Standard Chemoimmunotherapy (FCR/BR) Versus Rituximab + Venetoclax (RVe) Versus Obinutuzumab (GA101) + Venetoclax (GVe) Versus Obinutuzumab + Ibrutinib + Venetoclax (GIVe) in Fit Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL) Without Del(17p) or TP53 Mutation

Phase 3

Completed

• Conditions: Chronic Lymphocytic Leukemia
• Interventions: Drug: Fludarabine; Biological: Obinutuzumab; Drug: Cyclophosphamide; Drug: Venetoclax; Biological: Rituximab; Drug: Ibrutinib; Drug: Bendamustine

• Registration Number: NCT02950051
• Lead Sponsor: German CLL Study Group

Brief Summary

The aim of this study is to evaluate if standard chemoimmunotherapy (FCR, BR) in frontline treatment of physically fit CLL patients without del17p or TP 53 mutation can be replaced by combinations of targeted drugs (Venetoclax, Ibrutinib) with anti-CD20-antibodies (Rituximab, Obinutuzumab), which may induce extremely long lasting remissions.

Detailed Description

Chemoimmunotherapy is the standard of care in first-line treatment of CLL patients without del17p or TP 53 mutation; physically fit patients are treated with fludarabine, cyclophosphamide and rituximab (FCR)1. Due to the high risk of severe neutropenias and infections with FCR, bendamustine and rituximab (BR) must be considered in patients aged \>65 years.

However, these conventional chemoimmunotherapies are associated with side effects caused by the rather unspecific mode of action of the chemotherapy. Therefore, there is an urgent need for alternatives, especially chemotherapy-free regimens.

In first line treatment of elderly patients with CLL and coexisting conditions, the anti-CD20-antibody obinutuzumab is the new standard therapy. In the CLL11 trial the combination of obinutuzumab with chlorambucil proved to be safe and lead to markedly improved response rates as well as PFS times in comparison to chlorambucil alone or combined with rituximab.

The BCL2 antagonist venetoclax (GDC-0199/ABT-199) showed striking activity with tumor lysis syndrome as dose limiting toxicity in patients with relapsed and refractory CLL. 400 mg venetoclax was determined to be a safe and efficacious dose. Several patients treated with the combination of venetoclax and rituximab in relapsed refractory CLL even achieved MRD negativity. The FDA approved Venetoclax for the treatment of relapsed CLL with 17p/TP53 on 12th April 2016.

Therefore, venetoclax plus CD20-antibody based combinations have the potential to induce higher rates of MRD negativity in frontline therapy of CLL and concomitantly induce lower rates of toxicities so that chemotherapy might be replaced. Furthermore, venetoclax and obinutuzumab demonstrated synergistic activity in a preclinical study of a murine Non-Hodgkin lymphoma xenograft model, and additive activity in a CLL lymph node model. The combination appears tolerable in the firstline treatment of CLL patients with coexisting conditions whilst the toxicity profile of both drugs compares favorably to those of the chemotherapies currently used in the treatment of CLL. Consequently, it should be tested if rituximab can be replaced by obinutuzumab in combination with venetoclax in this trial.

Ibrutinib, a selective, irreversible small molecular inhibitor of Bruton´s Tyrosine Kinase (BTK), showed excellent responses and a safe toxicity profile9,10, even in combination with BR. Ibrutinib is approved for treatment of relapsed CLL as well as frontline therapy of CLL by the FDA and EMA (April 29th 2016).

The combination of ibrutinib and venetoclax showed synergy in primary CLL cells.

Consequently, the aim of the current trial is to evaluate if chemoimmunotherapy in the frontline treatment of physically fit patients in CLL can be replaced by combinations of these targeted drugs with anti-CD20-antibodies.

Study Timeline

• Study First Submitted: 2016-10-27
• Study First Submitted QC: 2016-10-27
• Study First Posted: 2016-10-31
• Study Start: 2016-12-13
• Primary Completion: 2024-02-29
• Study Completion: 2024-02-29
• Status Verified: 2024-03
• Last Update Submitted: 2024-12-27
• Last Update Posted: 2024-12-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 926

Inclusion Criteria

1. Documented CLL requiring treatment according to iwCLL criteria
2. Age at least 18 years
3. Life expectancy ≥ 6 months
4. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements
5. Adequate bone marrow function indicated by a platelet count >30 x10^9/l (unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy)
6. Creatinine clearance ≥70ml/min directly measured with 24hr urine collection or 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). 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 70 ml/min may be eligible if a repeat estimate after adequate hydration is > 70 ml/min
7. 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
8. 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
9. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2

Exclusion Criteria

1. Any prior CLL-specific therapies (except corticosteroid treatment administere due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents of 20 mg prednisolone are permitted).

