ALITHIOS: Long-term Safety, Tolerability and Effectiveness Study of Ofatumumab in Patients With Relapsing MS

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03650114

Collaborator

(none)

2,010

Enrollment

292

Locations

Arm

117.2

Anticipated Duration (Months)

6.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to collect long-term safety, tolerability, effectiveness and health outcomes data in eligible subjects who have participated in a Novartis ofatumumab clinical MS study.

Vaccination sub-study The purpose of this research sub-study is to find out the effects of ofatumumab on the development of antibody responses to selected vaccines and keyhole limpet hemocyanin (KLH) neo-antigen in subjects with relapsing multiple sclerosis (RMS).

Condition or Disease	Intervention/Treatment	Phase
Relapsing Multiple Sclerosis	Biological: Ofatumumab Biological: Tetanus toxoid (TT) containing vaccine (Td, Tdap) Biological: 13-valent pneumococcal conjugate vaccine (13-PCV) Biological: 23-valent pneumococcal polysaccharide vaccine (23-PPV) Biological: Seasonal Quadrivalent influenza vaccine Biological: Keyhole limpet hemocyanin (KLH) neo-antigen	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

2010 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-label, Single Arm, Multi-center Extension Study Evaluating Long-term Safety, Tolerability and Effectiveness of Ofatumumab in Subjects With Relapsing Multiple Sclerosis

Actual Study Start Date :

Dec 28, 2018

Anticipated Primary Completion Date :

Oct 3, 2028

Anticipated Study Completion Date :

Oct 3, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ofatumumab Subcutaneous injection	Biological: Ofatumumab subcutaneous injection of 20 mg ofatumumab every 4 weeks Biological: Tetanus toxoid (TT) containing vaccine (Td, Tdap) 0.5mL Vial/Syringe Containing 5 limit of flocculation (LF) tetanus toxoid Biological: 13-valent pneumococcal conjugate vaccine (13-PCV) 0.5mL Vial/Syringe Biological: 23-valent pneumococcal polysaccharide vaccine (23-PPV) 0.5mL Vial/Syringe Biological: Seasonal Quadrivalent influenza vaccine Seasonal 2020-2021 0.5mL Vial/Syringe (trivalent may be used where quadrivalent is not available) Biological: Keyhole limpet hemocyanin (KLH) neo-antigen 1mg Vial

Arm

Intervention/Treatment

Experimental: Ofatumumab

Subcutaneous injection

Biological: Ofatumumab

subcutaneous injection of 20 mg ofatumumab every 4 weeks

Biological: Tetanus toxoid (TT) containing vaccine (Td, Tdap)

0.5mL Vial/Syringe Containing 5 limit of flocculation (LF) tetanus toxoid

Biological: 13-valent pneumococcal conjugate vaccine (13-PCV)

0.5mL Vial/Syringe

Biological: 23-valent pneumococcal polysaccharide vaccine (23-PPV)

0.5mL Vial/Syringe

Biological: Seasonal Quadrivalent influenza vaccine

Seasonal 2020-2021 0.5mL Vial/Syringe (trivalent may be used where quadrivalent is not available)

Biological: Keyhole limpet hemocyanin (KLH) neo-antigen

1mg Vial

Outcome Measures

Primary Outcome Measures

Number of patients that experience an adverse event or abnormal laboratory, vital and/or ECG results and positive suicidiality outcomes [Up to 5 years]

