CLL17: Ibrutinib Monotherapy Versus Fixed-duration Venetoclax Plus Obinutuzumab Versus Fixed-duration Ibrutinib Plus Venetoclax in Patients With Previously Untreated Chronic Lymphocytic Leukaemia (CLL)

Sponsor

German CLL Study Group (Other)

Overall Status

Recruiting

CT.gov ID

NCT04608318

Collaborator

Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON) (Other), Nordic CLL Study Group (NCLLSG) (Other), Swiss Group for Clinical Cancer Research (SAKK) (Other), Cancer Trials Ireland (Other), Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) (Other), Grupo Español de Leucemia Linfocítica Crónica (GELLC) (Other), The Israeli CLL Study Group (ICLLSG) (Other)

897

Enrollment

181

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of this study is to compare the efficacy of continuous ibrutinib monotherapy with fixed-duration venetoclax plus obinutuzumab and fixed-duration ibrutinib plus venetoclax by measuring progression-free survival (PFS) in patients with previously untreated CLL.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphoid Leukemia	Biological: Ibrutinib Biological: Venetoclax Biological: Obinutuzumab	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

897 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 3 Multicentre, Randomized, Prospective, Open-label Trial of Ibrutinib Monotherapy Versus Fixed-duration Venetoclax Plus Obinutuzumab Versus Fixed-duration Ibrutinib Plus Venetoclax in Patients With Previously Untreated Chronic Lymphocytic Leukaemia (CLL)

Actual Study Start Date :

Mar 1, 2021

Anticipated Primary Completion Date :

Mar 1, 2027

Anticipated Study Completion Date :

Mar 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: I (Ibrutinib) Ibrutinib p.o. will be administered until occurrence of unacceptable toxicity, progression of CLL or end of trial, whichever occurs first.	Biological: Ibrutinib Cycles 1 - X: 420 mg daily, d1-28 p.o. Other Names: Imbruvica
Experimental: VG (Obinutuzumab + Venetoclax) 12 cycles (q 28d): Obinutuzumab i.v. + Venetoclax p.o. will be administered for 6 cycles, followed by 6 additional cycles of Venetoclax alone	Biological: Venetoclax Arm VG Cycle 1: 20 mg (2 tabl. at 10 mg), d22-28 p.o. Cycle 2: 50 mg (1 tabl. at 50 mg), d1-7; 100 mg (1 tabl. at 100 mg), d8-14; 200 mg (2 tabl. at 100 mg), d15-21; 400 mg (4 tabl. at 100 mg), d22-28 p.o. Cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28 p.o. Arm VI Cycle 4: 20 mg (2 tabl. at 10 mg), d1-7; 50 mg (1 tabl. at 50 mg), d8-14; 100 mg (1 tabl. at 100 mg), d15-21; 200 mg (2 tabl. at 100 mg), d22-28 p.o. Cycles 5-15: 400 mg (4 tabl. at 100 mg), d1-28 p.o. Other Names: ABT-199, Venclyxto Biological: Obinutuzumab Cycle 1: (100 mg, d1 + 900 mg, d2) or 1000 mg, d1; 1000 mg, d8 + d15 i.v. Cycle 2 - 6: 1000 mg, d1 i.v. Other Names: GA101, Gazyvaro
Experimental: VI (Venetoclax + Ibrutinib) 15 cycles (q 28d): Ibrutinib p.o. + Venetoclax p.o. will be administered for a total of 12 cycles with a prior Ibrutinib monotherapy lead-in of 3 cycles	Biological: Ibrutinib Cycles 1 - X: 420 mg daily, d1-28 p.o. Other Names: Imbruvica Biological: Venetoclax Arm VG Cycle 1: 20 mg (2 tabl. at 10 mg), d22-28 p.o. Cycle 2: 50 mg (1 tabl. at 50 mg), d1-7; 100 mg (1 tabl. at 100 mg), d8-14; 200 mg (2 tabl. at 100 mg), d15-21; 400 mg (4 tabl. at 100 mg), d22-28 p.o. Cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28 p.o. Arm VI Cycle 4: 20 mg (2 tabl. at 10 mg), d1-7; 50 mg (1 tabl. at 50 mg), d8-14; 100 mg (1 tabl. at 100 mg), d15-21; 200 mg (2 tabl. at 100 mg), d22-28 p.o. Cycles 5-15: 400 mg (4 tabl. at 100 mg), d1-28 p.o. Other Names: ABT-199, Venclyxto

Arm

Intervention/Treatment

Experimental: I (Ibrutinib)

Ibrutinib p.o. will be administered until occurrence of unacceptable toxicity, progression of CLL or end of trial, whichever occurs first.

