 years old currently uncontrolled on ICS. The study will be conducted over a total duration of approximately 29 weeks: 4 week run-in period, 24-week double-blind treatment period and 1-week follow-up period. Subjects will be randomized to receive FDC of FF/VI or FF administered via ELLIPTA® dry powder inhaler (DPI). The dose of both FF/VI and FF alone will be selected based on the age of subjects. Subjects will receive a short acting beta 2 agonist (SABA) (albuterol /salbutamol) as a rescue medication throughout the study. A total of 870 subjects will be randomized in the study. Of this, 652 subjects will be aged 5 to 11 years (cohort A), and 218 will be aged 12 to 17 years inclusive (cohort B). ELLIPTA is a registered trademark of GlaxoSmithKline (GSK) group of companies.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: FF/VI via ELLIPTA DPI Drug: FF via ELLIPTA DPI	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

908 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Subjects will be randomized to receive FDC of FF/VI inhalation powder compared to FF inhalation powder, once daily in cohort A and cohort B.Subjects will be randomized to receive FDC of FF/VI inhalation powder compared to FF inhalation powder, once daily in cohort A and cohort B.

Masking:

Double (Participant, Investigator)

Masking Description:

This will be a double blind study. Subjects and investigator will be masked.

Primary Purpose:

Treatment

Official Title:

A Randomised, Double-blind, Parallel Group, Multicentre, Stratified, Study Evaluating the Efficacy and Safety of Once Daily Fluticasone Furoate/Vilanterol Inhalation Powder Compared to Once Daily Fluticasone Furoate Inhalation Powder in the Treatment of Asthma in Participants Aged 5 to 17 Years Old (Inclusive) Currently Uncontrolled on Inhaled Corticosteroids

Actual Study Start Date :

Oct 20, 2017

Actual Primary Completion Date :

Mar 21, 2022

Actual Study Completion Date :

Mar 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Subjects receiving FF/VI in cohort A Subjects will be randomized in 1:1 ratio to receive a FDC of FF/VI with a dose of 50/25 mcg administered once daily in the morning via ELLIPTA DPI.	Drug: FF/VI via ELLIPTA DPI ELLIPTA DPI inhaler will contain two individual blister strips; the first strip will contain FF(50 or 100 mcg) and second strip will contain VI (25 mcg).
Active Comparator: Subjects receiving FF in cohort A Subjects will be randomized in 1:1 ratio to receive FF with a dose of 50 mcg administered once daily in the morning via ELLIPTA DPI.	Drug: FF via ELLIPTA DPI ELLIPTA DPI inhaler will contain a single blister strip of FF (50 or 100 mcg).
Experimental: Subjects receiving FF/VI in cohort B Subjects will be randomized in 1:1 ratio to receive a FDC of FF/VI with a dose of 100/25 mcg administered once daily in the morning via ELLIPTA DPI.	Drug: FF/VI via ELLIPTA DPI ELLIPTA DPI inhaler will contain two individual blister strips; the first strip will contain FF(50 or 100 mcg) and second strip will contain VI (25 mcg).
Active Comparator: Subjects receiving FF in cohort B Subjects will be randomized in 1:1 ratio to receive FF with a dose of 100 mcg administered once daily in the morning via ELLIPTA DPI.	Drug: FF via ELLIPTA DPI ELLIPTA DPI inhaler will contain a single blister strip of FF (50 or 100 mcg).

Outcome Measures

Primary Outcome Measures

Cohort A: Change from Baseline, in pre-dose (i.e. trough) morning peak expiratory flow (PEF) averaged over weeks 1-12 of the treatment period [Baseline and up to Week 12]
PEF is defined as the maximum speed of expiration of a person. PEF will be measured using a hand-held electronic peak flow meter each morning prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. The best of three measurements will be recorded in the daily diary.
Cohort A and B: Weighted mean forced expiratory volume in 1 second (FEV1) (0-4 hours) at Week 12 [Week 12]
Pulmonary function will be measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 will be measured using a standardized calibrated spirometer prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use.