Secondary Outcome Measures

Number of relapse rates per year [Core studies up to 5 years from first dose of ofatumumab (depending on if first dose was in the core or in this extension study or comparator randomization)]
Annual Relapse Rate (ARR) time calculated as number of confirmed relapses divided by time in study per year and will also be presented for the entire duration
Patients with confirmed 3 and 6 month disability worsening [Duration of the study, approximately 5 years]
A confirmed disability worsening is an increase from baseline in Expanded Disability Status Scale (EDSS) score sustained for at last 3, or 6 months EDSS consists of seven functional systems and an ambulation score that are then combined to determine the EDSS steps (ranging from 0 (normal) to 10 (death due to MS)). The functional systems are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, and Cerebral functions (Fatigue contributes).
Patients with confirmed 6, 12 and 24 month disability improvement and improvement until end of study [Duration of the study, approximately 5 years]
Confirmed disability improvement is a decrease from baseline in Expanded Disability Status Scale (EDSS) score sustained for at least 6, 12 or 24 months EDSS consists of seven functional systems and an ambulation score that are then combined to determine the EDSS steps (ranging from 0 (normal) to 10 (death due to MS)). The functional systems are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, and Cerebral functions (Fatigue contributes).
Patients with changes in Expanded Disability Status Scale (EDSS) scores [Core studies up to 5 years from first dose of ofatumumab (depending on if first dose was in the core or in this extension study or comparator randomization)]
Score changes in Expanded Disability Status Scale (EDSS) over time EDSS consists of seven functional systems and an ambulation score that are then combined to determine the EDSS steps (ranging from 0 (normal) to 10 (death due to MS)). The functional systems are Visual, Brain Stem, Pyramidal, Cerebellar, Sensory, Bowel and Bladder, and Cerebral functions (Fatigue contributes).
Changes in and time to 6 month confirmed worsening of Symbol Digit Modalities Test Scores [Duration of the study, approximately 5 years]
Score changes and confirmed 4-point worsening sustained for 6 months in Symbol Digit Modalities Test (SDMT) scores The Symbol Digit Modalities Test is a neuropsychological, timed test for sustained attention and concentration. 3 versions will be used, alternating at each visit where done. The number of correct responses will be counted for the score.
Changes in the Magnetic Resonance Image (MRI) related to brain volume loss [Core studies up to 5 years from first dose of ofatumumab (depending on if first dose was in the core or in this extension study or comparator randomization)]
Percent change from baseline in brain volume loss (BVL)
Changes in the Magnetic Resonance Image (MRI) related to T2 lesions [Core studies up to 5 years from first dose of ofatumumab (depending on if first dose was in the core or in this extension study or comparator randomization)]
Number of new or enlarging T2 lesions
Changes in the Magnetic Resonance Image (MRI) related to Gd-enhancing lesions [Core studies up to 5 years from first dose of ofatumumab (depending on if first dose was in the core or in this extension study or comparator randomization)]
Total number of Gd-enhancing lesions on all MRI scans adjusted for different time of scan versus follow up time in study
Changes in neurofilament light change serum concentration [Core studies up to 5 years from first dose of ofatumumab (depending on if first dose was in the core or in this extension study or comparator randomization)]
Extent of neurofilament light change concentration in blood NfL is a component of the neuronal cytoskeleton and is released into the cerebrospinal fluid and into subsequently blood following neuro-axonal damage

