HOVON 156 AML: A Study of Gilteritinib Versus Midostaurin in Combination With Induction and Consolidation Therapy Followed by One-year Maintenance in Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndromes With Excess Blasts-2 With FLT3 Mutations Eligible for Intensive Chemotherapy

Sponsor

Stichting Hemato-Oncologie voor Volwassenen Nederland (Other)

Overall Status

Recruiting

CT.gov ID

NCT04027309

Collaborator

Deutsch-Österreichische Studiengruppe Akute Myeloische Leukämie (AMLSG) (Other), Astellas Pharma Global Development, Inc. (Industry)

768

Enrollment

202

Locations

Arms

152.4

Anticipated Duration (Months)

3.8

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Activating mutations in the fms like tyrosine kinase 3 (FLT3) gene are observed in approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML). Addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy prolongs event-free survival (EFS) and overall survival (OS) in patients with a FLT3 mutation. Gilteritinib is a more potent and more specific inhibitor of mutant FLT3 in comparison to midostaurin and has shown promising clinical activity in AML.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia Myelodysplastic Syndrome With Excess Blasts-2	Drug: Gilteritinib Drug: Midostaurin	Phase 3

Detailed Description

AML and MDS-EB2 are malignant diseases of the bone marrow. The standard treatment for these diseases is chemotherapy. A subgroup of these diseases is characterized by a specific error in the DNA of the leukemic cells. This is the FLT3 mutation, which leads to a change of a certain protein (FLT3) on the blasts. This altered protein plays an important role in the development of leukemia and the survival of leukemic cells.

FLT3 can be inhibited by the drug midostaurin. Adding midostaurin to chemotherapy leads to better treatment results in patients with AML. Therefore, the standard treatment for AML or MDS-EB2 with a FLT3 mutation (FLT3-AML) is a combination of chemotherapy and midostaurin.

Gilteritinib is also a drug that inhibits FLT3. In laboratory studies, gilteritinib was found to be significantly more specific and potent than midostaurin in inhibiting FLT3.

Gilteritinib has subsequently been studied in patients with AML, who relapsed after previous treatment with chemotherapy. This resulted in a much larger number of complete remissions than previously seen when comparable patients were treated with midostaurin.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

768 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 3, Multicenter, Open-label, Randomized, Study of Gilteritinib Versus Midostaurin in Combination With Induction and Consolidation Therapy Followed by One-year Maintenance in Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes With Excess Blasts-2 (MDS-EB2) With FLT3 Mutations Eligible for Intensive Chemotherapy (HOVON 156 AML / AMLSG 28-18)

Actual Study Start Date :

Dec 20, 2019

Anticipated Primary Completion Date :

May 1, 2023

Anticipated Study Completion Date :

Sep 1, 2032

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A (Midostaurin) Midostaurin (50 mg BID PO) - Cycle 1 (day 8-21), Cycle 2 (day 8-21), Consolidation (only during chemo consolidation (day 8-21 - with max of 3 cycles), Maintenance (day 1-365)	Drug: Midostaurin Patients with a FLT3 mutation w ill be randomized to receive either the investigational drug gilteritinib or midostaurin given sequentially to standard induction and consolidation chemotherapy. After completing induction and consolidation treatment, patients who achieve CR/CRi/MLFS will receive maintenance therapy with gilteritinib or midostaurin Other Names: Rydapt
Experimental: Arm B (Gilteritinib) Gilteritinib (120 mg QD PO) - Cycle 1 (day 8-21), Cycle 2 (day 8-21), Consolidation (only during chemo consolidation (day 8-21 - with max of 3 cycles), Maintenance (day 1-365)	Drug: Gilteritinib Patients with a FLT3 mutation w ill be randomized to receive either the investigational drug gilteritinib or midostaurin given sequentially to standard induction and consolidation chemotherapy. After completing induction and consolidation treatment, patients who achieve CR/CRi/MLFS will receive maintenance therapy with gilteritinib or midostaurin Other Names: ASP2215

Arm

Intervention/Treatment

Active Comparator: Arm A (Midostaurin)