Secondary Outcome Measures

Cohort A: Weighted mean of FEV1 (0-4 hours) at Week 12 [Week 12]
Pulmonary function will be measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 will be measured using a standardized calibrated spirometer prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use.
Cohort A and B: Change from Baseline, in pre-dose (i.e. trough) morning PEF averaged over weeks 1-12 of the treatment period [Baseline and up to Week 12]
PEF is defined as the maximum speed of expiration of a person. PEF will be measured using a hand-held electronic peak flow meter each morning prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use. The best of three measurements will be recorded in the daily diary.
Cohort A and B: Change from Baseline in the percentage of rescue-free 24-hour periods over weeks 1-12 of the treatment period [Baseline and up to Week 12]
The number of inhalations of rescue albuterol/salbutamol aerosol used during the day and night will be recorded in a daily electronic diary. A 24-hour period in which the response of subjects to both the morning and evening assessments indicated no use of rescue medication will be considered as 'rescue free'.
Cohort A and B: Change from Baseline in the percentage of symptom-free 24-hour periods over weeks 1-12 of the treatment period [Baseline and up to Week 12]
The symptom-free days will be recorded in a daily electronic diary every day in the morning and evening before taking any rescue or study medication and before the PEF measurement. A 24-hour period in which the response of subjects to both the morning and evening assessments indicated no symptoms will be considered as 'symptom free'.
Cohort A and B: Change from Baseline in morning (ante meridiem [AM]) FEV1 at Week 12 [Baseline and at Week 12]
Pulmonary function will be measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. Morning FEV1 will be measured using a standardized calibrated spirometer prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use.
Cohort A and B: Change from Baseline in asthma control questionnaire (ACQ-5) at Week 24 [Baseline and at Week 24]
The ACQ-5 is a five-item questionnaire, which includes five questions (concerning nocturnal awakening, waking in the morning, activity limitation, shortness of breath and wheeze). The questions will enquire about the frequency and/or severity of symptoms over the previous week and will be self-completed by the subjects. The response options for all these questions will consist of a scale ranging from 0 (no impairment/limitation) to 6 (total impairment/ limitation). A score of <0.75 indicates well-controlled asthma and a score >=1.5 indicates poorly controlled asthma. A change of >=0.5 in score suggests a clinically important change in score.
Cohort A and B: Number of subjects with incidence of exacerbations over the 24-Week treatment period [Up to Week 24]
An exacerbation is defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days or a single depot corticosteroid injection or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids. Information regarding asthma exacerbations will be collected and recorded over the specified period.
Cohort A and B: Number of subjects with adverse events (AEs), serious adverse events (SAEs) [Up to Week 25]
An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.
Cohort A and B: Number of subjects with abnormal electrocardiogram (ECG) findings [Up to Week 24]
A single 12-lead ECG will be obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT interval corrected (QTc).
Cohort A and B:Number of subjects with abnormal fasting blood glucose levels [Up to Week 24]
Blood samples will be collected for evaluation of fasting blood glucose pre- and post-treatment.

Eligibility Criteria

Criteria

Ages Eligible for Study:

5 Years to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

For all subjects: Between 5 and 17 years of age inclusive, at the time of signing the informed consent.
A history of symptoms consistent with a diagnosis of asthma for at least 6 months.
Pre-bronchodilator FEV1 >50 percent to <=90 percent predicted normal. A minimum of 2 efforts that are considered acceptable (not necessarily repeatable) are required to be eligible.
Lung function reversibility defined as an increase of >=12 percent in FEV1 within 10 to 40 minutes following 2 to 4 inhalations of salbutamol inhalation aerosol (or 1 nebulized treatment with albuterol/salbutamol solution). Use of a spacer is permitted.
Uncontrolled asthma, with a childhood asthma control test (cACT)/ACT score <=19.
Receiving stable asthma therapy (SABA inhaler plus ICS [total daily dose <=FP 250 micrograms (mcg) or equivalent]) for at least 4 weeks prior to Visit 1 (i.e. screening).
Able to replace their current SABA treatment with salbutamol aerosol inhaler at Visit 1 for use as needed for the duration of the study. Salbutamol metered dose inhaler (MDI) will be administered with or without a spacer, to be used as determined by the investigator. The use or non-use of the spacer should be consistent for an individual subject throughout the study.
Male or female subjects will be included. Females of reproductive potential must agree to follow 1 of the options listed (which include abstinence) in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication and until at least five terminal half-lives or until any continuing pharmacologic effect has ended, whichever is longer after the last dose of study medication and completion of the follow-up call. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
Written informed consent from at least 1 parent/care giver (legal guardian) and accompanying informed assent from the subject (where the subject is able to provide assent) prior to admission to the study. If applicable, subject must be able and willing to give assent to take part in the study according to the local requirement. The study investigator is accountable for determining a child's capacity to assent to participation in a research study, taking into consideration any standards set by the responsible independent ethics committee (IEC); subject and their legal guardian(s) understand that the study requires them to be treated on an outpatient basis; subject and their legal guardian(s) understand that they must comply with study medication and study assessments including recording of PEF and rescue SABA use, attending scheduled study visits, and being accessible by a telephone call.
For subjects eligible for randomization; asthma control: uncontrolled asthma, with a cACT/ACT score <=19.
A technically acceptable pre-bronchodilator FEV1 >50 percent to <=90 percent predicted normal at Visit 2. A minimum of 2 efforts that are considered acceptable and repeatable following the over read are required to be eligible.
Symptoms and rescue use: demonstrated and reported in a daily diary symptoms of asthma (a score of >=1 on the day-time or night-time asthma symptom scores) and/or daily albuterol/salbutamol on at least 3 of the last 7 consecutive days of the run-in period (not including the date of randomization).
Compliance with run-in medication: compliance is defined as use of run-in medication on at least 4 of the last 7 consecutive days of the run-in period (not including the date of randomization) recorded in the electronic subject diary.
Compliance with completion of the daily diary reporting: defined as completion of all questions on 4 out of the last 7 days during the run-in period (not including the date of randomization).

