INDEPENDENCE: An Efficacy and Safety Study of Luspatercept (ACE-536) Versus Placebo in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis on Concomitant JAK2 Inhibitor Therapy and Who Require Red Blood Cell Transfusions

Sponsor

Celgene (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04717414

Collaborator

(none)

309

Enrollment

185

Locations

Arms

43.7

Anticipated Duration (Months)

1.7

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this Phase 3 study is to evaluate the efficacy and safety of Luspatercept compared with placebo in subjects with myeloproliferative neoplasm (MPN)-associated Myelofibrosis (MF) and anemia on concomitant Janus kinase 2 (JAK2) inhibitor therapy and who require red blood cell count (RBC) transfusions.

The study is divided into Screening Period, a Treatment Phase (consisting of a Blinded Core Treatment Period, a Day 169 Response Assessment, a Blinded Extension Treatment Period, and an Open-label Extension Treatment Period), and a Posttreatment Follow-up Period.

Condition or Disease	Intervention/Treatment	Phase
Myeloproliferative Disorders Myelofibrosis Primary Myelofibrosis Post-Polycythemia Vera Myelofibrosis Anemia	Drug: ACE-536 Other: Placebo	Phase 3

Detailed Description

Permitted Concomitant Medications and Procedures

Subjects are receiving a JAK2 inhibitor for the treatment of MPN-associated MF that is approved in the country where the study is being conducted. JAK2 inhibitors are to be used according to their respective label and as prescribed as part of the subject's standard-of-care therapy as prescribed by their physician prior to study entry.
Best supportive care (BSC) includes, but is not limited to, treatment with transfusions (eg, RBC, platelet, whole blood), ICTs, antibiotic, antiviral and/or antifungal therapy, and nutritional support as needed.
Granulocyte colony-stimulating factors (ie, G-CSF, granulocyte macrophage colony-stimulating factor [GM-CSF]) are allowed only in cases of neutropenic fever or as clinically indicated per product label.
Prophylactic antithrombotic therapy is permitted.
Thrombopoietin and platelet transfusions are permitted.
Treatment with systemic corticosteroids is permitted for nonhematological conditions providing the subject is receiving a constant dose equivalent to ≤ 10 mg prednisone during the study.
Administration of attenuated vaccines (eg, influenza vaccine) is allowed if clinically indicated per Investigator discretion.
Iron chelation therapy (ICT) is to be used according to the product label. If the label permits, the ICT dose should be stable during at least the first 24 weeks of IP. Initiation of ICT while within the first 24 weeks of IP should be clinically indicated to treat an AE.

Prohibited Concomitant Medications

The following concomitant medications are specifically excluded during the course of the study:

Cytotoxic, chemotherapeutic, targeted, or investigational agents/therapies (excluding JAK2 inhibitor therapy)
Azacitidine, decitabine, or other hypomethylating agents
Lenalidomide, thalidomide, and pomalidomide
Erythropoietin stimulating agents (ESAs) and other RBC hematopoietic growth factors (eg, IL-3)
Hydroxyurea or other alkylating agents
Androgens (unless given to treat hypogonadism)
Oral retinoids (topical retinoids are permitted)
Arsenic trioxide
Interferon
Anagrelide
Systemic corticosteroids at a dose equivalent to > 10 mg prednisone
Investigational products for the treatment of MPN-associated MF

Study Design

Study Type:

Interventional

Anticipated Enrollment :

309 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

A Phase 3, Double-blind, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Placebo in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis on Concomitant JAK Inhibitor Therapy and Who Require Red Blood Cell Transfusions

Actual Study Start Date :

Feb 25, 2021

Anticipated Primary Completion Date :

Oct 18, 2024

Anticipated Study Completion Date :

Oct 18, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental Arm: Luspatercept (ACE-536) Luspatercept will be given to participants via subcutaneous injection (administered on Day 1 of each 21-day treatment cycle)	Drug: ACE-536 Subcutaneous Injection Other Names: Luspatercept
Placebo Comparator: Control Arm: Placebo Placebo starting dose with volume equivalent to experimental arm subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle)	Other: Placebo Subcutaneous Injection