2. Transformation of CLL (Richter transformation)

3. Decompensated hemolysis, defined as ongoing hemoglobin drop in spite of three more concurrent treatments being administered for hemolysis

4. Detected del(17p) or TP53 mutation

5. Patients with a history of PML

6. Any comorbidity or organ system impairment rated with a single CIRS (cumulative illness rating scale) score of 4 (excluding the eyes/ears/nose/throat/larynx organ system), a total CIRS score of more than 6 or any other life-threatening illness, medical condition or organ system dysfunction that, in the investigator´s opinion, could comprise 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)

7. Urinary outflow obstruction

8. Malignancies other than CLL currently requiring systemic therapies, not being treated in curative intention 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

9. Uncontrolled or active infection

10. Patients with known infection with human immunodeficiency virus (HIV)

11. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers

12. Anticoagulant therapy with warfarin or phenoprocoumon, (rotation to alternative anticoagulation is allowed, but note that patients being treated with NOAKs can be included, but must be properly informed about the potential risk of bleeding under treatment with ibrutinib)

13. History of stroke or intracranial hemorrhage within 6 months prior to registration

14. Use of investigational agents which might interfere with the study drug within 28 days prior to registration

15. Vaccination with live vaccines 28 days prior to registration

16. Major surgery less than 30 days before start of treatment

17. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products

18. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial

19. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment; further pregnancy testing will be performed regularly)

20. Fertile men or women of childbearing potential unless:

    1. surgically sterile or ≥ 2 years after the onset of menopause
    2. 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

21. Legal incapacity

22. Prisoners or subjects who are institutionalized by regulatory or court order

23. Persons who are in dependence to the sponsor or an investigator

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Obinutuzumab + Venetoclax (GVe)	Obinutuzumab	6 cycles (q28d) of GVe + 6 cycles (q28d) of Venetoclax (alone)
Standard chemoimmunotherapy (SCIT)	Rituximab	Patients up to age 65: 6 cycles (q28d) of Fludarabine + Cyclophosphamide + Rituximab (FCR) Patients older than 65 years: 6 cycles (q28d) of Bendamustine + Rituximab (BR)
Rituximab + Venetoclax (RVe)	Rituximab	6 cycles (q28d) of RVe + 6 cycles (q28d) of Venetoclax (alone)
Obinutuzumab + Ibrutinib + Venetoclax (GIVe)	Obinutuzumab	6 cycles (q28d) of GIVe + 6 cycles (q28d) of Ibrutinib plus Venetoclax. Administration of ibrutinib will be continued for a maximum of 36 months or until MRD negativity, start of new anti-CLL therapy or inacceptable toxicity, whatever occurs first.
Standard chemoimmunotherapy (SCIT)	Cyclophosphamide	Patients up to age 65: 6 cycles (q28d) of Fludarabine + Cyclophosphamide + Rituximab (FCR) Patients older than 65 years: 6 cycles (q28d) of Bendamustine + Rituximab (BR)
Standard chemoimmunotherapy (SCIT)	Fludarabine	Patients up to age 65: 6 cycles (q28d) of Fludarabine + Cyclophosphamide + Rituximab (FCR) Patients older than 65 years: 6 cycles (q28d) of Bendamustine + Rituximab (BR)
Standard chemoimmunotherapy (SCIT)	Bendamustine	Patients up to age 65: 6 cycles (q28d) of Fludarabine + Cyclophosphamide + Rituximab (FCR) Patients older than 65 years: 6 cycles (q28d) of Bendamustine + Rituximab (BR)
Rituximab + Venetoclax (RVe)	Venetoclax	6 cycles (q28d) of RVe + 6 cycles (q28d) of Venetoclax (alone)
Obinutuzumab + Venetoclax (GVe)	Venetoclax	6 cycles (q28d) of GVe + 6 cycles (q28d) of Venetoclax (alone)
Obinutuzumab + Ibrutinib + Venetoclax (GIVe)	Venetoclax	6 cycles (q28d) of GIVe + 6 cycles (q28d) of Ibrutinib plus Venetoclax. Administration of ibrutinib will be continued for a maximum of 36 months or until MRD negativity, start of new anti-CLL therapy or inacceptable toxicity, whatever occurs first.
Obinutuzumab + Ibrutinib + Venetoclax (GIVe)	Ibrutinib	6 cycles (q28d) of GIVe + 6 cycles (q28d) of Ibrutinib plus Venetoclax. Administration of ibrutinib will be continued for a maximum of 36 months or until MRD negativity, start of new anti-CLL therapy or inacceptable toxicity, whatever occurs first.

