COBALT: Phase 4 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cholangitis

Sponsor

Intercept Pharmaceuticals (Industry)

Overall Status

Terminated

CT.gov ID

NCT02308111

Collaborator

(none)

334

Enrollment

131

Locations

Arms

83.9

Actual Duration (Months)

2.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Primary Biliary Cholangitis (PBC) is a serious, life-threatening, bile acid related liver disease of unknown cause. Without treatment, it frequently progresses to liver fibrosis and eventual cirrhosis requiring liver transplantation or resulting in death. The investigational drug, Obeticholic Acid (OCA) is a modified bile acid and FXR agonist that is derived from the primary human bile acid chenodeoxycholic acid. The key mechanisms of action of OCA, including its choleretic, anti-inflammatory, and anti-fibrotic properties, underlie its hepatoprotective effects and result in attenuation of injury and improved liver function in a cholestatic liver disease such as PBC. The study will assess the effect of OCA compared to placebo, combined with stable standard care, on clinical outcomes in PBC patients.

Condition or Disease	Intervention/Treatment	Phase
Liver Cirrhosis, Biliary	Drug: Obeticholic Acid (OCA) Drug: Placebo	Phase 4

Detailed Description

This Phase 4, double-blind, randomized, placebo-controlled, multicenter study is being undertaken at up to 170 sites internationally to evaluate the effect of OCA on clinical outcomes in 428 subjects with PBC. The study will include a screening period of up to 8 weeks, requiring two clinic visits. Eligible participants will be randomly allocated (1:1) to treatment with either OCA 5 mg or matching placebo tablets, taken orally once daily for the majority of subjects; dose and frequency will be modified for subjects with cirrhosis and classified as Child-Pugh B or C. Randomization will be stratified by standard treatment with UDCA (yes/no) and baseline liver function. The treatment period involves clinic visits approximately every 3 months. At the 3 month visit or any study visit thereafter, if study treatment is tolerated, participants' dose should be titrated per protocol in a blinded manner eg for participants who are non-cirrhotic or classified as Child-Pugh A and randomized to OCA, they should receive the maximum daily dose of 10 mg OCA, those on placebo continue to receive placebo. Subsequently, daily dosage may return to 5 mg if necessary for these participants who are non-cirrhotic or classified as Child-Pugh A, but should be increased to 10 mg if possible, based on tolerability and clinical judgment. Safety and tolerability will be assessed by monitoring adverse events and vital signs, and blood and urine testing. The study is event driven and total duration will be determined by the time required to accrue approximately 127 primary endpoint events, estimated to be approximately 10 years. Subjects are expected to have a minimum follow-up time of approximately 6 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

334 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

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

Primary Purpose:

Treatment

Official Title:

A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Patients With Primary Biliary Cholangitis

Actual Study Start Date :

Dec 26, 2014

Actual Primary Completion Date :

Dec 23, 2021

Actual Study Completion Date :

Dec 23, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Obeticholic Acid (OCA) 5 mg to 10 mg Obeticholic Acid (OCA) 5 mg for a minimum 3 months and then titrating up to a maximum 10 mg for the remainder of the trial (based on tolerability and Child Pugh Score).	Drug: Obeticholic Acid (OCA) Non-cirrhotic and classified as Child-Pugh Class A: 5 mg tablet of OCA once daily titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of patients). Cirrhotic and classified as Child-Pugh Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, subsequently titrating up to a maximum dose and frequency of 10 mg OCA twice weekly based on tolerability and biochemical response for the duration of the study. Other Names: 6alpha-ethylchenodeoxycholic acid (6-ECDCA) INT-747
Placebo Comparator: Placebo	Drug: Placebo One tablet daily (or a lower frequency depending on Child Pugh score) for the remainder of the study

Arm

Intervention/Treatment

Experimental: Obeticholic Acid (OCA) 5 mg to 10 mg

Obeticholic Acid (OCA) 5 mg for a minimum 3 months and then titrating up to a maximum 10 mg for the remainder of the trial (based on tolerability and Child Pugh Score).