Exclusion Criteria:

For all subjects: History of life threatening asthma defined as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic seizures.
Any asthma exacerbation requiring the use of oral steroids within 6 weeks of Visit 1, systemic or depot corticosteroids within 12 weeks of Visit 1, or ER attendance within 3 months of Visit 1 or hospitalization within 6 months of Visit 1.
A culture documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that has not resolved within 4 weeks of Visit 1 and which led to a change in asthma management or, in the opinion of the investigator, is expected to affect the subject's asthma status or the subject's ability to participate in the study.
Clinical visual evidence of oropharyngeal candidiasis.
Fasting blood glucose at screening >100 milligrams/deciliter (mg/dL) (5.6 moles per liter [mol/L]).
Obesity (Body Mass Index [BMI] above the 97th centile based on the centers for disease control and prevention [CDC] charts).
Any significant abnormality or medical condition identified at the screening medical assessment (including serious psychological disorder) that in the investigator's opinion, preclude entry into the study due to risk to the subject or that may interfere with the conduct and/or outcome of the study.
QTc >450 milliseconds (msec) or QTc >480 msec in subjects with bundle branch block or any other clinically significant abnormality in the screening 12-lead ECG.
Use of any prohibited medications.
Present use of any tobacco products.
Drug allergies: any adverse reaction including immediate or delayed hypersensitivity to any beta 2-agonists, sympathomimetic drug or any intranasal, inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of the ELLIPTA Inhaler (i.e. lactose or magnesium stearate).
Milk Protein Allergy: history of severe milk protein allergy.
Participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, five half-lives or twice the duration of the biological effect of the study treatment (whichever is longer).
Exposure to more than 4 investigational medicinal products within 12 months prior to the first dosing day.
An affiliation with the investigator site: the parents/guardians or child is an immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator.
The parent or guardian has a history of psychiatric disease, intellectual deficiency, substance abuse or other condition (example, inability to read, comprehend or write) which may affect: validity of consent to participate in the study; adequate supervision of the subject during the study; compliance of subject with study medication and study procedures (example, completion of daily diary, attending scheduled clinic visits); subject safety and well-being.
Children in care: children who are wards of the government or state are not eligible for participation in this study.
For subjects eligible for randomization; Changes in asthma medication that occur after screening.
Occurrence of a culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear during the run-in period that led to a change in asthma management or, in the opinion of the investigator, is expected to affect the subject's asthma status or the subject's ability to participate in the study.
Evidence of an exacerbation, defined as a: deterioration of asthma requiring the use of oral corticosteroids for at least 3 days, or a depot corticosteroid injection, or an in-patient hospitalization due to asthma that required systemic corticosteroids between screening and randomization.
Clinical visual evidence of oropharyngeal candidiasis at the randomization Visit.
Unable to use the ELLIPTA inhaler correctly.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Hoover	Alabama	United States	35244
