Safety and Efficacy of Ruxolitinib Versus Best Available Therapy in Patients With Corticosteroid-refractory Acute Graft vs. Host Disease After Allogeneic Stem Cell Transplantation

NCT02913261 | Completed Phase 3 Results DMC

• 2 other identifiers: CINC424C23012016-002584-33
• Study Type: interventional
• Target: 310
• Locations: 21 countries
• Sites: 99

Brief Summary

Assess the efficacy and safety of ruxolitinib compared to Best Available Therapy (BAT) in patients with corticosteroid-refractory acute graft vs. host disease (aGvHD) after allogeneic stem cell transplantation.

Conditions

Corticosteroid Refractory Acute Graft vs Host Disease

Keywords

GvHD (Graft versus Host Disease); INC424; ruxolitinib; best available therapy (BAT); corticosteroid-refractory acute graft vs. host disease; allogeneic stem cell transplantation; steroid refractory acute graft vs. host disease; Janus Kinase (JAK) inhibitor

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate (ORR) at Day 28

  Overall response rate at Day 28 after randomization was defined as the percentage participants in each arm demonstrating a complete response (CR) or partial response (PR), based on investigator assessment \& according to standard criteria, without requirement for additional systemic therapies for an earlier progression, mixed response or non-response. Scoring of response was relative to the organ stage at the time of randomization. CR was defined as a score of 0 for the aGvHD grading in all evaluable organs that indicates complete resolution of all signs \& symptoms of aGvHD in all evaluable organs without administration of additional systemic therapies for any earlier progression, mixed response or non-response of aGvHD. PR was defined as improvement of 1 stage in 1 or more organs involved with aGvHD signs or symptoms without progression in other organs or sites without administration of additional systemic therapies for an earlier progression, mixed response or non-response of aGvHD.

  Day 28

Secondary Outcomes (25)

• Durable Overall Response Rate (DORR) (Key Secondary Endpoint) at Day 56

  Day 56

• Overall Response Rate (ORR) at Day 14

  Day 14

• Duration of Response (DOR)

  Up to 24 months

• Cumulative Steroid Dosing Until Day 56

  up to Day 56

• Kaplan Meier Estimates of Probability of Overall Survival (OS) by Time Interval

  1, 2, 6, 12, 18 & 24 months

Study Arms (2)

Ruxolitinib

EXPERIMENTAL

These patients were administered Ruxolitinib orally twice per day (b.i.d) at a dose of 10 mg bid, as two 5-mg tablets. Ruxolitinib was taken without regards to food.

Drug: Ruxolitinib (RUX)

Best Available Therapy (BAT)

ACTIVE COMPARATOR

These patients were administered BAT per the Investigator's best judgement based on a specific list of BAT.

Drug: Best Available Therapy (BAT)

Interventions

Ruxolitinib (RUX) DRUG

Ruxolitinib was provided as 5 mg tablets for oral use.

Also known as: INC424

Ruxolitinib

Best Available Therapy (BAT) DRUG

BAT was based on the investigator's best judgment, taking into account the manufacturer's instructions, labeling, patient's medical condition, and institutional guidelines for any dose adjustment. The BAT in this study was identified by the investigator prior to patient randomization among the following treatments currently used in this setting: anti-thymocyte globulin (ATG), extracorporeal photopheresis (ECP), mesenchymal stromal cells (MSC), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), etanercept, or infliximab. No other types or combinations of BAT were permitted.

Best Available Therapy (BAT)

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Have undergone Allogeneic Stem Cell Transplanttaion (alloSCT) from any donor source (matched unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of non- myeloablative, myeloablative, and reduced intensity conditioning are eligible
• Clinically diagnosed Grades II to IV acute GvHD as per standard criteria occurring after alloSCT requiring systemic immune suppressive therapy. Biopsy of involved organs with aGvHD is encouraged but not required for study screening.
• Confirmed diagnosis of steroid refractory aGvHD defined as patients administered high-dose systemic corticosteroids (methylprednisolone 2 mg/kg/day \[or equivalent prednisone dose 2.5 mg/kg/day\]), given alone or combined with calcineurin inhibitors (CNI) and either:
• Progressing based on organ assessment after at least 3 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD, OR
• Failure to achieve at a minimum partial response based on organ assessment after 7 days compared to organ stage at the time of initiation of high-dose systemic corticosteroid +/- CNI for the treatment of Grade II-IV aGvHD,OR
• Patients who fail corticosteroid taper defined as fulfilling either one of the following criteria:
• Requirement for an increase in the corticosteroid dose to methylprednisolone ≥2 mg/kg/day (or equivalent prednisone dose ≥2.5 mg/kg/day) , OR
• Failure to taper the methylprednisolone dose to \<0.5 mg/kg/day (or equivalent prednisone dose \<0.6 mg/kg/day) for a minimum 7 days.