Midostaurin (50 mg BID PO) - Cycle 1 (day 8-21), Cycle 2 (day 8-21), Consolidation (only during chemo consolidation (day 8-21 - with max of 3 cycles), Maintenance (day 1-365)

Drug: Midostaurin

Patients with a FLT3 mutation w ill be randomized to receive either the investigational drug gilteritinib or midostaurin given sequentially to standard induction and consolidation chemotherapy. After completing induction and consolidation treatment, patients who achieve CR/CRi/MLFS will receive maintenance therapy with gilteritinib or midostaurin

Other Names:

Rydapt

Experimental: Arm B (Gilteritinib)

Gilteritinib (120 mg QD PO) - Cycle 1 (day 8-21), Cycle 2 (day 8-21), Consolidation (only during chemo consolidation (day 8-21 - with max of 3 cycles), Maintenance (day 1-365)

Drug: Gilteritinib

Other Names:

ASP2215

Outcome Measures

Primary Outcome Measures

Event-free survival (EFS) [Approximately up to 45 months following first patient enrollment]
EFS is defined as the time from randomization to failure to achieve CR after remission induction, death or relapse after achieving CR, whichever occurs first. A patient is said to have failed to achieve CR after induction therapy if his/her best response during or at completion of the induction treatment is less than CR. Patients who achieved CR after remission induction and are not known to have relapsed or died will be censored at the date of last clinical assessment.

