COMBI-i: A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02967692

Collaborator

(none)

569

Enrollment

179

Locations

Arms

76.7

Anticipated Duration (Months)

3.2

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To evaluate the safety and efficacy of the combination of an anti-PD-1 antibody (Spartalizumab (PDR001)), a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in unresectable or metastatic BRAF V600 mutant melanoma

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Biological: Spartalizumab Other: Placebo Drug: Dabrafenib Drug: Trametinib	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

569 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Randomized, Double-blind, Placebo-controlled, Phase III Study Comparing the Combination of PDR001, Dabrafenib and Trametinib Versus Placebo, Dabrafenib and Trametinib in Previously Untreated Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma

Actual Study Start Date :

Feb 17, 2017

Actual Primary Completion Date :

Aug 11, 2020

Anticipated Study Completion Date :

Jul 11, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1: Safety run-in Cohort Patients with previously untreated unresectable or metastatic BRAF V600 mutated melanoma will be enrolled and treated at different dose levels to determine the recommended Phase 3 regimen of PDR001 in combination with dabrafenib and trametinib.	Biological: Spartalizumab Spartalizumab (PDR001) will be supplied in vial in liquid or lyophilized pharmaceutical form. Spartalizumab (PDR001) will be administered via intravenous infusion over 30 minutes (up to 2 hours) once every 4 or 8 weeks. Other Names: PDR001 Drug: Dabrafenib Dabrafenib will be provided by the sponsor to the investigative site or supplied locally as commercially available. Dabrafenib will be administered orally twice daily (150 mg BID) for Days 1-28 of a 28-day cycle. Drug: Trametinib Trametinib will be provided by the sponsor to the investigative site or supplied locally as commercially available. Trametinib will be administered orally once daily (2 mg QD) for Days 1-28 of a 28-day cycle.
Experimental: Part 2: Biomarker cohort Patients with previously unresectable or metastatic BRAF V600 mutated melanoma will be enrolled to describe changes in the immune microenvironment and biomarker modulations	Biological: Spartalizumab Spartalizumab (PDR001) will be supplied in vial in liquid or lyophilized pharmaceutical form. Spartalizumab (PDR001) will be administered via intravenous infusion over 30 minutes (up to 2 hours) once every 4 or 8 weeks. Other Names: PDR001 Drug: Dabrafenib Dabrafenib will be provided by the sponsor to the investigative site or supplied locally as commercially available. Dabrafenib will be administered orally twice daily (150 mg BID) for Days 1-28 of a 28-day cycle. Drug: Trametinib Trametinib will be provided by the sponsor to the investigative site or supplied locally as commercially available. Trametinib will be administered orally once daily (2 mg QD) for Days 1-28 of a 28-day cycle.
Experimental: Part 3: Randomized double blind cohort Patients with previously untreated unresectable and metastatic BRAF V600 mutated melanoma will be enrolled to compare the anti-tumor activity of PDR001 in combination with dabrafenib and trametinib versus placebo plus dabrafenib and trametinib.	Biological: Spartalizumab Spartalizumab (PDR001) will be supplied in vial in liquid or lyophilized pharmaceutical form. Spartalizumab (PDR001) will be administered via intravenous infusion over 30 minutes (up to 2 hours) once every 4 or 8 weeks. Other Names: PDR001 Drug: Dabrafenib Dabrafenib will be provided by the sponsor to the investigative site or supplied locally as commercially available. Dabrafenib will be administered orally twice daily (150 mg BID) for Days 1-28 of a 28-day cycle. Drug: Trametinib Trametinib will be provided by the sponsor to the investigative site or supplied locally as commercially available. Trametinib will be administered orally once daily (2 mg QD) for Days 1-28 of a 28-day cycle.
Placebo Comparator: Part 3: Placebo Cohort Matching placebo in combination with dabrafenib and trametinib	Other: Placebo Placebo will be a Dextrose 5% in water (D5W) infusion supplied by the site. Drug: Dabrafenib Dabrafenib will be provided by the sponsor to the investigative site or supplied locally as commercially available. Dabrafenib will be administered orally twice daily (150 mg BID) for Days 1-28 of a 28-day cycle. Drug: Trametinib Trametinib will be provided by the sponsor to the investigative site or supplied locally as commercially available. Trametinib will be administered orally once daily (2 mg QD) for Days 1-28 of a 28-day cycle.