Primary Outcome Measures

Name	Time	Method
Miminimal residual disease (MRD) negativity rate in peripheral blood (PB)	Month 15	Proportion of MRD negative patients at month15 based on the intention-to-treat population (ITT population), that is the number of MRD negative patients divided by the number of the ITT population. MRD negativity is defined as \<1 CLL-cell among 10,000 leukocytes analyzed \[0.01%\], i.e. \< 10-4.; Primary outcome measure for the comparison of GVe vs. SCIT
Progression free survival (PFS)	anticipated for January 2023 (after 213 events occured and 73 months after the first patient has been randomized	Time from randomization to the first occurrence of progression or relapse (determined using standard IWCLL guidelines \[2008\]), or death from any cause, whichever occurs first.; Primary outcome measure for the comparison GIVe vs. SCIT

Secondary Outcome Measures

Name	Time	Method
Overall response rate (ORR)	Month 3, 9, 13 and 15
MRD levels in PB	Month 2, 9, 13 and later time points according to the discretion of the treating physician at local laboratories
MRD levels in bone marrow (BM)	at final restaging (RE): 2 month after the end of the last treatment cycle
MRD negativity rate in PB	Month 15	Time from randomization to the first occurrence of progression or relapse (determined using standard IWCLL guidelines \[2008\]), or death from any cause, whichever occurs first.; Secondary outcome measure for all other comparisons with the exception of GVe vs. SCIT
PFS	anticipated for January 2023 (after 213 events occured and 73 months after the first patient has been randomized)	Time from randomization to the first occurrence of progression or relapse (determined using standard IWCLL guidelines \[2008\]), or death from any cause, whichever occurs first.; Secondary outcome measure for all other comparisons with the exception of GIVe vs.SCIT
Rate of complete responses (CR) / complete responses with incomplete bone marrow recovery(CRi)	Interim staging (IST: cycle 4 d1), cycle 9 d1 (or final restaging (RE) for patients in the SCIT arm), IR (or three month after RE for patients in the SCIT arm respectively) and Month 15, with regard to best response achieved	Complete response (CR) rate is defined by the proportion of patients having achieved a CR/CRi defined by the IWCLL guidelines as best response until and including the response assessment at Month 6, 9, 12 and 15 (= number of patients with best response CR/CRi divided by the ITT population).

Trial Locations

Locations (161)