Biological: Ibrutinib

Cycles 1 - X: 420 mg daily, d1-28 p.o.

Other Names:

Imbruvica

Experimental: VG (Obinutuzumab + Venetoclax)

12 cycles (q 28d): Obinutuzumab i.v. + Venetoclax p.o. will be administered for 6 cycles, followed by 6 additional cycles of Venetoclax alone

Biological: Venetoclax

Arm VG Cycle 1: 20 mg (2 tabl. at 10 mg), d22-28 p.o. Cycle 2: 50 mg (1 tabl. at 50 mg), d1-7; 100 mg (1 tabl. at 100 mg), d8-14; 200 mg (2 tabl. at 100 mg), d15-21; 400 mg (4 tabl. at 100 mg), d22-28 p.o. Cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28 p.o. Arm VI Cycle 4: 20 mg (2 tabl. at 10 mg), d1-7; 50 mg (1 tabl. at 50 mg), d8-14; 100 mg (1 tabl. at 100 mg), d15-21; 200 mg (2 tabl. at 100 mg), d22-28 p.o. Cycles 5-15: 400 mg (4 tabl. at 100 mg), d1-28 p.o.

Other Names:

ABT-199, Venclyxto

Biological: Obinutuzumab

Cycle 1: (100 mg, d1 + 900 mg, d2) or 1000 mg, d1; 1000 mg, d8 + d15 i.v. Cycle 2 - 6: 1000 mg, d1 i.v.

Other Names:

GA101, Gazyvaro

Experimental: VI (Venetoclax + Ibrutinib)

15 cycles (q 28d): Ibrutinib p.o. + Venetoclax p.o. will be administered for a total of 12 cycles with a prior Ibrutinib monotherapy lead-in of 3 cycles

Biological: Ibrutinib

Cycles 1 - X: 420 mg daily, d1-28 p.o.

Other Names:

Imbruvica

Biological: Venetoclax

Other Names:

ABT-199, Venclyxto

Outcome Measures

Primary Outcome Measures

Investigator-assessed progression-free survival (PFS) [Up to 80 month]
Time from randomization to the first occurrence of progression or relapse (determined using standard iwCLL guidelines), or death from any cause, whichever occurs first

Secondary Outcome Measures

Rates of undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM) [At final restaging (RE): 18 months after start of treatment and additional BM assessment approx. 12 months after RE]
Undetectable MRD (uMRD) is defined as <10-4 (=1 CLL-cell per 10,000 leukocytes analyzed).The uMRD rate is defined as the proportion of patients having achieved uMRD.
MRD levels in PB at different time points [Up to 80 month]
MRD is defined as the number of CLL-cells that can be detected in peripheral blood (PB) or bone marrow (BM). MRD values will be categorized into negative (<10-4) and positive (≥10-4)
Overall response rate (ORR) [At final restaging (RE): 18 months after start of treatment]
Proportion of patients having achieved a complete response (CR), a CR with incomplete recovery of the bone marrow (CRi), or a partial response (PR) as best response.
CR/CRi rate [At final restaging (RE): 18 months after start of treatment]
Proportion of patients having achieved a CR or CRi as best response (= number of patients with best response CR or CRi divided by the number of the intention-to-treat population (ITT) population)
Incidence of safety parameters such as adverse events (AE) and adverse events of particular/special interest (AEPI/AESI) [Up to 80 month]
Type, frequency, severity and relationship to study treatment.of AEs and AEPIs/AESIs

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Documented CLL requiring treatment according to iwCLL criteria.
Age at least 18 years.
Life expectancy ≥ 6 months.
Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
Adequate bone marrow function independent of growth factor or transfusion support within 2 weeks of screening initiation as follows, unless cytopenia is due to CLL:
Absolute neutrophil count ≥ 1.0 × 109/L
Platelet counts ≥ 30 × 109/L; in cases of thrombocytopenia clearly due to CLL (per the discretion of the investigator), platelet count should be ≥ 10 × 109/L
Total haemoglobin ≥ 9 g/dL (without transfusion support, unless anaemia is due to CLL)
GFR >30ml/min directly measured with 24hr urine collection, calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 - age) x bodyweight)/ (72 x creatinine), for women x 0, 85) or an equally accurate method.