2	GSK Investigational Site	Little Rock	Arkansas	United States	72205
3	GSK Investigational Site	Huntington Beach	California	United States	92648
4	GSK Investigational Site	Riverside	California	United States	92506
5	GSK Investigational Site	Colorado Springs	Colorado	United States	80907
6	GSK Investigational Site	Denver	Colorado	United States	80206
7	GSK Investigational Site	Denver	Colorado	United States	80230
8	GSK Investigational Site	Aventura	Florida	United States	33180
9	GSK Investigational Site	Miami Lakes	Florida	United States	33014
10	GSK Investigational Site	Miami	Florida	United States	33134
11	GSK Investigational Site	Miami	Florida	United States	33135
12	GSK Investigational Site	Miami	Florida	United States	33142
13	GSK Investigational Site	Miami	Florida	United States	33173
14	GSK Investigational Site	Miami	Florida	United States	33186
15	GSK Investigational Site	Ocala	Florida	United States	34470
16	GSK Investigational Site	Orlando	Florida	United States	32806
17	GSK Investigational Site	Orlando	Florida	United States	32827
18	GSK Investigational Site	Gainesville	Georgia	United States	30501
19	GSK Investigational Site	Savannah	Georgia	United States	31406
20	GSK Investigational Site	Evanston	Illinois	United States	60201
21	GSK Investigational Site	Oak Park	Illinois	United States	60301
22	GSK Investigational Site	Evansville	Indiana	United States	47715
23	GSK Investigational Site	Owensboro	Kentucky	United States	42301
24	GSK Investigational Site	Baltimore	Maryland	United States	21236
25	GSK Investigational Site	White Marsh	Maryland	United States	21162
26	GSK Investigational Site	Ypsilanti	Michigan	United States	48197
27	GSK Investigational Site	Piscataway	New Jersey	United States	08854
28	GSK Investigational Site	Verona	New Jersey	United States	07044
29	GSK Investigational Site	Great Neck	New York	United States	11021
30	GSK Investigational Site	New Hartford	New York	United States	13413
31	GSK Investigational Site	Asheville	North Carolina	United States	28801
32	GSK Investigational Site	Charlotte	North Carolina	United States	28277
33	GSK Investigational Site	Raleigh	North Carolina	United States	27607
34	GSK Investigational Site	Grove City	Ohio	United States	43123
35	GSK Investigational Site	Oklahoma City	Oklahoma	United States	73120
36	GSK Investigational Site	Medford	Oregon	United States	97504
37	GSK Investigational Site	Wexford	Pennsylvania	United States	15090
38	GSK Investigational Site	Greenville	South Carolina	United States	29607
39	GSK Investigational Site	Orangeburg	South Carolina	United States	29118-2040
40	GSK Investigational Site	Spartanburg	South Carolina	United States	29303
41	GSK Investigational Site	Summerville	South Carolina	United States	29485
42	GSK Investigational Site	Dallas	Texas	United States	75231-4307
43	GSK Investigational Site	Houston	Texas	United States	77055
44	GSK Investigational Site	Lewisville	Texas	United States	75067
45	GSK Investigational Site	San Antonio	Texas	United States	78207
46	GSK Investigational Site	San Antonio	Texas	United States	78215
47	GSK Investigational Site	San Antonio	Texas	United States	78249
48	GSK Investigational Site	Waco	Texas	United States	76712
49	GSK Investigational Site	Murray	Utah	United States	84107
50	GSK Investigational Site	Berazategui	Buenos Aires	Argentina	1837
51	GSK Investigational Site	Caba	Buenos Aires	Argentina	C1028AAP
52	GSK Investigational Site	Caba	Buenos Aires	Argentina	C1425BEN
53	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1122AAK
54	GSK Investigational Site	Florida	Buenos Aires	Argentina	1602
55	GSK Investigational Site	La Plata	Buenos Aires	Argentina	1900
56	GSK Investigational Site	Lanús	Buenos Aires	Argentina	B1824KAJ
57	GSK Investigational Site	Lobos	Buenos Aires	Argentina	7240