Other Outcome Measures

Hummoral immune response to TT vaccine [Pre-vaccination, 4 and 8 weeks post-vaccination]
Proportion of subjects with a positive antibody response to TT vaccine measured 4 and 8 weeks after vaccination while treated with ofatumumab 2-fold increase in titer level Tetanus anti-bodies ≥ 0.2 IU/mL Mean titers of anti-tetanus antibody
Hummoral immune response to 13-valent pneumococcal conjugate vaccine (13-PCV) [4 and 8 weeks]
Proportion of subjects with a positive antibody response against individual anti-pneumococcal antibody serotypes while treated with ofatumumab 2-fold increase in titer level or a > 1 microgram/mL rise in titer compared with pre-immunization titer Positive anti-body response against at least 2 of the 13 pneumococcal antibody serotypes Positive anti-body response against at least 50% of serotypes Mean titers of anti-pneumococcal antibody
Hummoral immune response to 13-PCV boosted eight weeks later by 23-valent pneumococcal polysaccharide vaccine (23-PPV) [Pre-vaccination, 4 and 8 weeks post-vaccination]
Proportion of subjects with a positive antibody response against individual anti-pneumococcal antibody serotypes (23 serotypes to be tested individually) measured 4 and 8 weeks after the booster 23-PPV while the subject continues to be treated with ofatumumab 2-fold increase in titer level or a > 1 microgram/mL rise in titer compared with pre-immunization titer Positive anti-body response against at least 2 of the 23 pneumococcal antibody serotypes Positive anti-body response against at least 50% of serotypes Mean titers of anti-pneumococcal antibody
Humoral immune response to KLH neo-antigen [Pre-administration, 4, 8, 12 weeks after initial administration and 4 weeks after last administration]
Mean titers of anti-KLH antibody measured immediately prior the first administration of KLH and measured immediately prior to the first administration, 4, 8 and 12 weeks after the first administration, and measured 4 weeks post last administration of KLH
Hummoral immune response to 2020-2021 seasonal quadrivalent influenza vaccine [Pre-vaccination and 4 weeks post-vaccination]
Proportion of subjects fulfilling: Seroconversion: The pre-vaccination HI antibody titer is < 1:10 and the postvaccination measurement is ≥ 1:40 (this applies to subjects with a pre-vaccination HI titer < 1:10), or Significant increase in HI antibody titer: The pre-vaccination HI antibody titer is ≥ 1:10 and the increase from the pre- to the post-vaccination measurement is ≥ 4-fold (this applies to subjects with a pre-vaccination HI titer ≥ 1:10)
Antibody response rate to TT and influenza vaccination as a function of exposure to ofatumumab [8 weeks]
Immune response to TT and influenza vaccination

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 100 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Must have completed a selected Novartis MS study which dosed ofatumumab 20 mg sc every 4 weeks
Written informed consent

Exclusion Criteria:

Emergence of any clinically significant condition/disease during the previous ofatumumab study in which study participation might result in safety risk for the subject
Subjects with active systemic bacterial, viral or fingal infections, or chronic infection (e.g. AIDS)
Subjects taking medications prohibited by the protocol
Pregnant or nursing (lactating) women Other protocol-defined inclusion/exclusion criteria may apply

Vaccination sub-study:

Inclusion criteria

Informed consent
Actively enrolled in the COMB157G2399 Study
12 weeks of continuous treatment within the COMB157G2399 Study
prior vaccination history as per protocol-defined

Exclusion criteria

known hypersensitivity or history of systemic allergic, neurologic or other reactions to vaccines
allergies to egg or shellfish
any safety findings including low IgG/IgM requiring ofatumumab interruption within 12 weeks prior to vaccination sub-study start
any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 2 weeks of the first vaccination sub-study visit