Outcome Measures

Primary Outcome Measures

Safety Run-In (Part 1): Percentage of participants with of dose limiting toxicities (DLTs) [8 weeks]
Percentage of participants with DLTs during the first 8 weeks of treatment with spartalizumab in combination of dabrafenib and trametinib
Biomarker cohort (Part 2): Changes from baseline in programmed cell death-ligand 1 (PD-L1) levels upon treatment with spartalizumab in combination with dabrafenib and trametinib [2 years]
Changes in PD-L1 levels upon treatment with spartalizumab in combination with dabrafenib and trametinib
Biomarker cohort (Part 2): Changes from baseline in CD8+ cells upon treatment with spartalizumab in combination with dabrafenib and trametinib [2 years]
Changes in CD8+ cells upon treatment with spartalizumab in combination with dabrafenib and trametinib
Randomized (Part 3): Progression-Free Survival (PFS), investigator assessed by RECIST 1.1 [Up to disease progression or death due to any cause, whichever occurs first, assessed up to approximately 3 years]
Progression-free survival is defined as the time from the date of first dose to the date of the first documented radiological progression per investigator's assessment according to RECIST 1.1

Secondary Outcome Measures

Overall survival (OS) [Up to death due to any cause, assessed up to approximately 5 years]
Overall survival is defined as the time from date of randomization to date of death due to any cause
Overall response rate (ORR) as per investigator's assessment by RECIST 1.1 [Up to approximately 3 years]
ORR is defined as the proportion of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per investigator's assessment by RECIST 1.1. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters
Duration of response (DOR) by investigator's assessment according to RECIST 1.1 [From first documented response to date of first documented progression or death, up to approximately 3 years]
Duration of response is defined as the time from first documented response of CR or PR to date of first documented progression or death, according to RECIST 1.1 criteria. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters
Disease control rate (DCR) by investigator's assessment according to RECIST 1.1 [Up to approximately 3 years]
Disease control rate is defined as the proportion of patients with CR or PR or subjects with stable disease (SD) lasting for a duration of at least 24 weeks as per local review according to RECIST 1.1 criteria. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease.
Change from baseline in EORTC QLQ-C30 score [From baseline to 60 days post progression, assessed up to approximately 3 years]
The EORTC QLQ-C30 is a patient completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a global health status/QoL scale. Global health status/QoL response options are 1 to 4. Scores were averaged and transformed to 0 to 100. Higher scores indicate better functioning.
Change from baseline in FACT-M melanoma subscale score [From baseline to 60 days post progression, assessed up to approximately 3 years]
The Function Assessment Cancer Therapy-melanoma (FACT-M) ncludes melanoma-specific subscale consists of 16 questions for Melanoma Subscale Each of these questions could have a response of Not at all, a little bit, somewhat, quite a bit and very much. The responses were given a value between 0 and 4 with 4 being best response. The FACT-M total score ranges from 0 to 172. Higher scores on all the FACT-M scales indicate a higher quality of life.
Change from baseline in EQ-5D-5L score [From baseline to 60 days post progression, up to approximately 3 years]
The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression).Overall scores range from 0 to 1 with lower scores representing a higher level of dysfunction.
Time to 10 point definitive deterioration in overall quality of life score from EORTC QLQ-C30 [From baseline to date of at least 10 points relative to baseline worsening of the EORTC QLQ-C30 score or death due to any cause, up to approximately 3 years]
The EORTC QLQ-C30 is a patient completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a global health status/QoL scale. Global health status/QoL response options are 1 to 4. Scores were averaged and transformed to 0 to 100. Higher scores indicate better functioning. The time to definitive 10 point deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10 points relative to baseline worsening of the EORTC QLQ-C30 score or death due to any cause
PFS by PD-L1 expression [Up to disease progression or death due to any cause, up to approximately 3 years]
PFS is defined as the time from the date of first dose to the date of the first documented radiological progression using RECIST 1.1 response criteria. PFS analysis will be performed by PD-L1 status (positive, negative) where a positive status is defined as having ≥ 1% expression and a negative status is defined as having < 1% expression.
OS by PD-L1 expression [Up to death due to any cause, up to 5 years]
OS is defined as the time from date of randomization to date of death due to any cause. OS analysis will be performed by PD-L1 subgroup (positive, negative) where a positive status is defined as having ≥ 1% expression and a negative status is defined as having < 1% expression.
Anti-drug Antibody (ADA) prevalence at baseline [Baseline]
Immunogenicity to PDR001 prior to PDR001 exposure
ADA incidence on treatment [Throughout study until 150 day safety follow-up, up to 3 years]
Immunogenicity to PDR001 on treatment and after treatment
Trough serum concentration for PDR001 [Pre-dose on Day 1 of each cycle (from Cycle 2), up to 3 years. Cycle=28 days]
Pre-dose concentrations of PDR001 collected before dose administration
Trough serum concentration for dabrafenib [Pre-dose on Day 15 of each cycle (from Cycle 1), up to 3 years. Cycle=28 days]
Pre-dose concentrations of dabrafenib collected before dose administration
Trough serum concentration for trametinib [Pre-dose on Day 15 of each cycle (from Cycle 1), up to 3 years. Cycle=28 days]
Pre-dose concentrations of trametinib collected before dose administration
Number of patients with dose interruptions [From baseline to end of treatment, up to 5 years]
Number of patients with dose interruptions for PDR001, dabrafenib and trametinib
Number of patients with dose reductions [From baseline to end of treatment, up to 5 years]
Number of patients with dose reductions for PDR001, dabrafenib and trametinib
Relative dose intensity [From baseline to end of treatment, up to 5 years]
Relative dose intensity for PDR001, dabrafenib and trametinib computed as computed as the ratio of dose intensity and planned dose intensity