Arm

Intervention/Treatment

Experimental: Experimental Arm: Luspatercept (ACE-536)

Luspatercept will be given to participants via subcutaneous injection (administered on Day 1 of each 21-day treatment cycle)

Drug: ACE-536

Subcutaneous Injection

Other Names:

Luspatercept

Placebo Comparator: Control Arm: Placebo

Placebo starting dose with volume equivalent to experimental arm subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle)

Other: Placebo

Subcutaneous Injection

Outcome Measures

Primary Outcome Measures

Red blood cell-transfusion independence (RBC-TI) ≥ 12 weeks (RBC-TI 12) [Up to 24 weeks]
Proportion of subjects who become RBC-transfusion free over any consecutive 12-week period starting within the first 24 weeks.

Secondary Outcome Measures

Red blood cell-transfusion independence ≥ 16 weeks (RBC-TI 16) [Up to 24 weeks]
Proportion of subjects who become RBC-transfusion free over any consecutive 16-week period
Duration of Red blood cell-transfusion independence (RBC-TI 12) [Up to end of treatment, approximately 3 years]
Maximum duration of RBC-TI response
Reduction of transfusion burden by ≥ 50% and by ≥ 4 units/12 weeks from baseline over any consecutive 12-week period [Up to 24 weeks]
Proportion of subjects who reduce their transfusion burden by ≥ 50% and by ≥ 4 units/12 weeks from baseline over any consecutive 12-week period
Duration of reduction in transfusion burden [Up to end of treatment, approximately 3 years]
Maximum duration of when RBC-transfusion dependent subjects who reduce their transfusion burden by ≥ 50% and by ≥ 4 units/12 weeks from baseline over any consecutive 12 week period
Red blood cell-transfusion independence ≥ 12 weeks in the treatment period (RBC-TI 12/TP) [Up to end of treatment, approximately 3 years]
Proportion of subjects who become RBC-transfusion free over any consecutive 12-week period
Red blood cell-transfusion independence ≥ 16 weeks in the treatment period (RBC-TI 16/TP) [Up to end of treatment, approximately 3 years]
Proportion of subjects who become RBC-transfusion free over any consecutive 16-week period
Change in RBC transfusion burden [Up to 24 weeks]
Mean change in transfusion burden (RBC units) from baseline
Cumulative duration of RBC-transfusion independence [Up to end of treatment, approximately 3 years]
Cumulative response duration for subjects achieving multiple episodes of RBC-TI 12
Mean Hgb increase ≥ 1 g/dL from baseline over any consecutive 12-week period in absence of RBC transfusions [Up to end of treatment, approximately 3 years]
Proportion of subjects achieving a mean Hgb increase ≥ 1 g/dL from baseline over any consecutive 12-week period in absence of RBC transfusions
Change in serum ferritin from baseline [Up to end of treatment, approximately 3 years]
Change in serum ferritin
Incidence of Adverse Events (AEs) [From screening up to 42 days post last dose]
Number of participants with adverse events
Transformation to blast phase: Number of subjects who transform into AML [Up to approximately 5 years]
AML = acute myeloid leukemia
Frequency of Antidrug antibodies (ADA) [From randomization and up to including 48 weeks post first dose]
Will be collected for assessment of anti-drug antibodies (ADA) against Luspatercept in serum in all subjects
Pharmacokinetics - Area Under the Concentration-Time Curve (AUC) [From randomization and up to including 48 weeks post first dose]
Measures of luspatercept exposure area under the curve
Pharmacokinetics - Maximum plasma concentration of drug (Cmax) [From randomization and up to including 48 weeks post first dose]
Maximum plasma concentration of drug

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subjects must satisfy the following criteria to be randomized in the study:

Subject is ≥18 years of age at the time of signing the ICF.
Subject has a diagnosis of PMF according to the 2016 World Health Organization (WHO) criteria or diagnosis of post-ET or post-PV MF according to the IWG-MRT 2007 criteria , confirmed by the most recent local pathology report.
Subject is requiring RBC transfusions as defined as:

Average RBC-transfusion frequency: 4 to 12 RBC units/12 weeks immediately up to randomization. There must be no interval > 6 weeks (42 days) without ≥ 1 RBC transfusion.
RBC transfusions are scored in determining eligibility when given for treatment of:

Symptomatic (ie, fatigue or shortness of breath) anemia with a pretransfusion Hgb ≤ 9.5 g/dL or
Asymptomatic anemia with a pretransfusion Hgb ≤ 7 g/dL c. RBC transfusions given for worsening of anemia due to bleeding or infections are not scored in determining eligibility.