Secondary Outcome Measures

Overall survival (OS) [Approximately up to 68 months following first patient enrollment]
OS is defined as the time from date of randomization to date of death due to any cause. Patients still alive or lost to follow up will be censored at the time they were last known to be alive.
CR rate after remission induction [Approximately up to 45 months following first patient enrollment]
CR rate after remission induction is defined as the percentage of patients with best response of CR during or at completion of induction therapy
CR and CRi rates after induction cycle 1 and after induction cycle 2 [Approximately up to 45 months following first patient enrollment]
CR and CRi are determined by the Investigator based on the European LeukemiaNet (ELN2017) recommended response criteria
Relapse-free survival (RFS) [Approximately up to 45 months following first patient enrollment]
RFS is defined as time from the date of achievement of CR until relapse or death from any cause, whichever comes first. Patients still in first CR and alive or lost to follow up will be censored at the date of last clinical assessment.
Cumulative incidence of relapse (CIR) after CR [Approximately up to 45 months following first patient enrollment]
CIR is measured from the date of achievement of CR until the date of relapse. Patients not known to have relapsed will be censored on the date of last clinical assessment. Patients who died without relapse will be counted as a competing cause of failure.
Cumulative incidence of death (CID) after CR [Approximately up to 45 months following first patient enrollment]
CID is measured from the date of achievement of CR until the date of death from any cause. Patients not known to have died will be censored on the date they were last known to be alive. Patients who experienced relapse in CR will be counted as competing cause of failure.
CR without minimal residual disease (CRMRD-) rate after induction cycle 2 [Approximately up to 45 months following first patient enrollment]
CRMRD- rate is defined as the percentage of patients who achieved CR with no evidence of MRD in bone marrow
Frequency and severity of adverse events according to CTCAE v5.0 [Continuously throughout the study, starting from informed consent until 30 days following the last administration of any study drug]
Adverse events will be evaluated using the National Cancer Institute's Common Terminology Criteria for AEs (CTCAE) version 5.0
Time to hematopoietic recovery after each chemotherapy treatment cycle [Approximately up to 45 months following first patient enrollment]
Time to hematopoietic recovery is defined as the time from the start of the cycle until recovery
Allogeneic stem cell transplantation (allo-SCT) rate [Approximately up to 45 months following first patient enrollment]
Allo-SCT rate is defined as the percentage of patients who underwent an allo-SCT
Individual domain scores and visual analogue scale (VAS) score of the European Quality of Life 5 Dimensions (EQ-5D-5L) Questionnaire [At entry, 1st day of maintenance and every 3 months during maintenance until relapse or treatment discontinuation (approximately up to 68 months following first patient enrollment)]
The EQ-5D-5L is a 5 item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating "health today". Each domain has 5 levels. Each level has a 1 digit number expressing the level selected for that domain. These levels are summed up and the self-rated health is recorded on a 20 cm vertical, visual analogue scale, with endpoints labelled "the best health you can imagine" and "the worst health you can imagine".
Individual subdomain scores and the global health status/QoL scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) [At entry, 1st day of maintenance and every 3 months during maintenance until relapse or treatment discontinuation (approximately up to 68 months following first patient enrollment)]
The EORTC QLQ-C30 is a 30-item questionnaire that assesses 5 functional subdomains (physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning), 1 global health status, 3 symptom subdomains (fatigue, nausea and vomiting and pain) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most of the 30 items have 4 response levels (1="not at all", 2="a little", 3="quite a bit", and 4="very much"), with 2 questions relying on a 7-point numeric rating scale from 1="very poor" to 7="excellent". Raw scores are transformed into scale scores ranging from 0 to 100, with higher scores representing better functioning/QoL or worse symptom burden.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥18 years
Newly diagnosed AML or MDS with excess of blasts-2 (EB2) defined according to WHO criteria (appendix A), with centrally documented FLT3 gene mutation (either TKD or ITD or both). AML may be secondary to prior hematological disorders, including MDS, and/or therapy-related. Patients may have had previous treatment with erythropoiesis stimulating agents (ESA) or hypomethylating agents (HMAs) for an antecedent phase of MDS. ESA and HMAs have to be stopped at least four weeks before registration.
FLT3 mutation as assessed by DNA fragment analysis PCR for FLT3-ITD and FLT3-TKD mutation. Positivity is defined as a FLT3-ITD or FLT3-TKD / FLT3-WT ratio of ≥ 0.05 (5%).
Considered to be eligible for intensive chemotherapy
Patient is suitable for oral administration of study drug
WHO/ECOG performance status ≤ 2
Adequate hepatic function as evidenced by
Serum total bilirubin ≤ 2.5 × upper limit of normal (ULN) unless considered due to leukemic involvement following written approval by the (co) Principal Investigator
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following written approval by the (co) Principal Investigator
Adequate renal function as defined by creatinine clearance > 40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR)
Written informed consent
Patient is capable of giving informed consent
Female patient must either:
Be of nonchildbearing potential:
Postmenopausal (defined as at least 1 year without any menses) prior to screening, or
Documented surgically sterile or status posthysterectomy (at least 1 month prior to screening)
Or, if of childbearing potential,
Agree not to try to become pregnant during the study and for 6 months after the final study drug administration
And have a negative urine or serum pregnancy test at screening
And, if heterosexually active, agree to consistently use highly effective* contraception per locally accepted standards in addition to a barrier method starting at screening and throughout the study period and for 6 months after the final study drug administration.
Highly effective forms of birth control include:
Consistent and correct usage of established hormonal contraceptives that inhibit ovulation,
Established intrauterine device (IUD) or intrauterine system (IUS),
Bilateral tubal occlusion,
Vasectomy (A vasectomy is a highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.)
Male is sterile due to a bilateral orchiectomy.
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.
(*)List is not all inclusive. Prior to enrollment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control per the requirements of the CTFG Guidance document 'Recommendations related to contraception and pregnancy testing in clinical trials', September 2014 (and any updates thereof) during the protocol defined period.
Female patient must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration.
Female patient must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
Male patient and their female partners who are of childbearing potential must be using highly effective contraception per locally accepted standards in addition to a barrier method starting at screening and continue throughout the study period and for 4 months and 1 week after the final study drug administration.
Male patient must not donate sperm starting at screening and throughout the study period and for 4 months and 1 week after the final study drug administration.
Patient agrees not to participate in another interventional study while on treatment

Exclusion Criteria:

Prior chemotherapy for AML or MDS-EB2, including prior treatment with hypomethylating agents. Hydroxyurea is allowed for the control of peripheral leukemic blasts in patients with leukocytosis (e.g., white blood cell [WBC] counts > 30 x 10^9/L)
Acute promyelocytic leukemia (APL) with PML-RARA or one of the other pathognomonic variant fusion genes/chromosome translocations
Blast crisis after CML
Known or suspected hypersensitivity to midostaurin or gilteritinib and/or any excipients
Patient requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A
Breast feeding at start of study treatment
Active infection, including hepatitis B or C or HIV infection that is uncontrolled at randomization. An infection controlled with an approved or closely monitored antibiotic/antiviral/antifungal treatment is allowed.
Patients with a currently active second malignancy. Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed:
Basal or squamous cell carcinoma of the skin;
Carcinoma in situ of the cervix;
Carcinoma in situ of the breast;
Incidental histologic finding of prostate cancer
Significant active cardiac disease within 6 months prior to the start of study treatment, including:
New York Heart Association (NYHA) Class III or IV congestive heart failure;
Myocardial infarction;
Unstable angina and/or stroke;
Left ventricular ejection fraction (LVEF) < 40% by ECHO or MUGA scan obtained within 28 days prior to the start of study treatment
QTc interval using Fridericia's formula (QTcF) ≥ 450 msec (average of triplicate determinations) or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, family history of long QT interval syndrome). Prolonged QTc interval associated with bundle branch block or pacemaking is permitted with written approval of the (co) Principal Investigator.
Patient with hypokalemia and/or hypomagnesemia before registration (defined as values below LLN) Note: electrolyte suppletion is allowed to correct LLN values before registration.
Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs
Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening
Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation
Any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient's ability to give informed consent or participate in the study
Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Contacts and Locations