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria Part 1: Safety run-in

Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation
Aspartate transaminase (AST) < 2.5× ULN and Alanine transaminase (ALT) < 2.5× ULN
ECOG performance status ≤ 1

Part 2: Biomarker cohort

Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation
At least two cutaneous or subcutaneous or nodal lesions for tumor sample collection
ECOG performance status ≤ 2

Part 3: Double-blind, randomized, placebo-controlled part

Histologically confirmed, unresectable or metastatic melanoma with BRAF V600 mutation
ECOG performance status ≤ 2

Exclusion Criteria:

Part 1: Safety run-in

Subjects with uveal or mucosal melanoma
Any history of CNS metastases
Prior systemic anti-cancer treatment for unresectable or metastatic melanoma
Prior loco-regional treatment for unresectable or metastatic melanoma in the last 6 month
Prior neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months
Radiation therapy within 4 weeks prior to start of study treatment
Active, known, suspected or a documented history of autoimmune disease

Parts 2 & 3: Biomarker cohort & double-blind, randomized, placebo-controlled part

Subjects with uveal or mucosal melanoma
Clinically active cerebral melanoma metastasis
Prior systemic anti-cancer treatment for unresectable or metastatic melanoma
Prior loco-regional treatment for unresectable or metastatic melanoma in the last 6 month
Prior neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months
Radiation therapy within 4 weeks prior to start of study treatment
Active, known, suspected or a documented history of autoimmune disease

