A Global Study of the Efficacy and Safety of Midostaurin + Chemotherapy in Newly Diagnosed Patients With FLT3 Mutation Negative (FLT3-MN) Acute Myeloid Leukemia (AML)

NCT03512197 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: CPKC412E23012017-003540-21
• Study Type: interventional
• Target: 511
• Locations: 19 countries
• Sites: 130

Brief Summary

The purpose of this study was to confirm the preliminary evidence from early clinical trials that midostaurin may provide clinical benefit not only to AML patients with the FLT3-mutations but also in FLT3-MN (SR\<0.05) AML (FLT3 mutant to wild type signal ratio below the 0.05 clinical cut-off). This study evaluated the efficacy and safety of midostaurin in combination with daunorubicin or idarubicin and cytarabine for induction and intermediate-dose cytarabine for consolidation, and midostaurin single agent post-consolidation therapy in newly diagnosed patients with FLT3-MN (SR\<0.05) AML.

Conditions

Acute Myeloid Leukemia (AML)

Keywords

Newly diagnosed FLT3-mutation negative; PKC412; midostaurin; cytarabine; daunorubicin; idarubicin; acute myeloid leukemia; AML; FLT3-MN (SR<0.05); combination treatment; induction failure; event free survival; EFS; minimal residual disease

Outcome Measures

Primary Outcomes (1)

• Event Free Survival (EFS)

  EFS was defined as the time from randomization to failure to obtain a complete remission (CR) or Complete remission with incomplete hematologic recovery (CRi) with adequate blood count recovery in induction, relapse after CR or CRi with adequate blood count recovery or death due to any cause, whichever occurred first as assessed by the investigator.

  From date of Randomization up to approx. 30 months

Secondary Outcomes (18)

• Overall Survival (OS) (Key Secondary)

  Between randomization to date of death up to approx. 30 months

• Percentage of Participants With Complete Remission (CR) and Complete Remission With Incomplete Hematological Recovery (CRi) But With Adequate Blood Count Recovery Rate.

  At maximum 93 days from induction therapy start

• Percentage of Participants With Minimal Residual Disease (MRD) Negative Status

  from start of treatment up to end of post-consolidation (approximately 17 months)

• Percentage of Participants With Minimal Residual Disease (MRD) Negative Status During Post-consolidation Phase

  from start of post-consolidation to end of post-consolidation phase (up to 12 months)

• Time to Measurable Residual Disease (MRD) Negativity by Flow Cytometry

  From date of Randomization up to approx. 17 months

Study Arms (2)

Midostaurin + chemotherapy

EXPERIMENTAL

Participants received Midostaurin in Induction 50mg twice daily on Day 8 until 48 hrs before start of next cycle. During Induction 2 and consolidation 50mg twice daily on Day 4 until 48 hrs before start of next cycle. During post-consolidation 50mg twice daily for 28 consecutive days of each 28-day treatment cycle up to 12 cycles. For participants who could not tolerate the protocol-specified dosing schedule, dose interruptions and/or reductions were either recommended or mandated allowing participants to continue the study treatment. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation.

Drug: Midostaurin; Drug: Chemotherapy

Placebo + chemotherapy

PLACEBO COMPARATOR

Participants received matching placebo to midostaurin with same dose, plus chemotherapy. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation

Drug: Placebo; Drug: Chemotherapy

Interventions

Midostaurin DRUG

Midostaurin was provided as 25 mg capsules 8PC, was supplied as double-blind in blister packs and taken orally.

Also known as: PKC412

Midostaurin + chemotherapy

Placebo DRUG

Placebo was provided as 25 mg soft gelatin capsules 8PC, was supplied as double-blind in blister packs and taken orally.

Placebo + chemotherapy

Chemotherapy DRUG

Along with the study drug/placebo, chemotherapy was given as well: either Daunorubicin or Idarubicin and Cytarabine - all taken by i.v.

Midostaurin + chemotherapy; Placebo + chemotherapy

Eligibility Criteria

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

You may qualify if:

• Diagnosis of AML (≥20% blasts in the bone marrow based on WHO 2016 classification). Patients with APL with PML-RARA are not eligible.
• Suitability for intensive induction chemotherapy in the judgment of the investigator
• Documented absence of an ITD and TKD activating mutation at codons D835 and I836 in the FLT3 gene, as determined by analysis in a Novartis designated laboratory using a validated clinical trial assay with clinical cutoff of 0.05 mutant to wild type signal ratio
• Age ≥18 years
• Laboratory values that indicate adequate organ function assessed locally at the screening visit

You may not qualify if:

• Central nervous system (CNS) leukemia
• Therapy-related secondary AML
• Isolated extramedullary leukemia
• Prior therapy for leukemia or myelodysplasia
• AML after antecedent myelodysplasia (MDS) with prior cytotoxic treatment (e.g., azacytidine or decitabine)
• Prior treatment with a FLT3 inhibitor (e.g., midostaurin, quizartinib, sorafenib)

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (133)

University of Chicago Medical Center .