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Birmingham	Alabama	United States	35233-0271
2	Novartis Investigative Site	Cullman	Alabama	United States	35058
3	Novartis Investigative Site	Phoenix	Arizona	United States	85013
4	Novartis Investigative Site	Fullerton	California	United States	92835
5	Novartis Investigative Site	Sacramento	California	United States	95817
6	Novartis Investigative Site	Aurora	Colorado	United States	80045
7	Novartis Investigative Site	Basalt	Colorado	United States	81621
8	Novartis Investigative Site	Boulder	Colorado	United States	80301
9	Novartis Investigative Site	Colorado Springs	Colorado	United States	80907
10	Novartis Investigative Site	Denver	Colorado	United States	80210
11	Novartis Investigative Site	Fort Collins	Colorado	United States	80528
12	Novartis Investigative Site	Fort Collins	Colorado	United States	80528
13	Novartis Investigative Site	Newark	Delaware	United States	19713
14	Novartis Investigative Site	Washington	District of Columbia	United States	20007
15	Novartis Investigative Site	Atlantis	Florida	United States	33462-6608
16	Novartis Investigative Site	Bradenton	Florida	United States	34205
17	Novartis Investigative Site	Delray Beach	Florida	United States	33445
18	Novartis Investigative Site	Maitland	Florida	United States	32751
19	Novartis Investigative Site	Miami	Florida	United States	33032
20	Novartis Investigative Site	Miami	Florida	United States	33136
21	Novartis Investigative Site	Naples	Florida	United States	34102
22	Novartis Investigative Site	Oldsmar	Florida	United States	34677
23	Novartis Investigative Site	Ormond Beach	Florida	United States	32174
24	Novartis Investigative Site	Pensacola	Florida	United States	32514
25	Novartis Investigative Site	Port Charlotte	Florida	United States	33952
26	Novartis Investigative Site	Sarasota	Florida	United States	34243
27	Novartis Investigative Site	Sunrise	Florida	United States	33351
28	Novartis Investigative Site	Tallahassee	Florida	United States	32312
29	Novartis Investigative Site	Tampa	Florida	United States	33603
30	Novartis Investigative Site	Tampa	Florida	United States	33609
31	Novartis Investigative Site	Tampa	Florida	United States	33612
32	Novartis Investigative Site	West Palm Beach	Florida	United States	33407
33	Novartis Investigative Site	Savannah	Georgia	United States	31406
34	Novartis Investigative Site	Suwanee	Georgia	United States	30024
35	Novartis Investigative Site	Honolulu	Hawaii	United States	96817
36	Novartis Investigative Site	Chicago	Illinois	United States	60612
37	Novartis Investigative Site	Northbrook	Illinois	United States	60062
38	Novartis Investigative Site	Indianapolis	Indiana	United States	46256
39	Novartis Investigative Site	Des Moines	Iowa	United States	50314-2611
40	Novartis Investigative Site	Kansas City	Kansas	United States	66160
41	Novartis Investigative Site	Overland Park	Kansas	United States	66210
42	Novartis Investigative Site	Alexandria	Louisiana	United States	71301
43	Novartis Investigative Site	Baton Rouge	Louisiana	United States	70810
44	Novartis Investigative Site	Wellesley	Massachusetts	United States	02481
45	Novartis Investigative Site	Detroit	Michigan	United States	48201
46	Novartis Investigative Site	Detroit	Michigan	United States	48202
47	Novartis Investigative Site	Golden Valley	Minnesota	United States	55422
48	Novartis Investigative Site	Chesterfield	Missouri	United States	63017
49	Novartis Investigative Site	Ozark	Missouri	United States	65721
50	Novartis Investigative Site	Saint Louis	Missouri	United States	63110
51	Novartis Investigative Site	Billings	Montana	United States	59101
52	Novartis Investigative Site	Great Falls	Montana	United States	59405
53	Novartis Investigative Site	Las Vegas	Nevada	United States	89106