58	GSK Investigational Site	Mar del Plata	Buenos Aires	Argentina	7600
59	GSK Investigational Site	Nueve de Julio	Buenos Aires	Argentina	B6500BWQ
60	GSK Investigational Site	Buenos Aires		Argentina	C1121ABE
61	GSK Investigational Site	Buenos Aires		Argentina	C1425FVH
62	GSK Investigational Site	Ciudad Autónoma de Buenos Aires		Argentina	C1121ABE
63	GSK Investigational Site	Ciudad Autónoma de Buenos Aires		Argentina	C1426ABP
64	GSK Investigational Site	Mendoza		Argentina	M5500CCG
65	GSK Investigational Site	Rosario		Argentina	S2000BRH
66	GSK Investigational Site	Santa Fe		Argentina	3000
67	GSK Investigational Site	Ruse		Bulgaria	7002
68	GSK Investigational Site	Sofia		Bulgaria	1510
69	GSK Investigational Site	Sofia		Bulgaria	1784
70	GSK Investigational Site	Stara Zagora		Bulgaria	5400
71	GSK Investigational Site	Brampton	Ontario	Canada	L6T 0G1
72	GSK Investigational Site	Windsor	Ontario	Canada	N8X2G1
73	GSK Investigational Site	Québec		Canada	G1V 4W2
74	GSK Investigational Site	Panzhihua	Sichuan	China	617023
75	GSK Investigational Site	Taiyuan		China	030013
76	GSK Investigational Site	Heidelberg	Baden-Wuerttemberg	Germany	69126
77	GSK Investigational Site	Mannheim	Baden-Wuerttemberg	Germany	68161
78	GSK Investigational Site	Rosenheim	Bayern	Germany	83026
79	GSK Investigational Site	Geesthacht	Schleswig-Holstein	Germany	21502
80	GSK Investigational Site	Budapest		Hungary	1083
81	GSK Investigational Site	Budapest		Hungary	1089
82	GSK Investigational Site	Szeged		Hungary	H-6720
83	GSK Investigational Site	Parma	Emilia-Romagna	Italy	43126
84	GSK Investigational Site	Roma	Lazio	Italy	00165
85	GSK Investigational Site	Bergamo	Lombardia	Italy	24127
86	GSK Investigational Site	Milano	Lombardia	Italy	20122
87	GSK Investigational Site	Milano	Lombardia	Italy	20154
88	GSK Investigational Site	Ancona	Marche	Italy	60123
89	GSK Investigational Site	Palermo	Sicilia	Italy	9000
90	GSK Investigational Site	Perugia	Umbria	Italy	06156
91	GSK Investigational Site	Chiba		Japan	260-0001
92	GSK Investigational Site	Fukui		Japan	918-8205
93	GSK Investigational Site	Fukuoka		Japan	811-1394
94	GSK Investigational Site	Fukuoka		Japan	813-0017
95	GSK Investigational Site	Hiroshima		Japan	721-8511
96	GSK Investigational Site	Hokkaido		Japan	040-8585
97	GSK Investigational Site	Hokkaido		Japan	040-8611
98	GSK Investigational Site	Hyogo		Japan	653-0836
99	GSK Investigational Site	Kanagawa		Japan	223-0059
100	GSK Investigational Site	Osaka		Japan	583-8588
101	GSK Investigational Site	Tokyo		Japan	104-0031
102	GSK Investigational Site	Tokyo		Japan	154-0017
103	GSK Investigational Site	Tokyo		Japan	157-0066
104	GSK Investigational Site	Tokyo		Japan	158-0097
105	GSK Investigational Site	Tokyo		Japan	171-0014
106	GSK Investigational Site	Tokyo		Japan	176-0012
107	GSK Investigational Site	Vilnius		Lithuania	9108
108	GSK Investigational Site	Guadalajara	Jalisco	Mexico	44100
109	GSK Investigational Site	Guadalajara	Jalisco	Mexico	44670
110	GSK Investigational Site	Zapopan	Jalisco	Mexico	45070
111	GSK Investigational Site	Monterrey	Nuevo León	Mexico	64000
112	GSK Investigational Site	Monterrey	Nuevo León	Mexico	64710
113	GSK Investigational Site	Villahermosa	Tabasco	Mexico	86035
114	GSK Investigational Site	Bialystok		Poland	15-430
115	GSK Investigational Site	Bialystok		Poland	15879
116	GSK Investigational Site	Bydgoszcz		Poland	85-796
117	GSK Investigational Site	Czestochowa		Poland	42-200
118	GSK Investigational Site	Katowice		Poland	40-040
119	GSK Investigational Site	Krakow		Poland	31-011
120	GSK Investigational Site	Lodz		Poland	90-153
121	GSK Investigational Site	Lodz		Poland	90-329
122	GSK Investigational Site	Ostrow Wielkopolski		Poland	63-400
123	GSK Investigational Site	Ostrowiec Swietokrzyski		Poland	27-400