Drug: Obeticholic Acid (OCA)

Non-cirrhotic and classified as Child-Pugh Class A: 5 mg tablet of OCA once daily titrating up to a maximum of 10 mg OCA once daily based on tolerability at 3 months for the duration of the study (majority of patients). Cirrhotic and classified as Child-Pugh Class B and C: 5 mg tablet of OCA once weekly for at least 3 months, subsequently titrating up to a maximum dose and frequency of 10 mg OCA twice weekly based on tolerability and biochemical response for the duration of the study.

Other Names:

6alpha-ethylchenodeoxycholic acid (6-ECDCA)

INT-747

Placebo Comparator: Placebo

Drug: Placebo

One tablet daily (or a lower frequency depending on Child Pugh score) for the remainder of the study

Outcome Measures

Primary Outcome Measures

Composite endpoint of any of the five listed adjudicated events [Time to accrue approximately 127 primary endpoint events, estimated to be approximately 10 years]
Primary endpoint events include: death liver transplant MELD score ≥15 uncontrolled ascites hospitalization for new onset or recurrence of any of the following: variceal bleed hepatic encephalopathy spontaneous bacterial peritonitis

Secondary Outcome Measures

First occurrence of each of the listed individual events [Time to first occurrence from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, up to 10 years]
Individual events include: death liver transplant MELD score >15 uncontrolled ascites hospitalization for new onset or recurrence of any of the following: variceal bleed hepatic encephalopathy spontaneous bacterial peritonitis
First occurrence of liver-related death [Time to first occurrence from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, up to 10 years]
To assess the effect of OCA compared to placebo on time to occurrence of liver-related death
Progression to cirrhosis [Time to first occurrence from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, up to 10 years]
To assess the effect of OCA compared to placebo on progression to cirrhosis
Time to occurrence of hepatocellular carcinoma (HCC) [Time to first occurrence from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, up to 10 years]
To assess the effect of OCA compared to placebo on time to occurrence of hepatocellular carcinoma (HCC)
Changes from Baseline in bilirubin as a marker of liver biochemistry [Samples will be measured at Baseline and Months 3, 6, 9 and 12 for 10 Years]
bilirubin (total and conjugated)
Changes from Baseline in aspartate aminotransferase (AST) as a marker of liver biochemistry [Samples will be measured at Baseline and Months 3, 6, 9 and 12 for 10 Years]
aspartate aminotransferase (AST)
Changes from Baseline in alanine aminotransferase (ALT) as a marker of liver biochemistry [Samples will be measured at Baseline and Months 3, 6, 9 and 12 for 10 Years]
alanine aminotransferase (ALT)
Changes from Baseline in alkaline phosphatase (ALP) as a marker of liver biochemistry [Samples will be measured at Baseline and Months 3, 6, 9 and 12 for 10 Years]
alkaline phosphatase (ALP)
Changes from Baseline in gamma-glutamyl transferase (GGT) as a marker of liver biochemistry [Samples will be measured at Baseline and Months 3, 6, 9 and 12 for 10 Years]
gamma-glutamyl transferase (GGT)
Change from Baseline in IgM as a marker of inflammation [Samples will be measured at Baseline and Months 6 and 12 for up to 10 Years]
IgM
Change from Baseline in C-reactive protein (CRP) as a marker of inflammation [Samples will be measured at Baseline and Months 6 and 12 for up to 10 Years]
C-reactive protein (CRP)
Change from Baseline in tumor necrosis factor-alpha (TNF-α) as a marker of inflammation [Samples will be measured at Baseline and Months 6 and 12 for up to 10 Years]
tumor necrosis factor-alpha (TNF-α)
Change from Baseline in fibroblast growth factor-19 (FGF-19) as a marker of inflammation [Samples will be measured at Baseline and Months 6 and 12 for up to 10 Years]
fibroblast growth factor-19 (FGF-19)
Change from Baseline in cytokeratin-18 (CK-18) as a marker of liver fibrosis [Samples will be measured at baseline and Months 6 and 12 for up to 10 Years]
cytokeratin-18 (CK-18)
Change from Baseline in enhanced liver fibrosis (ELF) test as a marker of liver fibrosis [Samples will be measured at baseline and Months 6 and 12 for up to 10 Years]
enhanced liver fibrosis (ELF) test
Change from Baseline in transient elastography as a marker of liver fibrosis [Liver fibrosis will be measured at baseline and Month 12 for up to 10 Years]
Liver fibrosis measured using transient Elastography with Fibroscan®