Subjects on continuous (eg, absent of dose interruptions lasting ≥ 2 consecutive weeks) JAK2 inhibitor therapy as approved in the country of the study site for the treatment for MPN-associated MF as part of their standard-of-care therapy for at least 32 weeks, on stable daily dose for at least 16 weeks immediately up to the date of randomization and anticipated to be on a stable daily dose of that JAK2 inhibitor for at least 24 weeks after randomization.
Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
A female of childbearing potential (FCBP) for this study is defined as a female who:

has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (eg, has had menses at any time in the preceding 24 consecutive months). Females of childbearing potential (FCBP)participating in the study must:

Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the study, and after end of IP. This applies even if the subject practices true abstinence* from heterosexual contact.
Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective contraception** without interruption, 28 days prior to starting IP, during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal half-life of IP based on multiple-dose PK data) after discontinuation of study therapy.

Male subjects must: Practice true abstinence* (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential** while participating in the study, during dose interruptions and for at least 12 weeks (approximately 5 times the mean terminal half-life of IP based on multiple-dose PK data) following IP discontinuation, even if he has undergone a successful vasectomy.

True abstinence is acceptable when it is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.]

** Agreement to use highly effective methods of contraception that alone or in combination result in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly throughout the course of the study. Such methods include: Combined (estrogen and progestogen containing) hormonal contraception: Oral, Intravaginal, Transdermal; Progestogen-only hormonal contraception associated with inhibition of ovulation: Oral, Injectable hormonal contraception, Implantable hormonal contraception; Placement of an intrauterine device (IUD); Placement of an intrauterine hormone-releasing system (IUS); Bilateral tubal occlusion; Vasectomized partner; Sexual Abstinence.

Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
Subject is willing and able to adhere to the study visit schedule and other protocol requirements including the use of the electronic patient reported outcomes device.

Exclusion Criteria:

The presence of any of the following will exclude a subject from randomization:

Subject with anemia from cause other than MPN-associated MForJAK2 inhibitor therapy (eg, iron deficiency, vitamin B12 and/or folate deficiencies, autoimmune or hemolytic anemia, infection, or any type of known clinically significant bleeding or sequestration).
Subject use of hydroxyurea, immunomodulatory compounds such as pomalidomide, thalidomide, ESAs, androgenic steroids or other drugs with potential effects on hematopoiesis ≤ 8 weeks immediately up to the date of randomization.
Systemic corticosteroids are permitted for nonhematological conditions providing the subject is receiving a constant dose equivalent to ≤ 10 mg prednisone for the 4 weeks immediately up to randomization.
Iron chelation therapy (ICT) is permitted providing the subject is receiving a stable dose for the 8 weeks immediately up to randomization.
Subject with any of the following laboratory abnormalities at screening:
Neutrophils: < 1 x 109/L
White blood count (WBC): > 100 x 109/L
Platelets: the lowest allowable level as approved for the concomitant JAK2 inhibitor but not < 25 x 109/L or > 1000 x 109/L
Peripheral blood myeloblasts:> 5%
Estimated glomerular filtration rate:< 40 mL/min/1.73 m2 (via the 4-variable modification of diet in renal disease [MDRD] formula) or nephrotic subjects (eg, urine albumin-to-creatinine ratio > 3500 mg/g)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT):> 3.0 x upper limit of normal (ULN)
Direct bilirubin: ≥ 2 x ULN

Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (eg, ineffective erythropoiesis)