For patients with creatinine values within the normal range the calculation of the clearance is not necessary. Dehydrated patients with an estimated creatinine clearance less than 30 ml/min may be eligible if a repeat estimate after adequate hydration is > 30 ml/min.

Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST/ ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome.
Negative serological testing for hepatitis B (HbsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to registration for study screening (i.e. PCR only required when serology was positive).
Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2.

Exclusion criteria:

Any prior CLL-specific therapies (except corticosteroid treatment administered due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents up to 20 mg prednisolone are permitted).
Transformation of CLL (Richter transformation). When Richter transformation is suspected, PET-CT and/or biopsy should be performed to rule out transformation.
Patients with a history of PML.
An individual organ/ system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the study treatment or any other life-threatening illness, medical condition or organ system dysfunction that, in the investigator´s opinion, could compromise the patients' safety or interfere with the absorption or metabolism of the study drugs (e.g. inability to swallow tablets or impaired resorption in the gastrointestinal tract).
Malignancies other than CLL currently requiring systemic therapies, not being treated with curative intent before (unless the malignant disease is in a stable remission due to the discretion of the treating physician or showing signs of progression after curative treatment.
Uncontrolled or active infection.
Patients with known infection with human immunodeficiency virus (HIV).
Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/ inducers (incl. up to 7 days prior to study treatment start).
Anticoagulant therapy with warfarin or phenprocoumon, (alternative anticoagulation is allowed (e.g. DOACs), but patients must be properly informed about the potential risk of bleeding under treatment with ibrutinib).
History of stroke or intracranial hemorrhage within 6 months prior to registration for study screening.
Known bleeding disorders
Child B / C liver cirrhosis
Use of investigational agents which might interfere with the study drug within 28 days prior to registration for study screening.
Vaccination with live vaccines 28 days prior to registration for study screening.
Major surgery less than 30 days before start of study treatment.
History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products.
Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.
Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of study treatment; further pregnancy testing will be performed monthly).
Fertile men or women of childbearing potential unless:
surgically sterile or ≥ 2 years after the onset of menopause
willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after the end of study treatment.
Legal incapacity.
Prisoners or subjects who are institutionalized by regulatory or court order.
Persons who are in dependence to the sponsor or an investigator.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	LKH-Universtitätsklinikum Graz	Graz	Austria	8036
2	Landeskrankenhaus - Universitätskliniken Innsbruck	Innsbruck	Austria	6020
3	Medizinische Universität Wien	Wien	Austria	1090