Other protocol-defined Inclusion/Exclusion may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	California Cancer Associates for Research and Excellence SC-2	Encinitas	California	United States	92024
2	UC Irvine Medical Center SC	Orange	California	United States	92868
3	California Pacific Medical Center	San Francisco	California	United States	94115
4	Stanford Cancer Center SC-2	Stanford	California	United States	94305
5	University of Kansas Cancer Center SC	Westwood	Kansas	United States	66205
6	Johns Hopkins U SC	Lutherville	Maryland	United States	21093
7	Nebraska Cancer Specialists	Omaha	Nebraska	United States	68130
8	NYU Laura and Isaac Perlmutter Cancer Center SC	New York	New York	United States	10016
9	University of Pittsburgh Medical Center SC	Pittsburgh	Pennsylvania	United States	15213
10	University of Tennessee Medical Center SC	Knoxville	Tennessee	United States	37920
11	University of TX MD Anderson Cancer Center SC-2	Houston	Texas	United States	77030
12	Utah Cancer Specialists SC-2	Salt Lake City	Utah	United States	84106
13	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1125ABD
14	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1426ANZ
15	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000KZE
16	Novartis Investigative Site	Buenos Aires		Argentina	C1431FWO
17	Novartis Investigative Site	Gateshead	New South Wales	Australia	2290
18	Novartis Investigative Site	North Sydney	New South Wales	Australia	2060
19	Novartis Investigative Site	Greenslopes	Queensland	Australia	4120
20	Novartis Investigative Site	Prahran	Victoria	Australia	3181
21	Novartis Investigative Site	Nedlands	Western Australia	Australia	6009
22	Novartis Investigative Site	Innsbruck	Tyrol	Austria	6020
23	Novartis Investigative Site	Graz		Austria	8036
24	Novartis Investigative Site	Linz		Austria	4020
25	Novartis Investigative Site	Salzburg		Austria	A-5020
26	Novartis Investigative Site	St Poelten		Austria	3100
27	Novartis Investigative Site	Jette	Brussel	Belgium	1090
28	Novartis Investigative Site	Bruxelles		Belgium	1200
29	Novartis Investigative Site	Curitiba	PR	Brazil	80530 010
30	Novartis Investigative Site	Porto Alegre	RS	Brazil	90035-003
31	Novartis Investigative Site	Sao Paulo	SP	Brazil	01246 000
32	Novartis Investigative Site	Rio de Janeiro		Brazil	20560-120
33	Novartis Investigative Site	Plovdiv		Bulgaria	4004
34	Novartis Investigative Site	Sofia		Bulgaria	1303
35	Novartis Investigative Site	Vancouver	British Columbia	Canada	V5Z 4E6
36	Novartis Investigative Site	Toronto	Ontario	Canada	M4N 3M5
37	Novartis Investigative Site	Montreal	Quebec	Canada	H3T 1E2
38	Novartis Investigative Site	Montreal	Quebec	Canada	H4A 3J1
39	Novartis Investigative Site	Sherbrooke	Quebec	Canada	J1H 5N4
40	Novartis Investigative Site	Temuco	Araucania	Chile	4810469
41	Novartis Investigative Site	Santiago		Chile	7500921
42	Novartis Investigative Site	Santiago		Chile	8420383
43	Novartis Investigative Site	Ostrava Poruba	Czech Republic	Czechia	708 52
44	Novartis Investigative Site	Zlin	Czech Republic	Czechia	762 75
45	Novartis Investigative Site	Hradec Kralove	CZE	Czechia	500 05
46	Novartis Investigative Site	Olomouc	CZE	Czechia	775 20
47	Novartis Investigative Site	Brno		Czechia	65653
48	Novartis Investigative Site	Praha 10		Czechia	100 34
49	Novartis Investigative Site	Praha		Czechia	12808
50	Novartis Investigative Site	Aarhus		Denmark	8000 C
51	Novartis Investigative Site	Le Mans	Cedex 09	France	72037
52	Novartis Investigative Site	Limoges cedex	Haute Vienne	France	87000
53	Novartis Investigative Site	Amiens		France	80054
54	Novartis Investigative Site	Besancon Cedex		France	25030
55	Novartis Investigative Site	Bobigny Cedex		France	93009