Subject with uncontrolled hypertension, defined as repeated elevations of systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, that is not resolved at the time of randomization.
Subject with prior history of malignancies, other than disease under study, unless the subject has been free of the disease for ≥ 3 years. However, subject with the following history/concurrent conditions is 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 (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)
Subject with prior hematopoietic cell transplant or subject anticipated to receive a hematopoietic cell transplant during the 24 weeks from the date of randomization. 7. Subject with stroke, myocardial infarction, deep venous thrombosis, pulmonary or arterial embolism within 6 months immediately up to the date of randomization.
Subject with major surgery within 2 months up to the date of randomization. Subject must have completely recovered from any previous surgery immediately up to the date of randomization.
Subject with a major bleeding event (defined as symptomatic bleeding in a critical area or organ and/or bleeding causing a decrease in Hgb of ≥ 2 g/dL or leading to transfusion of ≥ 2 units of packed red cells) in the last 6 months prior to the date of randomization.

10.Subject with inadequately controlled heart disease and/or have a known left ventricular ejection fraction < 35%.

11.Subject with uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).

12.Subject with known human immunodeficiency virus (HIV), evidence of active Hepatitis B (HepB) as demonstrated by the presence of Hepatitis B surface antigen (HBsAg) and/or positive for Hepatitis B virus DNA (HBVDNA-positive), and/or evidence of active Hepatitis C (HepC) as demonstrated by a positive Hepatitis C virus RNA (HCV-RNA) test of sufficient sensitivity.

13.Subject with prior therapy of luspatercept or sotatercept. 14.Subject with history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product.

15.Pregnant or breastfeeding females. 16.Subject participation in any other clinical protocol or investigational trial that involves use of experimental therapy (including investigational agents) and/or therapeutic devices within 30 days or for investigational agents within five half-lives, whichever comes later, immediately up to the date of randomization.