4	Hanusch Krankenhaus	Wien	Austria	1140
5	Wiener Gesundheitsverbund Klinik Ottakring	Wien	Austria	1160
6	Algemeen Ziekenhuis St. Jan	Brugge	Belgium	8000
7	Universitair Ziekenhuis Leuven	Leuven	Belgium	3000
8	Algemeen Ziekenhuis Delta	Roeselare	Belgium	8800
9	Aalborg Universitetshospital	Aalborg	Denmark	9000
10	Aarhus Universitetshospital	Aarhus	Denmark	8200
11	Rigshospitalet	Copenhagen	Denmark	2100
12	Sydvestjysk Sygehus Esbjerg	Esbjerg	Denmark	6700
13	Regionshospitalet Holstebro	Holstebro	Denmark	7500
14	Odense Universitetshospital	Odense	Denmark	5000
15	Zealand University Hospital	Roskilde	Denmark	4000
16	Lillebaelt Vejle Sygehus	Vejle	Denmark	7100
17	Helsinki University Hospital	Helsinki	Finland	29
18	Tampere University Hospital	Tampere	Finland	33520
19	Turku University Hospital	Turku	Finland	20521
20	Universitätsklinikum Augsburg	Augsburg	Germany	86156
21	Onkologische Schwerpunktpraxis Kurfürstendamm	Berlin	Germany	10707
22	Charite Universitaetsmedizin - Campus Benjamin Franklin	Berlin	Germany	12203
23	Helios Klinikum Berlin Buch	Berlin	Germany	13125
24	Charite Universitätsmedizin - Campus Virchow Klinikum	Berlin	Germany	13353
25	Ev. Diakoniekrankenhaus	Bremen	Germany	28239
26	Gemeinschaftspraxis für Hämatologie & Onkologie	Dortmund	Germany	44263
27	Gemeinschaftspraxis Hämatologie Onkologie	Dresden	Germany	1307
28	Universitätsklinik Carl Gustav Carus	Dresden	Germany	1307
29	Sana Krankenhaus Benrath	Düsseldorf	Germany	40593
30	St. Georg Klinikum Eisenach	Eisenach	Germany	99817
31	ISP Erlangen Onkologische Schwerpunktpraxis	Erlangen	Germany	91052
32	Universitätsklinikum Erlangen	Erlangen	Germany	91054
33	Universitaetsklinikum Essen	Essen	Germany	45147
34	Onkologische Schwerpunktpraxis	Esslingen	Germany	73728
35	Centrum für Hämatologie und Onkologie Bethanien	Frankfurt	Germany	60389
36	Universitätsklinikum Freiburg	Freiburg	Germany	79106
37	Uniklinikum Gießen und Marburg	Gießen	Germany	35392
38	MVZ Onkologische Kooperation Harz	Goslar	Germany	38642
39	Universitätsklinikum Hamburg-Eppendorf	Hamburg	Germany	20246
40	OncoResearch Lerchenfeld	Hamburg	Germany	22081
41	Evangelische Krankenhaus Hamm	Hamm	Germany	59063
42	Onkologisches Ambulanzzentrum - MediProjekt	Hannover	Germany	30171
43	Onkologische Schwerpunktpraxis Heidelberg	Heidelberg	Germany	69115
44	Universitätsklinikum Heidelberg	Heidelberg	Germany	69120
45	Marien Hospital Herne	Herne	Germany	44625
46	Universitätskliniken des Saarlandes	Homburg	Germany	66424
47	Universitätsklinikum Jena	Jena	Germany	7747
48	Westpfalz-Klinikum GmbH	Kaiserslautern	Germany	67655
49	Universitaetsklinikum Schleswig-Holstein Campus Kiel	Kiel	Germany	24105
50	Praxis für Haematologie und Onkologie	Koblenz	Germany	56068
51	MVZ Hämatologie Onkologie Koblenz	Koblenz	Germany	56727
52	Universitätsklinik Köln	Köln	Germany	50924
53	H.O.T Onkologie Praxis Landshut	Landshut	Germany	84036
54	Universitätsklinikum Leipzig	Leipzig	Germany	4103
55	Onkopraxis Probstheida	Leipzig	Germany	4289
56	Klinikum Lippe Lemgo	Lemgo	Germany	32657
57	St Vincenz Krankenhaus	Limburg	Germany	65549
58	Lübecker Onkologische Schwerpunktpraxis	Lübeck	Germany	23562
59	Gemeinschaftspraxis Haematologie und Onkologie	Magdeburg	Germany	39104
60	Universitätsklinikum Magdeburg	Magdeburg	Germany	39120
61	Mannheimer Onkologie Praxis	Mannheim	Germany	68161
62	Praxis für Innere Medizin - Hämatologie und Onkologie	Marburg	Germany	35037