Locations

	Site	City	Country
1	AU-Adelaide-FLINDERS	Adelaide	Australia
2	AU-Adelaide-RAH	Adelaide	Australia
3	AU-Brisbane-PAH	Brisbane	Australia
4	AU-Brisbane-RBWH	Brisbane	Australia
5	AU-Camperdown-RPA	Camperdown	Australia
6	AU-Canberra-CANBERRAHOSPITAL	Canberra	Australia
7	AU-Douglas-TOWNSVILLE	Douglas	Australia
8	AU-Geelong VIC-BARWONHEALTH	Geelong	Australia
9	AU-Gosford NSW-GOSFORDHOSPITAL	Gosford	Australia
10	AU-Hobart TAS-RHOBART	Hobart	Australia
11	AU-Launceston TAS-LAUNCESTON	Launceston	Australia
12	AU-Melbourne-ALFRED	Melbourne	Australia
13	AU-Melbourne-AUSTIN	Melbourne	Australia
14	AU-Melbourne-BOXHILL	Melbourne	Australia
15	AU-Melbourne-MONASH	Melbourne	Australia
16	AU-Melbourne-RMELBOURNE	Melbourne	Australia
17	AU-Melbourne-SVHM	Melbourne	Australia
18	AU-Perth-FSH	Perth	Australia
19	AU-Perth-RPH	Perth	Australia
20	AU-Perth-SCGH	Perth	Australia
21	AU-Sydney-CONCORD	Sydney	Australia
22	AU-Sydney-NEPEAN	Sydney	Australia
23	AU-Sydney-RNSH	Sydney	Australia
24	AU-Sydney-WSAH	Sydney	Australia
25	St George Hospital	Sydney	Australia
26	AU-Waratah-CALVARYMATER	Waratah	Australia
27	AT-Graz-MEDUNIGRAZ	Graz	Austria
28	AT-Innsbruck-IMED	Innsbruck	Austria
29	AT-Linz-KEPLER	Linz	Austria
30	AT-Linz-ORDENSKLINIKUM	Linz	Austria
31	AT-Salzburg-SALK	Salzburg	Austria
32	AT-Vienna-HANUSCH	Vienna	Austria
33	BE-Antwerpen Edegem-UZA	Antwerpen	Belgium
34	BE-Antwerpen-ZNASTUIVENBERG	Antwerpen	Belgium
35	BE-Brugge-AZBRUGGE	Brugge	Belgium
36	BE-Brussel-BORDET	Brussels	Belgium
37	BE-Brussel-UZBRUSSEL	Brussels	Belgium
38	BE-Bruxelles-STLUC	Brussels	Belgium
39	BE-Gent-UZGENT	Gent	Belgium
40	BE-Haine-Saint-Paul-JOLIMONT	Haine-Saint-Paul	Belgium
41	BE-Hasselt-VIRGAJESSE	Hasselt	Belgium
42	BE-Leuven-UZLEUVEN	Leuven	Belgium
43	BE-Liege-CHRCITADELLE	Liège	Belgium
44	BE-Liege-CHULIEGE	Liège	Belgium
45	BE-Mons-AMBROISE	Mons	Belgium
46	BE-Roeselare-AZDELTA	Roeselare	Belgium
47	BE-Yvoir-MONTGODINNE	Yvoir	Belgium
48	FI-Helsinki-HUS	Helsinki	Finland
49	FI-Tampere-TAYS	Tampere	Finland
50	FR-Amiens-CHUAMIENS	Amiens	France
51	FR-Angers-CHUANGERS	Angers	France
52	FR-Argenteuil-CHARGENTEUIL	Argenteuil	France
53	FR-Bayonne-CHCOTEBASQUE	Bayonne	France
54	FR-Besançon Cedex-JEANMINJOZ	Besançon	France
55	FR-Bobigny-AVICENNE	Bobigny	France
56	FR-Le Chesnay cedex-CHVERSAILLES	Chesnay	France
57	FR-Clamart-HIAPERCY	Clamart	France
58	FR-Clermont-Ferrand-ESTAING	Clermont-Ferrand	France
59	FR-Grenoble cedex 9-CHUGRENOBLE	Grenoble cedex 9	France
60	FR-Lens-CHLENS	Lens	France
61	FR-Lille-CHULILLE	Lille	France
62	FR-Limoges-CHULIMOGES	Limoges	France
63	FR-Lyon Pierre Benite cedex-LYONSUD	Lyon	France
64	FR-Lyon-LEONBERARD	Lyon	France
65	FR-Marseille-IPC	Marseille	France
66	FR-Montpellier-STELOI	Montpellier	France
67	FR-Nantes-CHUNANTES	Nantes	France
68	FR-Nice-CAL	Nice	France
69	FR-Nice-LARCHET	Nice	France
70	FR-Paris cedex 10-SAINTLOUIS	Paris	France