17.Subject with any significant medical condition, laboratory abnormality, psychiatric illness, or is considered vulnerable by local regulations (eg, imprisoned or institutionalized) that would prevent the subject from participating in the study or places the subject at unacceptable risk if he/she were to participate in the study. 18.Subject with any condition or concomitant medication that confounds the ability to interpret data from the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Diego	La Jolla	California	United States	92037
2	University of California Los Angeles	Los Angeles	California	United States	90095
3	Northwestern University	Chicago	Illinois	United States	60611
4	Rush University Medical Center	Chicago	Illinois	United States	60612
5	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
6	Washington University	Saint Louis	Missouri	United States	63110
7	John Theurer Cancer Center	Hackensack	New Jersey	United States	07601
8	John Theurer Cancer Center	Hackensack	New Jersey	United States	07601
9	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10021-6094
10	Mount Sinai Medical Center	New York	New York	United States	10029
11	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
12	West Penn Allegheny Lupus Center of Excellence	Pittsburgh	Pennsylvania	United States	15224
13	The University of Texas - MD Anderson Cancer Center	Houston	Texas	United States	77030
14	CTRC at The UT Health Science Center at San Antonio	San Antonio	Texas	United States	78229
15	University of Utah - Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
16	Monash Medical Centre	Clayton	Victoria	Australia	3168
17	The Alfred Hospital	Melbourne	Victoria	Australia	3004
18	Gosford Hospital	Gosford		Australia	2250
19	Local Institution - 601	Gosford		Australia	2250
20	Royal Hobart Hospital	Hobart		Australia	7000
21	Medizinische Universitat Graz	Graz		Austria	8036
22	Krankenhaus der Elisabethinen Linz, I Interne Abteilung	Linz		Austria	4020
23	Medizinische Universitat Wien, Universitatsklinik fur Dermatologie. Abteilung fur Immundermatologie	Vienna		Austria	1090
24	Hanusch Krankenhaus	Wien		Austria	1140
25	AZ Sint-Jan AV Brugge	Brugge		Belgium	8000
26	Cliniques Universitaires Saint-Luc	Brussels		Belgium	1200
27	Virga Jessa Ziekenhuis	Hasselt		Belgium	3500
28	UZ Leuven	Leuven		Belgium	3000
29	AZ Delta	Roeselare		Belgium	8800
30	Centre Hospitalier Peltzer - La Tourelle	Verviers		Belgium	4800
31	Cliniques Universitaires UCL de Mont-Godine	Yvoir		Belgium	5530
32	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
33	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2S2
34	St. Paul's Hospital	Vancouver	British Columbia	Canada	V6Z 2A5
35	Saint John Regional Hospital	Saint John	New Brunswick	Canada	E2L 4L2
36	London Health Sciences Centre	London	Ontario	Canada	N6C 6B5
37	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
38	Hopital Maisonneuve-Rosemont	Montreal	Quebec	Canada	H1T 2M4
39	Local Institution - 182	Montreal	Quebec	Canada	H3T 1E2
40	Sir Mortimer B. Davis - Jewish Genl	Montreal	Quebec	Canada	H3T 1E2
41	Centre Hospitalier Universitaire de Sherbrooke-Hospital Fleurimont	Sherbrooke	Quebec	Canada	J1H5N4
42	Peking Union Medical College Hospital	Beijing		China	100730
43	First Hospital of Jilin University	Changchun		China	130021
44	Local Institution - 802	Changchun		China	130021
45	Guangdong General Hospital	Guangzhou		China	510030
46	Local Institution - 807	Guangzhou		China	510515
47	Nanfang Hospital of Southern Medical University	Guangzhou		China	510515
48	Local Institution - 808	Harbin		China	150081
49	The First Affiliated Hospital of Harbin Medical University	Harbin		China	150081
50	Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University	Nanjing		China	210029
51	Local Institution - 809	Shanghai		China	200025
52	Ruijin Hospital Shanghai Jiaotong University	Shanghai		China	200025
53	Shanghai 6th Hospital	Shanghai		China	200233
54	The First Affiliated Hospital of Soochow University	Suzhou		China	215006
55	Chinese Academy of Medical Sciences & Peking Union Medical College	Tianjin		China	300041
56	Local Institution - 800	Tianjin		China	300041
57	Henan Cancer Hospital	Zhengzhou		China