56	Novartis Investigative Site	Bordeaux Cedex		France	33075
57	Novartis Investigative Site	Boulogne Billancourt		France	92104
58	Novartis Investigative Site	CAEN Cedex		France	14033
59	Novartis Investigative Site	Clermont Ferrand		France	63003
60	Novartis Investigative Site	Dijon		France	21000
61	Novartis Investigative Site	Grenoble		France	38043
62	Novartis Investigative Site	Lille Cedex		France	59037
63	Novartis Investigative Site	Lorient Cedex		France	56322
64	Novartis Investigative Site	Lyon Cedex		France	69373
65	Novartis Investigative Site	Marseille Cedex 05		France	13885
66	Novartis Investigative Site	Mulhouse cedex		France	68070
67	Novartis Investigative Site	Nice Cedex		France	06202
68	Novartis Investigative Site	Paris Cedex 10		France	75475
69	Novartis Investigative Site	Pierre Benite Cedex		France	69495
70	Novartis Investigative Site	Poitiers		France	86021
71	Novartis Investigative Site	Reims		France	51092
72	Novartis Investigative Site	Rouen Cedex		France	76031
73	Novartis Investigative Site	Strasbourg Cedex		France	67091
74	Novartis Investigative Site	Toulouse Cedex 9		France	31059
75	Novartis Investigative Site	Vandoeuvre-les-Nancy cedex		France	54519
76	Novartis Investigative Site	Villejuif Cedex		France	94800
77	Novartis Investigative Site	Mannheim	Baden-Wuerttemberg	Germany	68305
78	Novartis Investigative Site	Regensburg	Bavaria	Germany	93053
79	Novartis Investigative Site	Berlin		Germany	13353
80	Novartis Investigative Site	Berlin		Germany	13578
81	Novartis Investigative Site	Bonn		Germany	53105
82	Novartis Investigative Site	Chemnitz		Germany	09117
83	Novartis Investigative Site	Dresden		Germany	01307
84	Novartis Investigative Site	Duesseldorf		Germany	40225
85	Novartis Investigative Site	Erfurt		Germany	99089
86	Novartis Investigative Site	Essen		Germany	45147
87	Novartis Investigative Site	Freiburg		Germany	79106
88	Novartis Investigative Site	Gera		Germany	07548
89	Novartis Investigative Site	Halle Saale		Germany	06120
90	Novartis Investigative Site	Hamburg		Germany	20246
91	Novartis Investigative Site	Hannover		Germany	30625
92	Novartis Investigative Site	Heidelberg		Germany	69120
93	Novartis Investigative Site	Homburg		Germany	66421
94	Novartis Investigative Site	Kiel		Germany	24105
95	Novartis Investigative Site	Leipzig		Germany	04103
96	Novartis Investigative Site	Mainz		Germany	55131
97	Novartis Investigative Site	Marburg		Germany	35039
98	Novartis Investigative Site	Minden		Germany	32429
99	Novartis Investigative Site	Muenchen		Germany	81377
100	Novartis Investigative Site	Muenster		Germany	48157
101	Novartis Investigative Site	Stade		Germany	21682
102	Novartis Investigative Site	Tübingen		Germany	72076
103	Novartis Investigative Site	Athens		Greece	115 27
104	Novartis Investigative Site	Athens		Greece	18547
105	Novartis Investigative Site	Budapest		Hungary	H 1122
106	Novartis Investigative Site	Debrecen		Hungary	4032
107	Novartis Investigative Site	Szeged		Hungary	H 6725
108	Novartis Investigative Site	Haifa		Israel	3109601
109	Novartis Investigative Site	Jerusalem		Israel	9112001
110	Novartis Investigative Site	Ramat Gan		Israel	52621
111	Novartis Investigative Site	Bari	BA	Italy	70124
112	Novartis Investigative Site	Bergamo	BG	Italy	24127
113	Novartis Investigative Site	Bologna	BO	Italy	40138
114	Novartis Investigative Site	Brescia	BS	Italy	25123
115	Novartis Investigative Site	Meldola	FC	Italy	47014
116	Novartis Investigative Site	Genova	GE	Italy	16132
117	Novartis Investigative Site	Monza	MB	Italy	20900
118	Novartis Investigative Site	Milano	MI	Italy	20133
119	Novartis Investigative Site	Milano	MI	Italy	20141
120	Novartis Investigative Site	Modena	MO	Italy	41124