71	FR-Paris cedex 15-NECKER	Paris	France
72	FR-Pessac Cedex-CHUBORDEAUX	Pessac	France
73	FR-Poitiers-CHUPOITERS	Poitiers	France
74	FR-Reims-CHREIMS	Reims	France
75	FR-Rennes cedex 9-CHURENNES	Rennes	France
76	FR-Rouen cedex-BECQUEREL	Rouen	France
77	FR-Saint-Priest-en-Jarez-ICLOIRE	Saint-Priest-en-Jarez	France
78	FR-Strasbourg cedex-HAUTEPIERRE	Strasbourg	France
79	FR-Toulouse-CHUTOULOUSE	Toulouse	France
80	FR-Tours cedex-BRETONNEAU	Tours	France
81	FR-Vandoeuvre Les Nancy-CHRUNANCY	Vandœuvre-lès-Nancy	France
82	FR-Villejuif-GUSTAVEROUSSY	Villejuif	France
83	DE-Aschaffenburg-KLINIKUMAB	Aschaffenburg	Germany
84	DE-Bad Saarow-HELIOSBADSAAROW	Bad Saarow	Germany
85	DE-Berlin-CAMPUSBENFRANKLIN	Berlin	Germany
86	DE-Berlin-CAMPUSMITTE	Berlin	Germany
87	DE-Berlin-CAMPUSVIRCHOW	Berlin	Germany
88	DE-Berlin-VIVANTESNEUKOLLN	Berlin	Germany
89	DE-Berlin-VIVANTESURBAN	Berlin	Germany
90	DE-Bochum-RUB	Bochum	Germany
91	DE-Bonn-UNIBONN	Bonn	Germany
92	DE-Braunschweig-KLINIKUMBRAUNSCHWEIG	Braunschweig	Germany
93	DE-Bremen-KBM	Bremen	Germany
94	DE-Darmstadt-KLINIKUMDARMSTADT	Darmstadt	Germany
95	DE-Dortmund-JOHODORTMUND	Dortmund	Germany
96	DE-Düsseldorf-MEDUNIDUESSELDORF	Düsseldorf	Germany
97	DE-Essen-KEM	Essen	Germany
98	DE-Esslingen-KLINIKUMESSLINGEN	Esslingen	Germany
99	DE-Flensburg-MALTESER	Flensburg	Germany
100	DE-Frankfurt-KLINIKUMFRANKFURT	Frankfurt	Germany
101	DE-Giessen-UKGM	Gießen	Germany
102	DE-Goch-KKLE	Goch	Germany
103	DE-Greifswald-UNIGREIFSWALD	Greifswald	Germany
104	DE-Hamburg-ASKLEPIOSSTGEORG	Hamburg	Germany
105	DE-Hamburg-ASKLEPIOS	Hamburg	Germany
106	DE-Hamburg-UKE	Hamburg	Germany
107	DE-Hamm-EVKHAMM	Hamm	Germany
108	DE-Hanau-KLINIKUMHANAU	Hanau	Germany
109	DE-Hannover-MHHANNOVER	Hannover	Germany
110	DE-Hannover-SILOAHKRH	Hannover	Germany
111	DE-Heilbronn-SLK	Heilbronn	Germany
112	DE-Herne-MARIENHOSPITALHERNE	Herne	Germany
113	DE-Homburg-UNIKLINIKSAARLAND	Homburg	Germany
114	DE-Kaiserslautern-WESTPFALZ	Kaiserslautern	Germany
115	DE-Karlsruhe-KLINIKUMKARLSRUHE	Karlsruhe	Germany
116	DE-Lebach-CARITASKHLEBACH	Lebach	Germany
117	DE-Lemgo-KLINIKUMLIPPE	Lemgo	Germany
118	DE-Ludwigshafen-KLILU	Ludwigshafen	Germany
119	DE-Lübeck-UKSHLUBECK	Lübeck	Germany
120	DE-Luedenscheid-KLINIKUMLUEDENSCHEID	Lüdenscheid	Germany
121	DE-Magdeburg-OVGU	Magdeburg	Germany
122	DE-Mainz-KLINKUNIMAINZ	Mainz	Germany
123	DE-Mainz-UNIMEDIZINMAINZ	Mainz	Germany
124	DE-Meschede-HOCHSAUERLAND	Meschede	Germany
125	DE-Minden-MUEHLENKREISKLINKEN	Minden	Germany
126	DE-München-IRZTUM	München	Germany
127	DE-Offenburg-ORTENAUKLINIKUM	Offenburg	Germany
128	DE-Oldenburg-KLINIKUMOLDENBURG	Oldenburg	Germany
129	DE-Passau-KLINIKUMPASSAU	Passau	Germany
130	DE-Regensburg-UKR	Regensburg	Germany
131	DE-Saarbrücken-CARITASKLINIKUM	Saarbrücken	Germany
132	DE-Stuttgart-DIAKSTUTTGART	Stuttgart	Germany
133	DE-Stuttgart-KLINIKUMSTUTTGART	Stuttgart	Germany