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key Inclusion Criteria:

Definite or probable PBC diagnosis (consistent with American Association for the Study of Liver Diseases [AASLD] and the European Association for the Study of the Liver [EASL] practice guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥2 of the following 3 diagnostic factors:

History of elevated Alkaline phosphatase levels for at least 6 months
Positive antimitochondrial antibody (AMA) titer or if AMA negative or in low titer (<1:80) PBC-specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase complex])
Liver biopsy consistent with PBC

A mean total bilirubin >ULN and ≤5x ULN and/or a mean ALP >3x ULN
Either is not taking UDCA (no UDCA dose in the past 3 months) or has been taking UDCA for at least 12 months with a stable dose for ≥3 months prior to Day 0

Exclusion Criteria:

History or presence of other concomitant liver diseases including:

Hepatitis C virus infection
Active Hepatitis B infection; however, subjects who have seroconverted (hepatitis B surface antigen and hepatitis B e antigen negative) may be included in this study after consultation with the medical monitor
Primary sclerosing cholangitis (PSC)
Alcoholic liver disease
Definite autoimmune liver disease or overlap hepatitis
Nonalcoholic steatohepatitis (NASH)
Gilbert's Syndrome

Presence of clinical complications of PBC or clinically significant hepatic decompensation, including:

History of liver transplant, current placement on a liver transplant list, or current Model of End Stage Liver Disease (MELD) score >12. Subjects who are placed on a transplant list despite a relatively early disease stage (for example per regional guidelines) may be eligible as long as they do not meet any of the other exclusion criteria
Cirrhosis with complications, including history (within the past 12 months) or presence of:
Variceal bleed
Uncontrolled ascites
Encephalopathy
Spontaneous bacterial peritonitis
Known or suspected HCC
Prior transjugular intrahepatic portosystemic shunt procedure
Hepatorenal syndrome (type I or II) or screening (Visit 1 or 2) serum creatinine

2 mg/dL (178 μmol/L)