58	Local Institution - 341	Prague 2		Czechia	128 08
59	Vseobecna Fakultni Nemocnice v Praze	Prague 2		Czechia	128 08
60	CHRU Hopital du Bocage	Angers		France	49033
61	Hopital Henri Mondor	Creteil		France	94010
62	CHU de Grenoble	Grenoble		France	38043
63	CHRU de Lille-Hopital Claude Huriez	Lille		France	59037
64	Centre Leon Berard	Lyon		France	69008
65	CHU de Nice Archet I	Nice		France	06202
66	Centre Hospitalier Universitaire de Nimes (CHU) - Hopital Universitaire Caremeau	Nimes Cedex 9		France	30029
67	Hopital Saint Louis	Paris Cedex 10		France	75475
68	Groupe Hospitalier Sud Hopital Haut Leveque USN	Pessac		France	33604
69	CHU La Miletrie	Poitiers Cedex		France	86021
70	Local Institution - 326	Poitiers Cedex		France	86021
71	ICANS Institut de cancerologie Strasbourg Europe	Strasbourg		France	67200
72	Institut Universitaire du Cancer de Toulouse - Oncopole	Toulouse Cedex 9		France	31059
73	Unviversitatsklinikum Aachen	Aachen		Germany	52074
74	Local Institution - 294	Baden-Warttemberg		Germany	73557
75	Stauferklinikum Schwab. Gmund	Baden-Warttemberg		Germany	73557
76	Universitaetsklinikum Duesseldorf	Dusseldorf		Germany	40225
77	Universitatsklinikum Halle Saale	Halle		Germany	06120
78	Local Institution - 300	Hamburg		Germany	22081
79	OncoResearch Lerchenfeld GmbH	Hamburg		Germany	22081
80	Universitaetsklinikum Jena	Jena		Germany	07740
81	Universitatsklinikum Leipzig	Leipzig		Germany	04103
82	Universitaetsklinikum Mannheim	Mannheim		Germany	68167
83	Johannes Wiesling Klinikum Minden	Minden		Germany	32429
84	Local Institution - 292	Minden		Germany	32429
85	University Hospital of Alexandroupolis	Alexandroupolis		Greece	08100
86	Evangelismos General Hospital of Athens	Athens		Greece	10676
87	Laiko General Hospital of Athens	Athens		Greece	11 527
88	Attikon university General Hospital	Athens		Greece	12464
89	Local Institution - 381	Rio Patras		Greece	26500
90	University General Hospital of Patras	Rio Patras		Greece	26500
91	Georgios Papanikolaou General Hospital of Thessaloniki	Thessaloniki		Greece	57010
92	Local Institution - 382	Thessaloniki		Greece	57010
93	Local Institution - 661	Hong Kong		Hong Kong	0
94	Queen Mary Hospital	Hong Kong		Hong Kong
95	Prince of Wales Hospital the Chinese University of Hong Kong	Sha Tin		Hong Kong
96	Del-pesti Centrumkorhaz- Orszagos Hematologiai és Infektologiai Intezet	Budapest		Hungary	1096
97	Petz Aladár Egyetemi Oktató Kórház	Gyor		Hungary	9023
98	Somogy Megyei Kaposi Mor Oktato Korhaz	Kaposvar		Hungary	7400
99	Cork University Hospital	Cork		Ireland	T12 DFK4
100	Local Institution - 422	Dublin 7		Ireland	7
101	Mater Misercordiae Hospital	Dublin 7		Ireland	7
102	St James Hospital	Dublin		Ireland	Dublin 8
103	Rambam Medical Center	Haifa		Israel	31096
104	Hadassah Medical Organization	Jerusalem		Israel	91120
105	Local Institution - 522	Jerusalem		Israel	91120
106	Meir Medical Center	Kfar-Saba		Israel	44281
107	Tel-Aviv Sourasky Medical Center	Tel-Aviv		Israel	64239
108	Local Institution - 525	Zerifin		Israel	70300
109	Shamir Medical Center - Assaf Harofeh	Zerifin		Israel	70300
110	Azienda Ospedaliero Universitaria Ospedali Riuniti Umberto I, G.M. Lancisi, G. Salesi	Ancona		Italy	60126
111	Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi	Bologna		Italy	40138
112	Azienda Ospedaliero - Universitaria Policlinico - Vittorio Emanuele - Ospedale Gaspare Rodolico	Catania		Italy	95123
113	Local Institution - 243	Catania		Italy	95123
114	Azienda Ospedaliera Universitaria Careggi	Firenze		Italy	50134
115	Azienda Ospedaliera Universitaria Federico II	Napoli Campania		Italy	80131
116	A.O.U. Maggiore della Carit	Novara		Italy	28100
117	Azienda Ospedaliera di Padova	Padova		Italy	35128
118	Azienda Ospedaliero Universitaria Pisana	Pisa		Italy	56124
119	Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli	Reggio Di Calabria		Italy	89124
120	Local Institution - 244	Reggio Di Calabria		Italy	89124
121	Local Institution - 0812	Roma		Italy	00100
122	Local Institution - 254	Roma		Italy	00100
123	Azienda Ospedaliera Sant Andrea	Roma		Italy	00189
124	Local Institution - 251	Roma		Italy	00189
125	Ospedale S Eugenio	Roma		Italy	144
126	Azienda Ospedaliera S Maria di Terni	Terni		Italy	05100