63	Stauferklinikum Schwäbisch Gmünd	Mutlangen	Germany	73557
64	Kliniken Maria Hilf	Mönchengladbach	Germany	41063
65	München Klinik Schwabing	München	Germany	80804
66	Klinikum der Universitaet München - Grosshadern Campus	München	Germany	81377
67	Klinikum rechts der Isar - Technische Universitaet Muenchen	München	Germany	81675
68	Gemeinschaftspraxis für Hämatologie und Onkologie	Münster	Germany	48153
69	Klinikum Oldenburg	Oldenburg	Germany	26133
70	Brüderkrankenhaus St. Josef Paderborn	Paderborn	Germany	33098
71	Gemeinschaftspraxis für Hämatologie und Onkologie	Ravensburg	Germany	88212
72	Barmherzigen Brüder Krankenhaus	Regensburg	Germany	93049
73	Schwerpunktpraxis für Hämatologie & Onkologie - OncoPro GbR	Regensburg	Germany	93053
74	Universitätsklinik Rostock	Rostock	Germany	18057
75	OnkoSaar Praxis für Hämatologie und Onkologie	Saarbrücken	Germany	66113
76	Zentrum für abulante Hämatologie und Onkologie	Siegburg	Germany	53721
77	Marienhospital Stuttgart	Stuttgart	Germany	70199
78	Robert-Bosch-Krankenhaus	Stuttgart	Germany	70376
79	Universitätsklinik Tübingen	Tübingen	Germany	72076
80	Universitätsklinikum Ulm	Ulm	Germany	89081
81	MVZ Weiden GmbH	Weiden	Germany	92637
82	Hämatologisch Onkologische Schwerpunktpraxis	Würzburg	Germany	97080
83	Cork University Hospital	Cork	Ireland	T12DC4A
84	St Vincents University Hospital	Dublin	Ireland	Dublin 4
85	Mater Misericordiae University Hospital	Dublin	Ireland	Dublin 7
86	St. James's Hospital	Dublin	Ireland	Dublin 8
87	Beaumont Hospital	Dublin	Ireland	Dublin 9
88	University Hospital Galway	Galway	Ireland	H91 YR71
89	University Hospital Limerick	Limerick	Ireland	V94 F858
90	University Hospital Waterford	Waterford	Ireland	X91 ER8E
91	Soroka University Medical Center	Be'er Sheva	Israel	84101
92	Shamir Medical Center Assaf Harofeh	Be'er Ya'aqov	Israel	70300
93	Bnai-Zion Medical Center	Haifa	Israel	31048
94	Hadassah Medical Center Ein Kerem University Hospital	Jerusalem	Israel	91120
95	Meir Medical Center	Kfar-Saba	Israel	4428164
96	Galilee Medical Center	Nahariya	Israel	22100
97	Rabin Medical Center Beilinson Hospital	Petach-Tikva	Israel	4941492
98	Chaim Sheba Medical Center	Ramat Gan	Israel	52621
99	Kaplan Medical Center	Rechovot	Israel	7610001
100	Tel Aviv Sourasky Medical Center	Tel-Aviv	Israel	6423906
101	Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele	Catania	Italy	9513
102	Azienda Ospedaliero Universitaria di Ferrara	Ferrara	Italy	44124
103	Ospedale dell'Angelo	Mestre	Italy	30174
104	Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico	Milano	Italy	20122
105	ASST Grande Ospedale Metropolitano Niguarda	Milano	Italy	20162
106	IRCCS Ospedale San Raffaele	Milano	Italy	202132
107	Ospedale S. Maria della Misericordia	Perugia	Italy	6123
108	Umberto I - Policlinico di Roma - Sapienza Università	Roma	Italy	161
109	Gmelli University Hospital	Roma	Italy	168
110	Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino	Torino	Italy	10126
111	Nordwest Ziekenhuisgroep, Locatie Alkmaar	Alkmaar	Netherlands	1815JD
112	OLVG Amsterdam	Amsterdam	Netherlands	1091AC
113	Amsterdam Universitair Medische Centra	Amsterdam	Netherlands	1105AZ
114	Rijnstate, Locatie Arnhem	Arnhem	Netherlands	6815AD
115	Amphia Ziekenhuis	Breda	Netherlands	4818CK
116	Reinier de Graaf Ziekenhuis	Delft	Netherlands	2625AD
117	Slingeland ziekenhuis	Doetinchem	Netherlands	7009BL
118	Albert Schweitzer Ziekenhuis	Dordrecht	Netherlands	3318AT
119	Ziekenhuis Gelderse Vallei	Ede	Netherlands	6716RP