54	Novartis Investigative Site	Albuquerque	New Mexico	United States	87131-0001
55	Novartis Investigative Site	Latham	New York	United States	12110
56	Novartis Investigative Site	Asheville	North Carolina	United States	28806
57	Novartis Investigative Site	Charlotte	North Carolina	United States	28204
58	Novartis Investigative Site	Greensboro	North Carolina	United States	27405
59	Novartis Investigative Site	Raleigh	North Carolina	United States	27607
60	Novartis Investigative Site	Winston-Salem	North Carolina	United States	27103
61	Novartis Investigative Site	Akron	Ohio	United States	44320
62	Novartis Investigative Site	Cleveland	Ohio	United States	44195
63	Novartis Investigative Site	Columbus	Ohio	United States	43214
64	Novartis Investigative Site	Westerville	Ohio	United States	43082
65	Novartis Investigative Site	Oklahoma City	Oklahoma	United States	73104
66	Novartis Investigative Site	Portland	Oregon	United States	97225
67	Novartis Investigative Site	Willow Grove	Pennsylvania	United States	19090
68	Novartis Investigative Site	Greer	South Carolina	United States	29650
69	Novartis Investigative Site	Spartanburg	South Carolina	United States	29303
70	Novartis Investigative Site	Spartanburg	South Carolina	United States	29303
71	Novartis Investigative Site	Cordova	Tennessee	United States	38018
72	Novartis Investigative Site	Johnson City	Tennessee	United States	37604
73	Novartis Investigative Site	Knoxville	Tennessee	United States	37920
74	Novartis Investigative Site	Knoxville	Tennessee	United States	37922
75	Novartis Investigative Site	El Paso	Texas	United States	79935
76	Novartis Investigative Site	Houston	Texas	United States	77074
77	Novartis Investigative Site	Lubbock	Texas	United States	79410
78	Novartis Investigative Site	Round Rock	Texas	United States	78681
79	Novartis Investigative Site	San Antonio	Texas	United States	78258
80	Novartis Investigative Site	Sherman	Texas	United States	75092
81	Novartis Investigative Site	Salt Lake City	Utah	United States	84103
82	Novartis Investigative Site	Salt Lake City	Utah	United States	84132
83	Novartis Investigative Site	Virginia Beach	Virginia	United States	23456
84	Novartis Investigative Site	Kirkland	Washington	United States	98034
85	Novartis Investigative Site	Tacoma	Washington	United States	98405
86	Novartis Investigative Site	Green Bay	Wisconsin	United States	54311
87	Novartis Investigative Site	Madison	Wisconsin	United States	53792
88	Novartis Investigative Site	Milwaukee	Wisconsin	United States	53215
89	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000BZL
90	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000DSW
91	Novartis Investigative Site	Buenos Aires		Argentina	1061
92	Novartis Investigative Site	Cordoba		Argentina	X5004CDT
93	Novartis Investigative Site	Tucuman		Argentina	4000
94	Novartis Investigative Site	Liverpool	New South Wales	Australia	2170
95	Novartis Investigative Site	New Lambton Heights	New South Wales	Australia	2305
96	Novartis Investigative Site	St Leonards	New South Wales	Australia	2065
97	Novartis Investigative Site	Vienna		Austria	1090
98	Novartis Investigative Site	Wien		Austria	1010
99	Novartis Investigative Site	Edegem	Antwerpen	Belgium	2650
100	Novartis Investigative Site	Brasschaat		Belgium	2930
101	Novartis Investigative Site	Brugge		Belgium	8000
102	Novartis Investigative Site	Bruxelles		Belgium	1200
103	Novartis Investigative Site	Gent		Belgium	9000
104	Novartis Investigative Site	Sofia		Bulgaria	1113
105	Novartis Investigative Site	Sofia		Bulgaria	1309
106	Novartis Investigative Site	Sofia		Bulgaria	1413
107	Novartis Investigative Site	Sofia		Bulgaria	1431
108	Novartis Investigative Site	London	Ontario	Canada	N6A 5A5