Kaplan Medical Center; 🇮🇱 Rechovot, Israel

Canisius-Wilhelmina ZH; 🇳🇱 Nijmegen, Netherlands

Antonius Ziekenhuis Sneek; 🇳🇱 Sneek, Netherlands

St. Elisabeth ZH; 🇳🇱 Tilburg, Netherlands

KSBL Liestal; 🇨🇭 Liestal, Switzerland

Wilhelminenspital; 🇦🇹 Wien, Austria

Algemeen Ziekenhuis St. Jan; 🇧🇪 Brugge, Belgium

Mater Misericordiae Hospital; 🇮🇪 Dublin, Ireland

Reinier de Graaf Gasthuis; 🇳🇱 Delft, Netherlands

Maxima Medisch Centrum; 🇳🇱 Eindhoven, Netherlands

Radboud UMC; 🇳🇱 Nijmegen, Netherlands

Cork University Hospital; 🇮🇪 Cork, Ireland

University Hospital Waterford; 🇮🇪 Waterford, Ireland

Ziekenhuis Rijnstate; 🇳🇱 Arnhem, Netherlands

Maastricht university medial Center; 🇳🇱 Maastricht, Netherlands

IOSI, Ospedale Regionale Bellinzona e Valli; 🇨🇭 Bellinzona, Switzerland

Bnai-Zion Medical. Il-Haifa; 🇮🇱 Haifa, Israel

St. James's Hospital; 🇮🇪 Dublin, Ireland

Deventer ziekenhuizen; 🇳🇱 Deventer, Netherlands

Maasstadziekenhuis; 🇳🇱 Rotterdam, Netherlands

ZorgSaam Zeeuws Vlaanderen; 🇳🇱 Terneuzen, Netherlands

IJsselland Ziekenhuis; 🇳🇱 Capelle aan den Ijssel, Netherlands

UMCG; 🇳🇱 Groningen, Netherlands

Jeroen Bosch Ziekenhuis; 🇳🇱 s-Hertogenbosch, Netherlands

Zaans Medisch Centrum; 🇳🇱 Zaandam, Netherlands

Universitaetsspital Basel; 🇨🇭 Basel, Switzerland

Medizinische Universitaet Wien; 🇦🇹 Wien, Austria

VieCuri loc. Venlo; 🇳🇱 Venlo, Netherlands

UMCU; 🇳🇱 Utrecht, Netherlands

Isala; 🇳🇱 Zwolle, Netherlands

Kantonsspital Aarau; 🇨🇭 Aarau, Switzerland

Kantonsspital Graubunden; 🇨🇭 Chur, Switzerland

Spital Thurgau AG; 🇨🇭 Münsterlingen, Switzerland

Skane University Hospital Lund; 🇸🇪 Lund, Sweden

Kantonsspital Baden; 🇨🇭 Baden, Switzerland

Universitaire de Geneve; 🇨🇭 Genève, Switzerland

Universitetssjukhuset i Oerebro; 🇸🇪 Örebro, Sweden

Inselspital Bern; 🇨🇭 Bern, Switzerland

Kantonsspital Olten; 🇨🇭 Olten, Switzerland

Kantonsspital St. Gallen; 🇨🇭 St Gallen, Switzerland

KS Winterthur; 🇨🇭 Winterthur, Switzerland

Stadtspital Triemli; 🇨🇭 Zürich, Switzerland

Universitaetsspital Zuerich; 🇨🇭 Zürich, Switzerland

Soedra Aelvsborgs Sjukhus; 🇸🇪 Borås, Sweden

Falu lasarett; 🇸🇪 Falun, Sweden

Hallands hospital - Halmstad; 🇸🇪 Halmstad, Sweden

Universitetsjukhuset i Linkoeping; 🇸🇪 Linköping, Sweden

Sunderby Hospital; 🇸🇪 Luleå, Sweden

Akademiska Sjukhuset; 🇸🇪 Uppsala, Sweden

Hallands hospital - Varberg; 🇸🇪 Varberg, Sweden

Gelderse Vallei; 🇳🇱 Ede, Netherlands

Ziekenhuisgroep Twente Hengelo; 🇳🇱 Hengelo, Netherlands

Medisch Centrum Leeuwarden Zuid; 🇳🇱 Leeuwarden, Netherlands

Hanusch Hospital; 🇦🇹 Wien, Austria

ZNA Stuivenberg; 🇧🇪 Antwerpen, Belgium

Jan Yperman Ziekenhuis; 🇧🇪 Ieper, Belgium

UZ Gasthuisberg; 🇧🇪 Leuven, Belgium

AZ Delta; 🇧🇪 Roeselare, Belgium

Aalborg University Hospital; 🇩🇰 Aalborg, Denmark

Aarhus University Hospital; 🇩🇰 Aarhus, Denmark

Rigshospitalet/Copenhagen; 🇩🇰 Copenhagen, Denmark

Sydvestjysk Sygehus Esbjerg; 🇩🇰 Esbjerg, Denmark

University Hospital Herlev; 🇩🇰 Herlev, Denmark