Mean total bilirubin >5x ULN
Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) or ileal resection or plan to undergo either of these procedures
Other medical conditions that may diminish life expectancy, including known cancers (except carcinomas in situ or other stable, relatively benign conditions)
If female: plans to become pregnant, known pregnancy or a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating
Known history of human immunodeficiency virus infection
Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or fractures within 3 months)
Other clinically significant medical conditions that are not well controlled or for which medication needs are anticipated to change during the study
History of alcohol abuse or other substance abuse within 1 year prior to Day 0
Participation in another investigational product, biologic, or medical device study within 30 days prior to Screening. Participation in a previous study of OCA is allowed with 3 months washout prior to enrollment in this study
Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain
History of known or suspected clinically significant hypersensitivity to OCA or any of its components
UDCA naïve (unless contraindicated)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
2	Inland Empire Liver Foundation	Rialto	California	United States	92377
3	University of California Davis, Davis Medical Center	Sacramento	California	United States	95817
4	University of Colorado Denver and Hospital	Aurora	Colorado	United States	80045
5	UF Hepatology Research at CTRB	Gainesville	Florida	United States	32610
6	Schiff Center for Liver Diseases/University of Miami	Miami	Florida	United States	33163
7	Gastrointestinal Specialists of Georgia	Marietta	Georgia	United States	30060
8	Indiana University	Indianapolis	Indiana	United States	46202
9	University of Louisville, Medical Dental Complex	Louisville	Kentucky	United States	40202
10	Tulane University Medical Center	New Orleans	Louisiana	United States	70112
11	Mercy Medical Center	Baltimore	Maryland	United States	21202
12	Southern Therapy and Advanced Research (STAR)	Jackson	Mississippi	United States	39216
13	Kansas City Research Institute	Kansas City	Missouri	United States	64131
14	Saint Louis University Gastroenterology & Hepatology	Saint Louis	Missouri	United States	63104
15	Weill Cornell Medical College	New York	New York	United States	10021
16	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
17	The Liver Institute at Methodist Dallas Medical Center	Dallas	Texas	United States	75203
18	UT Southwestern Medical Center	Dallas	Texas	United States	75390
19	UT Health The University of Texas Health Science Center at Houston	Houston	Texas	United States	77030
20	American Research Corporation at Texas Liver Institute	San Antonio	Texas	United States	78215
21	Texas Digestive Disease Consultants	Southlake	Texas	United States	76092
22	Clinical Research Centers of America	Murray	Utah	United States	84123
23	Swedish Organ Transplant & Liver Center	Seattle	Washington	United States	98104
24	Hospital Universitario Austral	Presidente Derqui	Buenos Aires	Argentina	1629
25	Dim Clínica Privada	Ramos Mejía	Buenos Aires	Argentina	1704
26	Hospital Privado Universitario de Cordoba S.A.	Córdoba	Cordoba	Argentina	X5016KEH
27	Hospital Provincial del Centenario	Rosario	Santa Fe	Argentina	S2002KDS
28	Hospital Italiano de Buenos Aires	Ciudad Autónoma de Buenos Aires		Argentina	1181
29	Hospital de Gastroenterologia Dr. Carlos Bonorino Udaondo	Ciudad Autónoma de Buenos Aires		Argentina	1264
30	Hospital Aleman	Ciudad Autónoma de Buenos Aires		Argentina	C1118AAT
31	Hospital Britanico De Buenos Aires	Ciudad Autónoma de Buenos Aires		Argentina	C1280AEB
32	AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital	Camperdown	New South Wales	Australia	2050
33	Department of Gastroenterology & Hepatology, Nepean Hospital	Kingswood	New South Wales	Australia	2747