127	Universita degli Studi dell'Insubria - Ospedale di Circolo e Fondazione Macchi - Varese	Varese		Italy	21100
128	Local Institution - 711	Osakasayama	Osaka	Japan	5898511
129	Aomori Prefectural Central Hospital	Aomori		Japan	030-8553
130	Juntendo University Hospital	Bunkyo-ku		Japan	113-8431
131	Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital	Bunkyo-ku		Japan	113-8677
132	University of Yamanashi Hospital	Chuo		Japan	409-3898
133	Tokai University Hospital	Isehara City, Kanagawa		Japan	259-1193
134	Kameda General Hospital	Kamogawa		Japan	296-8602
135	Gunma University Hospital	Maebashi		Japan	371-8511
136	University of Miyazaki Hospital	Miyazaki		Japan	889-1692
137	Local Institution - 702	Nagasaki		Japan	852-8511
138	The Japanese Red Cross Nagasaki Genbaku Hospital	Nagasaki		Japan	852-8511
139	Kindai University Hospital	Osaka-Sayama		Japan	589-8511
140	Local Institution - 705	Osaka		Japan	545-8586
141	Osaka City University Hospital	Osaka		Japan	545-8586
142	Sapporo Hokuyu Hospital	Sapporo		Japan	003-0006
143	Local Institution - 704	Shinagawa-ku, Tokyo		Japan	141-8625
144	NTT Medical Center Tokyo	Shinagawa-ku, Tokyo		Japan	141-8625
145	Tokyo Women's Medical University Hospital	Shinjuku City		Japan	162-8666
146	Tokyo Medical University Hospital	Shinjyuku-ku		Japan	160-0023
147	Kyungpook National University Hospital	Daegu		Korea, Republic of	700-721
148	Local Institution - 646	Daegu		Korea, Republic of	700-721
149	Chonnam National University Hwasun Hospital	Hwasun-Gun		Korea, Republic of	58128
150	Local Institution - 643	Seongnam-si		Korea, Republic of	13620
151	Seoul National University Bundang Hospital	Seongnam-si		Korea, Republic of	13620
152	Samsung Medical Center	Seoul		Korea, Republic of	135-710
153	The Catholic University of Korea Seoul - Saint Mary's Hospital	Seoul		Korea, Republic of	137-701
154	Seoul National University Hospital	Seoul		Korea, Republic of	3080
155	Asan Medical Center	Seoul		Korea, Republic of	5505
156	Local Institution - 642	Seoul		Korea, Republic of	5505
157	Uniwersyteckie Centrum Kliniczne	Gdansk		Poland	80-952
158	Samodzielny Publiczny Zaklad Opieki Zdrowotnej Szpital Uniwersytecki w Krakowie	Krakow		Poland	31-501
159	Wojewódzki Szpital Specjalistyczny im. M. Kopernika w Lodzi	Lodz		Poland	93-510
160	ALVAMED	Poznan		Poland	61-696
161	Local Institution - 434	Walbrzych		Poland	58-309
162	Specjalistyczny Szpital im. dra Alfreda Sokolowskiego	Walbrzych		Poland	58-309
163	Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroclawiu	Wroclaw		Poland	50367
164	Moscow State Healthcare Institution City clinical hospital n.a. S.P.Botkin	Moscow		Russian Federation	125284
165	Federal Centre of Heart, Blood and Endocrinology of Rosmed technlologies V.A. Almazov	St Petersburg		Russian Federation	197341
166	First St Petersburg State Medical University na IP Pavlov	St. Petersburg		Russian Federation	197022
167	Hospital Clinic de Barcelona	Barcelona		Spain	08036
168	Hospital Universitari Germans Trias i Pujol ICO Badalona	Barcelona		Spain	08916
169	Hospital Virgenes de las Nieves	Granada		Spain	18014
170	Hospital Universitario de Gran Canaria Dr. Negrin	Las Palmas de Gran Canaria		Spain	35012
171	Local Institution - 200	Las Palmas de Gran Canaria		Spain	35012
172	Hospital Universitario Ramon y Cajal	Madrid		Spain	28034
173	Local Institution - 205	Madrid		Spain	28034
174	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
175	Hospital Son Espases	Palma de Mallorca		Spain	7120
176	Universitario de Salamanca - Hospital Clinico	Salamanca		Spain	37007
177	Complejo Hospitalario Universitario de Santiago	Santiago de Compostela		Spain	15706
178	Hospital Universitario Virgen del Rocio	Seville		Spain	41013
179	Hospital Clinico Universitario de Valencia	Valencia		Spain	46010
180	Heart of England NHS Foundation Trust	Birmingham		United Kingdom	B9 5SS
181	Local Institution - 366	Birmingham		United Kingdom	B9 5SS
182	United Lincolnshire Hospitals NHS Trust	Boston		United Kingdom	PE21 9QS
183	Guy's Cancer Centre	London		United Kingdom	SE1 9RT
184	Nottingham City Hospital	Nottingham		United Kingdom	NG5 1PB
185	Churchhill Hospital	Oxford		United Kingdom	OX3 7LI