109	Novartis Investigative Site	Ottawa	Ontario	Canada	K1H 8L6
110	Novartis Investigative Site	Toronto	Ontario	Canada	M4N 3M5
111	Novartis Investigative Site	Gatineau	Quebec	Canada	J9J 0A5
112	Novartis Investigative Site	Greenfield Park	Quebec	Canada	J4V 2J2
113	Novartis Investigative Site	Montreal	Quebec	Canada	H3A 2B4
114	Novartis Investigative Site	Quebec		Canada	G1J 1Z4
115	Novartis Investigative Site	Rijeka	HRV	Croatia	51000
116	Novartis Investigative Site	Osijek		Croatia	31000
117	Novartis Investigative Site	Zagreb		Croatia	10000
118	Novartis Investigative Site	Brno	Czech Republic	Czechia	656 91
119	Novartis Investigative Site	Havirov	Czech Republic	Czechia	736 01
120	Novartis Investigative Site	Teplice	Czech Republic	Czechia	415 01
121	Novartis Investigative Site	Hradec Kralove	CZE	Czechia	500 05
122	Novartis Investigative Site	Olomouc	CZE	Czechia	775 20
123	Novartis Investigative Site	JIhlava		Czechia	586 01
124	Novartis Investigative Site	Ostrava-Poruba		Czechia	708 52
125	Novartis Investigative Site	Pardubice		Czechia	532 03
126	Novartis Investigative Site	Praha 10		Czechia	100 34
127	Novartis Investigative Site	Praha 4		Czechia	140 59
128	Novartis Investigative Site	Praha 5		Czechia	150 06
129	Novartis Investigative Site	Copenhagen		Denmark	DK-2100
130	Novartis Investigative Site	Odense C		Denmark	5000
131	Novartis Investigative Site	Tallinn		Estonia	10617
132	Novartis Investigative Site	Tartu		Estonia	51014
133	Novartis Investigative Site	Tampere		Finland	33100
134	Novartis Investigative Site	Turku		Finland	20520
135	Novartis Investigative Site	Nice	Cedex1	France	06001
136	Novartis Investigative Site	Lille Cedex		France	59037
137	Novartis Investigative Site	Montpellier		France	34295
138	Novartis Investigative Site	Nantes Cedex 1		France	44093
139	Novartis Investigative Site	Nimes Cedex		France	30029
140	Novartis Investigative Site	Paris Cedex 13		France	75651
141	Novartis Investigative Site	Strasbourg		France	67098
142	Novartis Investigative Site	Barsinghausen		Germany	30890
143	Novartis Investigative Site	Bayreuth		Germany	95445
144	Novartis Investigative Site	Bielefeld		Germany	D 33647
145	Novartis Investigative Site	Bochum		Germany	44791
146	Novartis Investigative Site	Dresden		Germany	01307
147	Novartis Investigative Site	Essen		Germany	45147
148	Novartis Investigative Site	Hamburg		Germany	22179
149	Novartis Investigative Site	Hannover		Germany	30625
150	Novartis Investigative Site	Heidelberg		Germany	69120
151	Novartis Investigative Site	Koln		Germany	50935
152	Novartis Investigative Site	Leipzig		Germany	04103
153	Novartis Investigative Site	Marburg		Germany	35043
154	Novartis Investigative Site	Minden		Germany	32429
155	Novartis Investigative Site	Muenchen		Germany	80377
156	Novartis Investigative Site	Muenchen		Germany	81377
157	Novartis Investigative Site	Neuburg an der Donau		Germany	86633
158	Novartis Investigative Site	Potsdam		Germany	14471
159	Novartis Investigative Site	Siegen		Germany	57076
160	Novartis Investigative Site	Ulm		Germany	89073
161	Novartis Investigative Site	Unterhaching		Germany	82008
162	Novartis Investigative Site	Athens	GR	Greece	115 25
163	Novartis Investigative Site	Thessaloniki		Greece	GR 54636
164	Novartis Investigative Site	Budapest	HUN	Hungary	1135
165	Novartis Investigative Site	Budapest	HUN	Hungary	1204
166	Novartis Investigative Site	Esztergom	HUN	Hungary	2500
167	Novartis Investigative Site	Budapest		Hungary	1106
168	Novartis Investigative Site	Kistarcsa		Hungary	2143
169	Novartis Investigative Site	Szeged		Hungary	6725
170	Novartis Investigative Site	New Delhi	Delhi	India	110 060
171	Novartis Investigative Site	New Delhi	Delhi	India	110017