34	Department of Gastroenterology and Hepatology, Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
35	Flinders Medical Centre	Adelaide	South Australia	Australia	5042
36	Box Hill Hospital	Box Hill	Victoria	Australia	3128
37	St. Vincent's Hospital Melbourne	Fitzroy	Victoria	Australia	3065
38	Austin Hospital	Heidelberg	Victoria	Australia	3084
39	Fiona Stanley Hospital, Gastroenterology Department	Murdoch	Western Australia	Australia	6150
40	AKH, Medical University of Vienna	Vienna		Austria	1090
41	University Hospital Antwerp	Edegem	Antwerp	Belgium	2650
42	Cub Hôpital Erasme	Bruxelles		Belgium	1070
43	Hospital Sao Rafael	São Salvador	Bahia	Brazil	41253-190
44	Gastrocentro/ Universidade Estadual de Campinas (UNICAMP)	Sao Paulo	Campinas	Brazil	13083-878
45	Instituto Hospital de Base do Distrito Federal-IHBDF	Brasilia	Distrito Federal Brazil	Brazil	70335-900
46	Instituto Goiano de Gastroenterologia	Goiânia	Goias	Brazil	74535-170
47	Cepec Huufma	Sao Luis	Maranhao	Brazil	65020-600
48	Hospital das Clinicas da Universidade Federal de Minas Gerais (UFMG)	Belo Horizonte,	Minas Gerais	Brazil	30130-100
49	Hospital de Clinicas de Porto Alegre	Porto Alegre	Rio Grande Do Sul	Brazil	90035-903
50	Hospital Universitario Professor Edgard Santos	Bahia	Salvador	Brazil	40110-060
51	Gastrocentro. Unidad Estadual de CAmpinas UNICAMP	Campinas	Sao Paulo	Brazil	13083-878
52	Universidade Federal do Estado do Rio de Janeiro - Hospital Universitario Gaffree e Guinle/HUGG/UNIRIO	Rio de Janeiro		Brazil	20270-004
53	Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo-HCFMUSP	Sao Paulo		Brazil	05403-000
54	University of Calgary Liver Unit (Heritage Medical Research Clinic)	Calgary	Alberta	Canada	T2N-4Z6
55	University of Alberta, Walter C. Mackenzie Health Sciences Centre (WMC)	Edmonton	Alberta	Canada	T6G 2X8
56	University Health Network, Toronto General Hospital	Toronto	Ontario	Canada	M5G 2C4
57	Chum	Montreal	Quebec	Canada	H2X 3J4
58	Centro De Investigaciones Clínicas Viña Del Mar	Viña Del Mar	V Región	Chile	2540488
59	Aarhus University Hospital Department of Hepatology and Gastroenterology	Aarhus	Aarhus C	Denmark	8000
60	Medicinsk klinik for mave, tarm-og leversygdomme	København Ø		Denmark	2100
61	Odense University Hospital Afdeling for medicinske mave-tarmsygdomme S	Odense		Denmark	5000
62	East Tallinn Central Hospital Gastroenterology Center	Tallinn	Harju	Estonia	10138
63	Tartu University Hospital	Tartu		Estonia	51014
64	Helsinki University Central Hospital	Helsinki		Finland	00290
65	Turku University Central Hospital, Gastroenterology Outpatient Clinic	Turku,		Finland	20521
66	Hospital Saint-Antoine, A.P.-H.P.	Paris Cedex 12	Paris	France	75571
67	CHRU Hôpital HURIEZ	Lille		France	59037
68	Klinikum der Johann-Wolfgang Goethe, Universitaet Frankfurt am Main	Frankfurt am Main	Hessen	Germany	60590
69	Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie	Hannover	Lower Saxony	Germany	D-30625
70	Friedrich-Alexander-Uniersitat Erlangen	Erlangen	QLD	Germany	91054
71	CHARITÉ, Campus Virchow Klinikum	Berlin		Germany	D-13353
72	Universität Leipzig KöR, Medizinische Fakultät	Leipzig		Germany	04103
73	Queen Mary Hospital	Hong Kong	Pokfulam	Hong Kong
74	Prince Of Wales Hospital	Hong Kong	Shatin	Hong Kong
75	Tuen Mun Hospital	Hong Kong	Tuen Mun, New Territories	Hong Kong
76	Alice Ho Miu Ling Nethersole Hospital	Hong Kong		Hong Kong
77	Humanity & Health Research Centre	Hong Kong		Hong Kong
78	Békés Megyei Kozponti Korhaz - Dr. Rethy Pal Tagkorhaz	Bekescsaba		Hungary	H-5600
79	University Of Debrecen, Department Of Medicine, Division Of Gastroenterology	Debrecen		Hungary	4032
80	Hadassah Hebrew University Medical Center	Jerusalem	Nazareth Elit	Israel	POB 12000, 91120
81	Soroka Medical Center	Beer Sheva		Israel	84104
82	Shaare Zedek Medical Center	Jerusalem		Israel	91031 02
83	Rabin Medical Center	Petach Tikva		Israel	49100
84	Sheba Medical Center	Ramat-Gan		Israel	52656 01