You may not qualify if:

• Has received more than one systemic treatment for steroid refractory aGvHD.
• Presence of an active uncontrolled infection including significant bacterial, fungal, viral or parasitic infection requiring treatment. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of progression are present. Progression of infection is defined as hemodynamic instability attributable to sepsis, new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
• Evidence of uncontrolled viral infection including Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Human Herpes Virus-6 (HHV-6), Hepatitis Virus (HBV), or Hepatitis C Virus (HCV) based on assessment by the treating physician.
• Presence of relapsed primary malignancy, or who have been treated for relapse after the alloHSCT was performed, or who may require rapid immune suppression withdrawal as pre-emergent treatment of early malignancy relapse.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (103)

Novartis Investigative Site

Westmead, New South Wales, 2145, Australia

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Novartis Investigative Site

Herston, Queensland, 4029, Australia

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Parkville, Victoria, 3002, Australia

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Novartis Investigative Site

Murdoch, Western Australia, 6150, Australia

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Graz, 8036, Austria

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Novartis Investigative Site

Linz, A-4010, Austria

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Novartis Investigative Site

Sofia, 1797, Bulgaria

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Calgary, Alberta, T2N 4N2, Canada

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Vancouver, British Columbia, V5Z 1M9, Canada

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Hamilton, Ontario, L8V 5C2, Canada

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Ottawa, Ontario, K1H 8L6, Canada

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Toronto, Ontario, M5G 2M9, Canada

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Montreal, Quebec, H1T 2M4, Canada

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Montreal, Quebec, H4A 3J1, Canada

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Saskatoon, Saskatchewan, S7N 4H4, Canada

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Novartis Investigative Site

Prague, Czech Republic, 128 20, Czechia

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Copenhagen, DK-2100, Denmark

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Saint Priest En Jarez, Pays de la Loire Region, 42270, France

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Novartis Investigative Site

Angers, 49033, France

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Besançon, 25030, France

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Grenoble, 38043, France

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Lille, 59000, France

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Lille, 59037, France

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Limoges, 87042, France

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Nice, 06202, France

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Paris, 75012, France

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Paris, 75013, France

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Novartis Investigative Site

Paris, 75019, France

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Paris, 75475, France

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Pessac, 33604, France

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Pierre-Bénite, 69495, France

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Toulouse, 31059, France

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Vandœuvre-lès-Nancy, 54511, France

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Mannheim, Baden-Wurttemberg, 68305, Germany

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Augsburg, 86179, Germany

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Berlin, 13125, Germany

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Berlin, 13353, Germany

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Dresden, 01307, Germany

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Düsseldorf, 40225, Germany

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Essen, 45147, Germany

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Freiburg im Breisgau, 79106, Germany

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Hamburg, 20246, Germany

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Hanover, 30625, Germany

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Jena, 07740, Germany

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Leipzig, 04103, Germany

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Mainz, 55131, Germany

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Münster, 48149, Germany

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Tübingen, 72076, Germany

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Ulm, 89081, Germany

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Thessaloniki, GR, 570 10, Greece

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Hong Kong, Hong Kong

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Haifa, 3109601, Israel

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Jerusalem, 9112001, Israel

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Petah Tikva, 4941492, Israel

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Tel Aviv, 6423906, Israel

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Ancona, AN, 60126, Italy

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Bergamo, BG, 24127, Italy

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Bologna, BO, 40138, Italy

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Brescia, BS, 25123, Italy

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San Giovanni Rotondo, FG, 71013, Italy

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Florence, FI, 50134, Italy

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Genova, GE, 16147, Italy

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Milan, MI, 20162, Italy

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Roma, RM, 00168, Italy

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Torino, TO, 10126, Italy

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Udine, UD, 33100, Italy

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Novartis Investigative Site

Nagoya, Aichi-ken, 453-8511, Japan

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Fukuoka, Fukuoka, 812-8582, Japan

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Sapporo, Hokkaido, 060 8648, Japan

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Kobe, Hyōgo, 650-0047, Japan

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Nishinomiya, Hyōgo, 663 8501, Japan

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Isehara, Kanagawa, 259-1193, Japan

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Sendai, Miyagi, 980 8574, Japan

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Okayama, Okayama-ken, 700-8558, Japan

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Suita, Osaka, 565 0871, Japan

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Bunkyo Ku, Tokyo, 113-8677, Japan

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Chuo Ku, Tokyo, 104 0045, Japan