124	GSK Investigational Site	Poznan		Poland	60-693
125	GSK Investigational Site	Skierniewice		Poland	96-100
126	GSK Investigational Site	Strzelce Opolskie		Poland	47-100
127	GSK Investigational Site	Tarnow		Poland	33-100
128	GSK Investigational Site	Warszawa		Poland	01-192
129	GSK Investigational Site	Wroclaw		Poland	50-088
130	GSK Investigational Site	Zabrze		Poland	41-800
131	GSK Investigational Site	Brasov		Romania	500091
132	GSK Investigational Site	Brasov		Romania	500283
133	GSK Investigational Site	Bucuresti		Romania	020395
134	GSK Investigational Site	Bucuresti		Romania	030961
135	GSK Investigational Site	Bucuresti		Romania	051543
136	GSK Investigational Site	Targu Mures		Romania	540136
137	GSK Investigational Site	Krasnodar		Russian Federation	350012
138	GSK Investigational Site	Moscow		Russian Federation	1154461
139	GSK Investigational Site	Moscow		Russian Federation	119333
140	GSK Investigational Site	Moscow		Russian Federation	119435
141	GSK Investigational Site	Moscow		Russian Federation	119991
142	GSK Investigational Site	Moscow		Russian Federation	127473
143	GSK Investigational Site	Moscow		Russian Federation	129110
144	GSK Investigational Site	Omsk		Russian Federation	644050
145	GSK Investigational Site	Penza		Russian Federation	440067
146	GSK Investigational Site	Perm		Russian Federation	614066
147	GSK Investigational Site	Saint Petersburg		Russian Federation	191036
148	GSK Investigational Site	Saint Petersburg		Russian Federation	192148
149	GSK Investigational Site	Saint Petersburg		Russian Federation	192212
150	GSK Investigational Site	Saint Petersburg		Russian Federation	194291
151	GSK Investigational Site	Saint Petersburg		Russian Federation	196240
152	GSK Investigational Site	Saint Petersburg		Russian Federation	196657
153	GSK Investigational Site	Saint-Petersburg		Russian Federation	193312
154	GSK Investigational Site	Saint-Petersburg		Russian Federation	196191
155	GSK Investigational Site	Samara		Russian Federation	443031
156	GSK Investigational Site	Saransk		Russian Federation	430000
157	GSK Investigational Site	Saratov		Russian Federation	410012
158	GSK Investigational Site	St'Petersburg		Russian Federation	191144
159	GSK Investigational Site	St. Petersburg		Russian Federation	194100
160	GSK Investigational Site	St. Petersburg		Russian Federation	194223
161	GSK Investigational Site	Tomsk		Russian Federation	634 050
162	GSK Investigational Site	Ufa		Russian Federation	450008
163	GSK Investigational Site	Volgograd		Russian Federation	400131
164	GSK Investigational Site	Voronezh		Russian Federation	394036
165	GSK Investigational Site	Yaroslavl		Russian Federation	150003
166	GSK Investigational Site	Boksburg	Gauteng	South Africa	1459
167	GSK Investigational Site	Johannesburg	Gauteng	South Africa	1818
168	GSK Investigational Site	Pretoria	Gauteng	South Africa	0184
169	GSK Investigational Site	Middelburg	Mpumalanga	South Africa	1055
170	GSK Investigational Site	Panorama	Western Province	South Africa	7500
171	GSK Investigational Site	Bellville		South Africa	7530
172	GSK Investigational Site	Bloemfontein		South Africa	9301
173	GSK Investigational Site	Cape Town		South Africa	7700
174	GSK Investigational Site	Durban		South Africa	4001
175	GSK Investigational Site	Pretoria		South Africa	0001
176	GSK Investigational Site	Pretoria		South Africa	0181
177	GSK Investigational Site	Somerset West		South Africa	7130
178	GSK Investigational Site	Soweto		South Africa	1818
179	GSK Investigational Site	Umkomaas		South Africa	4170
180	GSK Investigational Site	Vosloorus Ext 2		South Africa	1475
181	GSK Investigational Site	Badalona		Spain	08916
182	GSK Investigational Site	Barcelona		Spain	08003
183	GSK Investigational Site	Barcelona		Spain	08035
184	GSK Investigational Site	Madrid		Spain	28041