134	DE-Trier-MUTTERHAUS	Trier	Germany
135	DE-Tübingen-MEDUNITUEBINGEN	Tübingen	Germany
136	DE-Ulm-UNIKLINKULM	Ulm	Germany
137	DE-Villingen-Schwenningen-SBKVS	Villingen-Schwenningen	Germany
138	DE-Wuppertal-HELIOSGESUNDHEIT	Wuppertal	Germany
139	IE-Cork-CUH	Cork	Ireland
140	IE-Dublin 24-TUH	Dublin	Ireland
141	IE-Dublin 4-SVUH	Dublin	Ireland
142	IE-Dublin 7-MATER	Dublin	Ireland
143	IE-Dublin 8-STJAMES	Dublin	Ireland
144	IE-Dublin 9-BEAUMONT	Dublin	Ireland
145	IE-Galway-UHGALWAY	Galway	Ireland
146	IE-Co. Limerick-UHL	Limerick	Ireland
147	LT-Vilnius-SANTA	Vilnius	Lithuania
148	LU-Luxembourg-CHL	Luxembourg	Luxembourg
149	NL-Amersfoort-MEANDERMC	Amersfoort	Netherlands
150	NL-Amsterdam-AMC	Amsterdam	Netherlands
151	NL-Amsterdam-OLVG	Amsterdam	Netherlands
152	NL-Amsterdam-VUMC	Amsterdam	Netherlands
153	NL-Arnhem-RIJNSTATE	Arnhem	Netherlands
154	NL-Breda-AMPHIA	Breda	Netherlands
155	NL-Delft-RDGG	Delft	Netherlands
156	NL-Den Bosch-JBZ	Den Bosch	Netherlands
157	NL-Den Haag-HAGA	Den Haag	Netherlands
158	NL-Dordrecht-ASZ	Dordrecht	Netherlands
159	NL-Eindhoven-MAXIMAMC	Eindhoven	Netherlands
160	NL-Enschede-MST	Enschede	Netherlands
161	NL-Groningen-UMCG	Groningen	Netherlands
162	NL-Leeuwarden-MCL	Leeuwarden	Netherlands
163	NL-Leiden-LUMC	Leiden	Netherlands
164	NL-Maastricht-MUMC	Maastricht	Netherlands
165	NL-Nieuwegein-ANTONIUS	Nieuwegein	Netherlands
166	NL-Nijmegen-RADBOUDUMC	Nijmegen	Netherlands
167	NL-Rotterdam-ERASMUSMC	Rotterdam	Netherlands
168	NL-Utrecht-UMCUTRECHT	Utrecht	Netherlands
169	NL-Zwolle-ISALA	Zwolle	Netherlands
170	NO-Bergen-HELSEBERGEN	Bergen	Norway
171	NO-Oslo-OSLOUH	Oslo	Norway
172	NO-Stavanger-HELSESTAVANGER	Stavanger	Norway
173	NO-Tromsø-NORTHNOORWEGEN	Tromsø	Norway
174	NO-Trondheim-STOLAV	Trondheim	Norway
175	ES-Barcelona-CLINICUB	Barcelona	Spain
176	ES-Barcelona-GERMANTRIALS	Barcelona	Spain
177	ES-Barcelona-ICODURANREYNALS	Barcelona	Spain
178	ES-Barcelona-MUTUATERRASSA	Barcelona	Spain
179	ES-Barcelona-PARCDESALUTMAR	Barcelona	Spain
180	ES-Barcelona-SANTPAU	Barcelona	Spain
181	ES-Barcelona-VHEBRON	Barcelona	Spain
182	ES-Girona-ICSTRUETA	Girona	Spain
183	ES-Lleida-ICSVILANOVA	Lleida	Spain
184	ES-Madrid-CSGREGORIOMARANON	Madrid	Spain
185	ES-Malaga-HUVV	Málaga	Spain
186	ES-Palma-HSLL	Palma	Spain
187	ES-Palma-SSIB	Palma	Spain
188	ES-Tarragona-JOAN	Tarragona	Spain
189	ES-Valencia-MALVARROSA	Valencia	Spain
190	SE-Lund-SUH	Lund	Sweden
191	SE-Stockholm-KAROLINSKAHUDDINGE	Stockholm	Sweden
192	SE-Uppsala-UPPSALAUH	Uppsala	Sweden
193	CH-Aarau-KSA	Aarau	Switzerland
194	CH-Basel-USB	Basel	Switzerland
195	CH-Bellinzona-IOSI	Bellinzona	Switzerland
196	CH-Bern-INSEL	Bern	Switzerland
197	CH-Fribourg-HFR	Fribourg	Switzerland
198	CH-Geneve (14)-HCUGE	Geneve	Switzerland
199	CH-Lausanne-CHUV	Lausanne	Switzerland
200	CH-Luzern-LUKS	Luzern	Switzerland
201	CH-St. Gallen-KSSG	Saint Gallen	Switzerland
202	CH-Zürich-USZ	Zürich	Switzerland