Regionshospitalet Holstebro; 🇩🇰 Holstebro, Denmark

Odense Universitets Hospital; 🇩🇰 Odense, Denmark

Sjællands Universitetshospital; 🇩🇰 Roskilde, Denmark

Leids Universitair Medisch Centrum; 🇳🇱 Leiden, Netherlands

Vejle Hospital; 🇩🇰 Vejle, Denmark

Helsinki University Hospital; 🇫🇮 Helsinki, Finland

Jyväskylä Central Hospital; 🇫🇮 Jyväskylä, Finland

Oulu University Hospital; 🇫🇮 Oulu, Finland

Tampere University Hospital; 🇫🇮 Tampere, Finland

Gesundheitszentrum Klinikum St Marien; 🇩🇪 Amberg, Germany

Turku University Hospital; 🇫🇮 Turku, Finland

Onkologische Schwerpunktpraxis Kurfürstendamm; 🇩🇪 Berlin, Germany

Helios-Klinikum Berlin; 🇩🇪 Berlin, Germany

ZAHO Bonn; 🇩🇪 Bonn, Germany

Ev. Diakonie-Krankenhaus gemeinnuetzige GmbH; 🇩🇪 Bremen, Germany

St. -Johannes-Hospital Dortmund; 🇩🇪 Dortmund, Germany

Gefos Dortmund mbH; 🇩🇪 Dortmund, Germany

BAG Dresden; 🇩🇪 Dresden, Germany

Universitaetsklinikum Freiburg; 🇩🇪 Freiburg, Germany

Universitaetsklinik Carl Gustav Carus; 🇩🇪 Dresden, Germany

Helios Klinikum Erfurt; 🇩🇪 Erfurt, Germany

Marien Hospital Düsseldorf GmbH; 🇩🇪 Düsseldorf, Germany

Centrum fuer Haematologie und Onkologie Bethanien; 🇩🇪 Frankfurt, Germany

St. Georg Klinikum Eisenach GmbH; 🇩🇪 Eisenach, Germany

Universitaetsklinikum Essen; 🇩🇪 Essen, Germany

Onkologische Schwerpunktpraxis Göttingen; 🇩🇪 Göttingen, Germany

MVZ Onkologische Kooperation Harz, Drs. Tessen/Hoyer/Zahn; 🇩🇪 Goslar, Germany

Universitaetsmedizin Greifswald; 🇩🇪 Greifswald, Germany

UKE Hamburg; 🇩🇪 Hamburg, Germany

Universitaetsmedizin Göttingen; 🇩🇪 Göttingen, Germany

OncoResearch Lerchenfeld GmbH; 🇩🇪 Hamburg, Germany

EVK Hamm; 🇩🇪 Hamm, Germany

Medizinische Hochschule Hannover; 🇩🇪 Hannover, Germany

MediProjekt GBR; 🇩🇪 Hannover, Germany

Universitaetsklinikum Heidelberg; 🇩🇪 Heidelberg, Germany

Marienhospital Herne; 🇩🇪 Herne, Germany

Onkologische Schwerpunktpraxis Des. Freier/Sievers, Hildesheim; 🇩🇪 Hildesheim, Germany

Universitaetsklinikum Jena; 🇩🇪 Jena, Germany

Westpfalz-Klinikum GmbH; 🇩🇪 Kaiserslautern, Germany

Städt. Klinikum Karlsruhe; 🇩🇪 Karlsruhe, Germany

Dres. Siehl / Soeling, Fachaerzte fuer Haematologie und Internistische Onkologie, Kassel; 🇩🇪 Kassel, Germany

Universitaetsklinikum Schleswig-Holstein Campus Kiel; 🇩🇪 Kiel, Germany

InVO-Institut fuer Versorgungsforschung in der Onkologie GbR; 🇩🇪 Koblenz, Germany

University Hospital of Cologne; 🇩🇪 Köln, Germany

Tagesklinik Landshut, Dr. Vehling-Kaiser; 🇩🇪 Landshut, Germany

Gemeinschaftspraxis Haemato/ Onkologie Lebach; 🇩🇪 Lebach, Germany

Onkologische Schwerpunktpraxis Dr. Mueller, Leer; 🇩🇪 Leer, Germany

Klinikum Lippe GmbH; 🇩🇪 Lemgo, Germany

Universitaetsklinikum Magdeburg; 🇩🇪 Magdeburg, Germany

Gemeinschaftspraxis Haematologie und Onkologie; 🇩🇪 Magdeburg, Germany

Universitaetsklinik Mainz; 🇩🇪 Mainz, Germany

Mannheimer Onkologie Praxis; 🇩🇪 Mannheim, Germany

Institut fuer Versorgungsforschung Dr. med. M. Maasberger/ M. Schmitz/ Dr. med. M. T. Keller; 🇩🇪 Mayen, Germany