172	Novartis Investigative Site	Kochi	Kerala	India	682 026
173	Novartis Investigative Site	Mumbai	Maharashtra	India	400008
174	Novartis Investigative Site	Pune	Maharashtra	India	411004
175	Novartis Investigative Site	Chandigarh	Punjab	India	160012
176	Novartis Investigative Site	Hyderabad	Telangana	India	500082
177	Novartis Investigative Site	Howrah	West Bengal	India	711103
178	Novartis Investigative Site	Mangalore		India	575018
179	Novartis Investigative Site	Ashkelon		Israel	78278
180	Novartis Investigative Site	Haifa		Israel	3109601
181	Novartis Investigative Site	Sefad		Israel	13100
182	Novartis Investigative Site	Tel Aviv		Israel	6423906
183	Novartis Investigative Site	Toon-city	Ehime	Japan	791-0295
184	Novartis Investigative Site	Sapporo city	Hokkaido	Japan	063-0005
185	Novartis Investigative Site	Morioka	Iwate	Japan	020-8505
186	Novartis Investigative Site	Sendai city	Miyagi	Japan	980 8574
187	Novartis Investigative Site	Sendai city	Miyagi	Japan	983 8512
188	Novartis Investigative Site	Kawagoe	Saitama	Japan	350 8550
189	Novartis Investigative Site	Kodaira	Tokyo	Japan	187-8551
190	Novartis Investigative Site	Shinjuku-ku	Tokyo	Japan	160 8582
191	Novartis Investigative Site	Chiba		Japan	260 8677
192	Novartis Investigative Site	Niigata		Japan	951 8520
193	Novartis Investigative Site	Osaka		Japan	556-0016
194	Novartis Investigative Site	Riga	LV	Latvia	LV-1005
195	Novartis Investigative Site	Riga		Latvia	LV 1002
196	Novartis Investigative Site	Riga		Latvia	LV-1038
197	Novartis Investigative Site	Kaunas	LTU	Lithuania	LT 50161
198	Novartis Investigative Site	Vilnius		Lithuania	LT-08661
199	Novartis Investigative Site	Mexico	Distrito Federal	Mexico	03100
200	Novartis Investigative Site	Chihuahua		Mexico	31238
201	Novartis Investigative Site	Amsterdam		Netherlands	1081 HV
202	Novartis Investigative Site	Rotterdam		Netherlands	3015 CE
203	Novartis Investigative Site	Sittard-Geleen		Netherlands	6162 BG
204	Novartis Investigative Site	Drammen		Norway	1086
205	Novartis Investigative Site	Cercado De Lima	Lima	Peru	01
206	Novartis Investigative Site	San Isidro	Lima	Peru	27
207	Novartis Investigative Site	Lima		Peru	LIMA 13
208	Novartis Investigative Site	Bydgoszcz	Woj Kujawsko-pomorskie	Poland	85-796
209	Novartis Investigative Site	Gdansk		Poland	80 952
210	Novartis Investigative Site	Gdansk		Poland	80-462
211	Novartis Investigative Site	Gdansk		Poland	80-803
212	Novartis Investigative Site	Glogow		Poland	36-060
213	Novartis Investigative Site	Katowice		Poland	40 571
214	Novartis Investigative Site	Kielce		Poland	25 726
215	Novartis Investigative Site	Lodz		Poland	90 324
216	Novartis Investigative Site	Rzeszow		Poland	35 055
217	Novartis Investigative Site	Warszawa		Poland	02 957
218	Novartis Investigative Site	Wroclaw		Poland	51-685
219	Novartis Investigative Site	Zabrze		Poland	41-800
220	Novartis Investigative Site	Matosinhos	Porto	Portugal	4454509
221	Novartis Investigative Site	Braga		Portugal	4710243
222	Novartis Investigative Site	Coimbra		Portugal	3000 075
223	Novartis Investigative Site	Lisboa		Portugal	1169-050
224	Novartis Investigative Site	Lisboa		Portugal	1500 650
225	Novartis Investigative Site	Loures		Portugal	2674514
226	Novartis Investigative Site	Porto		Portugal	4099-001
227	Novartis Investigative Site	Santa Maria da Feira		Portugal	4520 211
228	Novartis Investigative Site	Ekaterinburg		Russian Federation	620109
229	Novartis Investigative Site	Kazan		Russian Federation	420021
230	Novartis Investigative Site	Kemerovo		Russian Federation	650066
231	Novartis Investigative Site	Krasnoyarsk		Russian Federation	660049
232	Novartis Investigative Site	Moscow		Russian Federation	125367
233	Novartis Investigative Site	Moscow		Russian Federation	127015