85	Azienda Ospedaliero - Universitaria di Cagliari - Centro per lo Studio delle Malattie del Fegato	Monserrato	Cagliari	Italy	09042
86	Università Politecnica delle Marche - Azienda Ospedaliero	Ancona		Italy	71-60126
87	AOU Policlinico Sant' Orsola Malpighi	Bologna		Italy	40138
88	Azienda Ospedaliero Universitaria Sant´ Orsola Malpighi	Bologna		Italy	40138
89	Azienda Ospedaliero Universitaria Careggi Universita di Firenze	Florence		Italy	50139
90	Azienda Socio-Sanitarla Territoriale (ASST) Santi Paolo e Carlo	Milano		Italy	20142
91	AOU Ospedale Civile S. Agostino Estense - UO Medicina Metabolica	Modena		Italy	41126
92	Azienda Socio Sanitaria Territoriale (ASST) di Monza	Monza		Italy	20900
93	Azienda Ospedaliero - Universita di Padova	Padova		Italy	35128
94	AOU Policlinico Paolo Giaccone - Di.Bi.M.I.S	Palermo		Italy	90127
95	Policlinico Universitario Agostino Gemelli - Universita Cattolica del Sacro Cuore	Rome		Italy	00168
96	Inje University Busan Paik Hospital	Busan	Busanjin-gu	Korea, Republic of	47392
97	Gangnam Severance Hospital	Seoul	Gangnam-gu	Korea, Republic of	06273
98	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-do	Korea, Republic of	13620
99	Seoul National University Hospital	Seoul	Jongno-Gu	Korea, Republic of	03080
100	Pusan National University Hospital	Busan	Seo-gu	Korea, Republic of	49241
101	Hospital of Lithuanian University of Health Sciences, Kauno klinikos	Kaunas		Lithuania	LT 50009
102	Vilnius University Hospital Santaros klinikos	Vilnius		Lithuania	LT-08661
103	Medica Sur, S.A.B. de C.V.	Ciudad de mexico	Ciudad De Mexico,	Mexico	14050
104	Radboud UMC	Nijmegen	Gelderland	Netherlands	6525 GA
105	Vrije Universiteit Medisch Centrum (VUMC)	Amsterdam	Noord-Holland	Netherlands	1081HV
106	Erasmus Mc	Rotterdam	Zuid Holland	Netherlands	3015 CE
107	Amsterdam University Medical Centre (AMC)	Amsterdam		Netherlands	1105 AZ
108	University Medical Center Utrecht	Utrecht		Netherlands	3584CX
109	Wojewodzki Szpital Specjalistyczny im. J. Gromkowskiego, Pierwszy Oddzial Chorob Zakaznych	Wroclaw	Lover Silesia	Poland	51-149
110	Medical University of Warsaw Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie (SPCSK in Warsaw	Warsaw	Masovia	Poland	02-097
111	Centrum Onkologii - Instytut im. Marii Skłodowskiej - Curie, Klinika Gastroenterologii Onkologicznej	Warsaw	Mazovia	Poland	02-781
112	Oddział Gastr. I Hepat. Uniwersyteckie Centrum Kliniczne Im. Prof. K. Gibińskiego Sum	Katowice	Silesia	Poland	40-752
113	Dep. Of Gastroenterology UM Lublin	Lublin		Poland	20-094
114	Hospital Vall d'Hebron	Barcelona		Spain	08035
115	Hospital Clinic de Barcelona	Barcelona		Spain	08036
116	Hospital Universitario Virgen del Rocio	Sevilla		Spain	41013
117	La Fe, Hospital ( Valence )	Valence		Spain	46026
118	Karolinska University Hospital	Stockholm	Huddinge	Sweden	14186
119	Sahlgrenska Universitetssjukhuset	Gothenburg		Sweden	413 45
120	Inselspital, University Of Bern, UVCM, DMLL	Bern		Switzerland	3010
121	Kantonsspital St. Gallen, Clinic for Gastroeterologie and Hepatologie	St. Gallen		Switzerland	9007
122	USZ, Klinik für Gastroenterologie und Hepatologie	Zurich		Switzerland	8091
123	Ankara University School of Medicine Gastroenterology Dept.	Ankara		Turkey	6100
124	Ege University School of Medicine Gastroenterology Dept.	Izmir		Turkey	35100
125	University Hospitals Bristol NHS Foundation Trust	Bristol	Avon	United Kingdom	BS2 8HW
126	Plymouth Hospitals NHS Trust, Derriford Hospital	Plymouth	Devon	United Kingdom	PL6 8DH
127	Gartnavel General Hospital	Glasgow	Lanarkshire	United Kingdom	G12 0YN
128	Institute of Cellular Medicine	Newcastle Upon Tyne	Tyne And Wear	United Kingdom	NE2 4HH
129	University Hospitals Birmingham NHS Foundation Trust	Birmingham	West Midlands	United Kingdom	B15 2GW
130	Cambrigde University Hospitals NHS Foundation Trust	Cambridge		United Kingdom	CB2 0QQ
131	The Royal Free Hospital	London		United Kingdom	NW3 2QG