120	Martini Ziekenhuis	Groningen	Netherlands	9728NT
121	Ziekenhuis St Jansdal	Harderwijk	Netherlands	3844DG
122	Medisch Centrum Leeuwarden	Leeuwarden	Netherlands	8934AD
123	Alrijne Ziekenhuis	Leiderdorp	Netherlands	2353GA
124	St. Antonius Ziekenhuis	Nieuwegein	Netherlands	3435CM
125	Canisius-Wilhelmina Ziekenhuis	Nijmegen	Netherlands	6532SZ
126	Maasstad Ziekenhuis	Rotterdam	Netherlands	3079DZ
127	Jeroen Bosch Ziekenhuis	s-Hertogenbosch	Netherlands	5223GZ
128	Franciscus Vlietland	Schiedam	Netherlands	3118JH
129	Ziekenhuis Rivierenland Tiel	Tiel	Netherlands	4002WP
130	Diakonessenhuis	Utrecht	Netherlands	3582 KE
131	VieCuri Medish Centrum	Venlo	Netherlands	5912BL
132	Isala Zwolle	Zwolle	Netherlands	8025AB
133	Haukeland University Hospital	Bergen	Norway	5021
134	Akershus University Hospital	Lørenskog	Norway	1478
135	Oslo University Hospital	Oslo	Norway	372
136	St. Olavs Hospital Trondheim University Hospital	Trondheim	Norway	7030
137	Hospital Germans Trias i Pujol	Badalona	Spain	8916
138	Vall d'Hebron University Hospital	Barcelona	Spain	8035
139	Hospital Clinic de Barcelona	Barcelona	Spain	8036
140	Hospital Duran i Reynals	Barcelona	Spain	8908
141	Hospital Universitario La Princesa	Madrid	Spain	28006
142	Hospital Universitario Infanta Leonor	Madrid	Spain	28031
143	Hospital Universitario 12 de Octubre	Madrid	Spain	28041
144	Hospital Costa del Sol	Málaga	Spain	29603
145	Hospital Universitario Central de Asturias	Oviedo	Spain	33011
146	Hospital Clinico Universitario de Salamanca	Salamanca	Spain	37007
147	Hospital Marques de Valdecilla	Santander	Spain	39008
148	Hospital Universitario Virgen de Valme	Sevilla	Spain	41014
149	Hospital Clinico Universitario Valencia	Valencia	Spain	46010
150	Residencia Sanitaria La Fe - Valencia	Valencia	Spain	46026
151	Hospital Clinico Universitario Lozano Blesa	Zaragoza	Spain	50009
152	Soedra Aelvsborgs Sjukhus	Borås	Sweden	50182
153	Falu Lasarett	Falun	Sweden	79182
154	Sahlgrenska University Hospital	Göteborg	Sweden	41346
155	Hallands Sjukhus Halmstad	Halmstad	Sweden	30185
156	Universitetssjukhuset Linköping	Linköping	Sweden	58185
157	Sunderby Hospital	Luleå	Sweden	97180
158	Skåne University Hospital	Lund	Sweden	22185
159	Karolinska University Hospital Solna	Stockholm	Sweden	17176
160	Umeå University Hospital	Umeå	Sweden	90185
161	Uppsala University Hospital	Uppsala	Sweden	75185
162	Hallands Sjukhus	Varberg	Sweden	43281
163	Örebro University Hospital	Örebro	Sweden	70185
164	Kantonsspital Aarau	Aarau	Switzerland	5001
165	Kantonsspital Baden	Baden	Switzerland	5404
166	Universitätsspital Basel	Basel	Switzerland	4031
167	Ospedale Regionale Bellinzona e Valli	Bellinzona	Switzerland	6500
168	Inselspital Bern	Bern	Switzerland	3010
169	Spitalzentrum Oberwallis	Brig	Switzerland	3900
170	Kantonsspital Graubünden	Chur	Switzerland	7000
171	HFR Fribourg Hôpital cantonal	Fribourg	Switzerland	1708
172	Hôpitaux Universitaires Genève	Geneve	Switzerland	1211
173	Kantonsspital Baselland	Liestal	Switzerland	4410
174	Luzerner Kantonsspital	Luzern	Switzerland	6000
175	Spital Thurgau AG - Kantonsspital Münsterlingen	Münsterlingen	Switzerland	8596
176	Kantonsspital Olten	Olten	Switzerland	4600
177	Kantonsspital St. Gallen	St Gallen	Switzerland	9007
178	Spital Thun	Thun	Switzerland	3600
179	Kantonsspital Winterthur	Winterthur	Switzerland	8401
180	Stadtspital Triemli	Zürich	Switzerland	8063
181	Universitätsspital Zuerich	Zürich	Switzerland	8091