121	Novartis Investigative Site	Padova	PD	Italy	35100
122	Novartis Investigative Site	Roma	RM	Italy	00167
123	Novartis Investigative Site	Siena	SI	Italy	53100
124	Novartis Investigative Site	Candiolo	TO	Italy	10060
125	Novartis Investigative Site	Torino	TO	Italy	10126
126	Novartis Investigative Site	Verona	VR	Italy	37126
127	Novartis Investigative Site	Napoli		Italy	80131
128	Kyushu University Hospital	Fukuoka city	Fukuoka	Japan	812-8582
129	Kyoto University Hospital	Sakyo Ku	Kyoto	Japan	606 8507
130	Osaka International Cancer Institute	Osaka-city	Osaka	Japan	541-8567
131	Tokyo Metropolitan Komagome Hospital	Bunkyo ku	Tokyo	Japan	113-8677
132	National Cancer Hospital	Chuo ku	Tokyo	Japan	104 0045
133	Novartis Investigative Site	Mexico	Distrito Federal	Mexico	14080
134	Novartis Investigative Site	Leon	Guanajuato	Mexico	37000
135	Novartis Investigative Site	Guadalajara Jalisco	Jalisco	Mexico
136	Novartis Investigative Site	Breda		Netherlands	4819 EV
137	Novartis Investigative Site	Leiden		Netherlands	2300 RC
138	Novartis Investigative Site	Oslo		Norway	0379
139	Novartis Investigative Site	Gdansk		Poland	80 952
140	Novartis Investigative Site	Warszawa		Poland	02 781
141	Novartis Investigative Site	Lisboa		Portugal	1099 023
142	Novartis Investigative Site	Porto		Portugal	4200-072
143	Novartis Investigative Site	Chelyabinsk		Russian Federation	454048
144	Novartis Investigative Site	Moscow		Russian Federation	115478
145	Novartis Investigative Site	Moscow		Russian Federation	143423
146	Novartis Investigative Site	Nizhny Novgorod		Russian Federation	603137
147	Novartis Investigative Site	Omsk		Russian Federation	644013
148	Novartis Investigative Site	Samara		Russian Federation	443011
149	Novartis Investigative Site	St Petersburg		Russian Federation	197022
150	Novartis Investigative Site	St Petersburg		Russian Federation	197758
151	Novartis Investigative Site	Malaga	Andalucia	Spain	29010
152	Novartis Investigative Site	Sevilla	Andalucia	Spain	41009
153	Novartis Investigative Site	Oviedo	Asturias	Spain	33011
154	Novartis Investigative Site	Jerez	Cadiz	Spain	11407
155	Novartis Investigative Site	Badalona	Catalunya	Spain	08916
156	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036
157	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46014
158	Novartis Investigative Site	La Coruna	Galicia	Spain	15006
159	Novartis Investigative Site	Las Palmas De Gran Canarias	Las Palmas De Gran Canaria	Spain	35016
160	Novartis Investigative Site	Madrid		Spain	28009
161	Novartis Investigative Site	Madrid		Spain	28034
162	Novartis Investigative Site	Madrid		Spain	28050
163	Novartis Investigative Site	Madrid		Spain	28222
164	Novartis Investigative Site	Goteborg		Sweden	SE-413 45
165	Novartis Investigative Site	Lund		Sweden	221 85
166	Novartis Investigative Site	Stockholm		Sweden	SE 171 76
167	Novartis Investigative Site	Aarau		Switzerland	5001
168	Novartis Investigative Site	Zuerich		Switzerland	8091
169	Novartis Investigative Site	Songkhla	Hat Yai	Thailand	90110
170	Novartis Investigative Site	Bangkok		Thailand	10330
171	Novartis Investigative Site	Truro	Cornwall	United Kingdom	TR1 3LJ
172	Novartis Investigative Site	Surrey	England	United Kingdom	GU2 7XX
173	Novartis Investigative Site	Northwood	Middlesex	United Kingdom	HA6 2RN
174	Novartis Investigative Site	Sutton	Surrey	United Kingdom	SM2 5PT
175	Novartis Investigative Site	Leicester		United Kingdom	LE1 5WW
176	Novartis Investigative Site	London		United Kingdom	NW3 2QG
177	Novartis Investigative Site	Manchester		United Kingdom	M20 4BX
178	Novartis Investigative Site	Middlesbrough		United Kingdom	TS4 3BW
179	Novartis Investigative Site	Preston		United Kingdom	PR2 9HT