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Minato Ku, Tokyo, 105-8470, Japan

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Novartis Investigative Site

Shinjuku-ku, Tokyo, 160 8582, Japan

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Osaka, 545-8586, Japan

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Novartis Investigative Site

Utrecht, The Netherlands, 3508 GA, Netherlands

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Oslo, 0372, Norway

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Moscow, 125167, Russia

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Riyadh, 11211, Saudi Arabia

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Seoul, 03080, South Korea

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Seoul, 06351, South Korea

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Seville, Andalusia, 41013, Spain

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Novartis Investigative Site

Barcelona, Catalonia, 08035, Spain

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Novartis Investigative Site

Barcelona, Catalonia, 08036, Spain

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Novartis Investigative Site

Vigo, Pontevedra, 36212, Spain

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Novartis Investigative Site

Oviedo, Principality of Asturias, 33006, Spain

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Novartis Investigative Site

Madrid, 28009, Spain

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Madrid, 28034, Spain

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Málaga, 29009, Spain

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Novartis Investigative Site

Valencia, 46026, Spain

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Novartis Investigative Site

Taichung, 40447, Taiwan

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Novartis Investigative Site

Ankara, 06100, Turkey (Türkiye)

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Ankara, 06500, Turkey (Türkiye)

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Istanbul, 41400, Turkey (Türkiye)

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Izmir, Turkey (Türkiye)

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Novartis Investigative Site

London, SE5 9RS, United Kingdom

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Novartis Investigative Site

London, WC1E 6HX, United Kingdom

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Novartis Investigative Site

Manchester, M13 9WL, United Kingdom

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Related Publications (5)

• Mohty M, Socie G, Szer J, Niederwieser D, Butler J, Wagner-Drouet E, Or R, Rovenvald-Zuckerman T, Bozdag SC, Forcade E, Grillo G, Kroger N, Stolzel F, Russo D, Sanz J, Sarkar R, Stefanelli T, Wilke C, Zeiser R, von Bubnoff N. Ruxolitinib Versus Best Available Therapy in Patients With Steroid-Refractory Acute Graft-Versus-Host Disease: Final Analysis From the Randomized Phase III REACH2 Trial. J Clin Oncol. 2025 Dec;43(34):3639-3645. doi: 10.1200/JCO-25-00809. Epub 2025 Oct 15.

  PMID: 41092247 DERIVED

• Mahmoudjafari Z, Kintsch E, Xue Z, Bhatt V, Galvin J, Locatelli F, Zeiser R. Impact of concomitant azoles on ruxolitinib treatment in patients with GVHD: post hoc analyses of REACH2 and REACH3. Blood Adv. 2025 Aug 26;9(16):4206-4216. doi: 10.1182/bloodadvances.2025016212.

  PMID: 40472328 DERIVED

• Socie G, Niederwieser D, von Bubnoff N, Mohty M, Szer J, Or R, Garrett J, Prahallad A, Wilke C, Zeiser R. Prognostic value of blood biomarkers in steroid-refractory or steroid-dependent acute graft-versus-host disease: a REACH2 analysis. Blood. 2023 Jun 1;141(22):2771-2779. doi: 10.1182/blood.2022018579.

  PMID: 36827620 DERIVED

• Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, Szer J, Wagner EM, Zuckerman T, Mahuzier B, Xu J, Wilke C, Gandhi KK, Socie G; REACH2 Trial Group. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med. 2020 May 7;382(19):1800-1810. doi: 10.1056/NEJMoa1917635. Epub 2020 Apr 22.

  PMID: 32320566 DERIVED

• Jagasia M, Zeiser R, Arbushites M, Delaite P, Gadbaw B, Bubnoff NV. Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials. Immunotherapy. 2018 Apr;10(5):391-402. doi: 10.2217/imt-2017-0156. Epub 2018 Jan 10.

  PMID: 29316837 DERIVED

MeSH Terms

Conditions

Graft vs Host Disease

Interventions

ruxolitinib

Condition Hierarchy (Ancestors)

Immune System Diseases

Results Point of Contact

• Title: Study Directr
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 18, 2016
• First Posted: September 23, 2016
• Study Start: March 10, 2017
• Primary Completion: June 24, 2019
• Study Completion: April 23, 2021
• Last Updated: February 8, 2023
• Results First Posted: February 8, 2023

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will share

Locations

ES (9); GB (3); BU (1); AU (2); RU (1); HK (1); SA (1); IT (11); DE (16); FR (16); NL (1); JP (14); CA (8); IL (4); GR (1); CZ (1); TW (1); KR (2); DK (1); TU (4); NO (1)