Stauferklinikum Schwaebisch-Gmuend; 🇩🇪 Mutlangen, Germany

MVZ MOP Elisenhof; 🇩🇪 München, Germany

Klinikum Schwabing; 🇩🇪 München, Germany

Ludwig-Maximilians-Universitaet Muenchen; 🇩🇪 München, Germany

Haematologische/Onkologische Praxis Neunkirchen; 🇩🇪 Neunkirchen, Germany

Klinikum rechts der Isar; 🇩🇪 München, Germany

Studiengesellschaft Onkologie Rhein Ruhr; 🇩🇪 Oberhausen, Germany

Tergooi Ziekenhuis; 🇳🇱 Hilversum, Netherlands

Gemeinschaftspraxis Dres. Ballo/Boeck; 🇩🇪 Offenbach, Germany

Klinik fuer Haematologie und Onkologie; 🇩🇪 Paderborn, Germany

Studienzentrum Onkologie Ravensburg; 🇩🇪 Ravensburg, Germany

Krankenhaus der Barmherzigen Brüder; 🇩🇪 Regensburg, Germany

OncoPro GbR; 🇩🇪 Regensburg, Germany

Praxis für Hämatologie und Onkologie Dres. Jacobs/Daus/Schmits; 🇩🇪 Saarbrücken, Germany

Leopoldina-Krankenhaus; 🇩🇪 Schweinfurt, Germany

ZAHO-Rheinland; 🇩🇪 Siegburg, Germany

Marienhospital Stuttgart; 🇩🇪 Stuttgart, Germany

Robert-Bosch-Krankenhaus; 🇩🇪 Stuttgart, Germany

Universitaetsklinikum Tuebingen; 🇩🇪 Tübingen, Germany

Universitaetsklinikum Ulm; 🇩🇪 Ulm, Germany

MVZ Weiden GmbH; 🇩🇪 Weiden, Germany

Haematologisch-Onkologische Schwerpunktpraxis Dres. Perker/Sandherr, Weilheim; 🇩🇪 Weilheim, Germany

Helios Klinikum Wuppertal; 🇩🇪 Wuppertal, Germany

Universitaetsklinik Wuerzburg; 🇩🇪 Würzburg, Germany

Gemeinschaftspraxis Dr. Schlag/Dr. Schoettker; 🇩🇪 Würzburg, Germany

Medisch Spectrum Twente; 🇳🇱 Enschede, Netherlands

Groene Hart Ziekenhuis; 🇳🇱 Gouda, Netherlands

University Hospital Galway; 🇮🇪 Galway, Ireland

Beaumont Hospital; 🇮🇪 Dublin, Ireland

Hadassah Ein Kerem; 🇮🇱 Jerusalem, Israel

Meir Medicail Center; 🇮🇱 Kfar-Saba, Israel

Rabin medical Center; 🇮🇱 Petach-Tikva, Israel

Souraski Tel-Aviv Medical Center; 🇮🇱 Tel-Aviv, Israel

MC Alkmaar; 🇳🇱 Alkmaar, Netherlands

Meander Medisch Centrum, Amersfoort; 🇳🇱 Amersfoort, Netherlands

VUmc, Amsterdam; 🇳🇱 Amsterdam, Netherlands

NL-Amsterdam-AMC; 🇳🇱 Amsterdam, Netherlands

Amphia Ziekenhuis; 🇳🇱 Breda, Netherlands

Albert Schweitzer Ziekenhuis, Dordrecht; 🇳🇱 Dordrecht, Netherlands

Kliniken Maria Hilf GmbH; 🇩🇪 Mönchengladbach, Germany

St. Antonius-Hospital; 🇩🇪 Eschweiler, Germany

Universitätsmedizin Rostock; 🇩🇪 Rostock, Germany

Spaarne Ziekenhuis; 🇳🇱 Hoofddorp, Netherlands

St. Antonius Ziekehuis; 🇳🇱 Nieuwegein, Netherlands

Luzerner Kantonsspital; 🇨🇭 Luzern, Switzerland