234	Novartis Investigative Site	Nizhny Novgorod		Russian Federation	603137
235	Novartis Investigative Site	Nizhny Novgorod		Russian Federation	603155
236	Novartis Investigative Site	Novosibirsk		Russian Federation	630007
237	Novartis Investigative Site	Novosibirsk		Russian Federation	630087
238	Novartis Investigative Site	Saint Petersburg		Russian Federation	194044
239	Novartis Investigative Site	Saint Petersburg		Russian Federation	197022
240	Novartis Investigative Site	Saransk		Russian Federation	430032
241	Novartis Investigative Site	Sestroretsk		Russian Federation	197706
242	Novartis Investigative Site	St Petersburg		Russian Federation	190000
243	Novartis Investigative Site	St. Petersburg		Russian Federation	197376
244	Novartis Investigative Site	Tyumen		Russian Federation	625000
245	Novartis Investigative Site	Banska Bystrica		Slovakia	975 17
246	Novartis Investigative Site	Bratislava		Slovakia	813 69
247	Novartis Investigative Site	Bratislava		Slovakia	82606
248	Novartis Investigative Site	Bratislava		Slovakia	83305
249	Novartis Investigative Site	Martin		Slovakia	036 59
250	Novartis Investigative Site	Nitra		Slovakia	94901
251	Novartis Investigative Site	Trnava		Slovakia	917 75
252	Novartis Investigative Site	Pretoria		South Africa	0041
253	Novartis Investigative Site	Rosebank		South Africa	2196
254	Novartis Investigative Site	Cadiz	Andalucia	Spain	11009
255	Novartis Investigative Site	Malaga	Andalucia	Spain	29010
256	Novartis Investigative Site	Sevilla	Andalucia	Spain	41017
257	Novartis Investigative Site	Barcelona	Cataluna	Spain	08026
258	Novartis Investigative Site	Salt	Cataluna	Spain	17190
259	Novartis Investigative Site	Barcelona	Catalunya	Spain	08003
260	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
261	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036
262	Novartis Investigative Site	L Hospitalet De Llobregat	Catalunya	Spain	08907
263	Novartis Investigative Site	Pozuelo de Alarcon	Madrid	Spain	28223
264	Novartis Investigative Site	El Palmar	Murcia	Spain	30120
265	Novartis Investigative Site	San Sebastian	Pais Vasco	Spain	20080
266	Novartis Investigative Site	Castilleja de la cuesta	Sevilla	Spain	41950
267	Novartis Investigative Site	Baracaldo	Vizcaya	Spain	48903
268	Novartis Investigative Site	Madrid		Spain	28006
269	Novartis Investigative Site	Madrid		Spain	28034
270	Novartis Investigative Site	Madrid		Spain	28040
271	Novartis Investigative Site	Madrid		Spain	28222
272	Novartis Investigative Site	Valencia		Spain	46026
273	Novartis Investigative Site	Goeteborg		Sweden	413 45
274	Novartis Investigative Site	Stockholm		Sweden	102 35
275	Novartis Investigative Site	Basel		Switzerland	4031
276	Novartis Investigative Site	Lugano		Switzerland	6900
277	Novartis Investigative Site	Tainan		Taiwan	70403
278	Novartis Investigative Site	Khon Kaen	THA	Thailand	40002
279	Novartis Investigative Site	Haseki / Istanbul		Turkey	34096
280	Novartis Investigative Site	Istanbul		Turkey	34147
281	Novartis Investigative Site	Izmir		Turkey	35040
282	Novartis Investigative Site	Izmir		Turkey	35340
283	Novartis Investigative Site	Kocaeli		Turkey	41380
284	Novartis Investigative Site	Mersin		Turkey	33079
285	Novartis Investigative Site	Samsun		Turkey	55139
286	Novartis Investigative Site	Trabzon		Turkey	61080
287	Novartis Investigative Site	Luton	Beds	United Kingdom	LU4 0DZ
288	Novartis Investigative Site	Headington	Oxfordshire	United Kingdom	OX3 9DU
289	Novartis Investigative Site	Sheffield	South Yorkshire	United Kingdom	S10 2JF
290	Novartis Investigative Site	Glasgow		United Kingdom	G51 4TF
291	Novartis Investigative Site	London		United Kingdom	E1 1BB
292	Novartis Investigative Site	London		United Kingdom	SW17 0QT