Chicago, Illinois, 60637, United States

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Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

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Oregon Health and Science Univ

Portland, Oregon, 97239, United States

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Novartis Investigative Site

CABA, Buenos Aires, C1118AAT, Argentina

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Westmead, New South Wales, 2145, Australia

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Woolloongabba, Queensland, 4102, Australia

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Prahran, Victoria, 3181, Australia

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Murdoch, Western Australia, 6150, Australia

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Linz, A-4010, Austria

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Vienna, 1090, Austria

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Vienna, 1140, Austria

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Antwerp, 2060, Belgium

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Bruges, 8000, Belgium

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Roeselare, 8800, Belgium

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Porto Alegre, Rio Grande do Sul, 90035-003, Brazil

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São Paulo, São Paulo, 04014-002, Brazil

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São Paulo, 01221 900, Brazil

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Sofia, 1756, Bulgaria

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Brno-Bohunice, 625 00, Czechia

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Plzen-Bory, 30599, Czechia

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Bayonne, Bayonne Cedex, 64109, France

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Angers, 49033, France

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Avignon, 84000, France

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Dijon, 21034, France

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Lille, 59037, France

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Nantes, 44093, France

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Paris, 75012, France

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Pierre-Bénite, 69495, France

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Toulouse, 31059, France

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Regensburg, Bavaria, 93053, Germany

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Schwerin, Brandenburg, 19049, Germany

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Bad Saarow, 15526, Germany

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Berlin, 10967, Germany

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Berlin, 12351, Germany

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Berlin, 13125, Germany

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Berlin, 13353, Germany

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Bochum, 44892, Germany

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Bonn, 53105, Germany

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Braunschweig, 38114, Germany

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Darmstadt, 64283, Germany

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Duisburg, 47166, Germany

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Düsseldorf, 40225, Germany

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Eschweiler, 52249, Germany

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Essen Werden, 45239, Germany

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Flensburg, 24939, Germany

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Giessen, 35392, Germany

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Göttingen, 37075, Germany

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Hamburg, 20099, Germany

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Hamburg, 20246, Germany

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Hanover, 30625, Germany

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Homburg, 66421, Germany

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Karlsruhe, 76133, Germany

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Kiel, 24116, Germany

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Leipzig, 04103, Germany

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Lübeck, 23538, Germany

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Magdeburg, 39120, Germany

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Mainz, 55131, Germany

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München, 80377, Germany

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Osnabrück, 49076, Germany

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Paderborn, 33098, Germany

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Rostock, 18057, Germany

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Siegen, 57072, Germany

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Stuttgart, 70176, Germany

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Stuttgart, 70376, Germany

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Ulm, 89081, Germany

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Würzburg, 97080, Germany

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Zwickau, 08060, Germany

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Haifa, 3109601, Israel

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Petah Tikva, 4941492, Israel

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Tel Aviv, 6423906, Israel

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Alessandria, AL, 15100, Italy

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Ancona, AN, 60126, Italy

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Bergamo, BG, 24127, Italy

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Brescia, BS, 25123, Italy

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Catania, CT, 95123, Italy

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Milan, MI, 20162, Italy

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Modena, MO, 41124, Italy

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Palermo, PA, 90146, Italy

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Piacenza, PC, 29100, Italy

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Pescara, PE, 65124, Italy

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Perugia, PG, 06129, Italy

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Reggio Calabria, RC, 89124, Italy

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Roma, RM, 00133, Italy

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Roma, RM, 00161, Italy

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Roma, RM, 00168, Italy

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Taranto, TA, 74100, Italy

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Torino, TO, 10126, Italy

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Vicenza, VI, 36100, Italy

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Nagoya, Aichi-ken, 466-8650, Japan

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Matsuyama, Ehime, 790-8524, Japan

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Fukuoka, Fukuoka, 812-8582, Japan

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Fukushima, Fukushima, 960 1295, Japan

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Gifu, Gifu, 500 8513, Japan

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Fukuyama, Hiroshima, 720-0001, Japan

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Tsukuba, Ibaraki, 305-8576, Japan

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Isehara, Kanagawa, 259-1193, Japan

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Nagasaki, Nagasaki, 852-8501, Japan

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Okayama, Okayama-ken, 701-1192, Japan

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Hirakata, Osaka, 573-1191, Japan

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Ōsaka-sayama, Osaka, 589 8511, Japan

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Hamamatsu, Shizuoka, 432-8580, Japan

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Shimotsuke, Tochigi, 329-0498, Japan

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Bunkyo Ku, Tokyo, 113-8677, Japan

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Bunkyo-ku, Tokyo, 113-8603, Japan

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Aomori, 030 8553, Japan

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Kyoto, 606 8507, Japan

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Osaka, 534-0021, Japan

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Yamagata, 990 9585, Japan

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Bergen, NO-5021, Norway

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Oslo, 0424, Norway

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Gdansk, 80 952, Poland

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Lisbon, 1099 023, Portugal

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Porto, 4200-072, Portugal

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Córdoba, Andalusia, 14004, Spain

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Seville, Andalusia, 41013, Spain

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Barakaldo, Basque Country, 48903, Spain

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Salamanca, Castille and León, 37007, Spain

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L'Hospitalet de Llobregat, Catalonia, 08907, Spain

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Cáceres, Extremadura, 10003, Spain

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Barcelona, 08041, Spain

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Madrid, 28034, Spain

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Madrid, 28041, Spain

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Valencia, 46026, Spain

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Zaragoza, 50009, Spain

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Bern, 3010, Switzerland

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Zurich, 8091, Switzerland

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Putzu City, Chiayi Hsien, 61363, Taiwan

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Kuei Shan Chiang, Taoyuan Taiwan ROC, 33305, Taiwan

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Kaohsiung City, 83301, Taiwan

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Taipei, 10002, Taiwan

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Adana, 01330, Turkey (Türkiye)

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Ankara, 06100, Turkey (Türkiye)

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Aydin, 09100, Turkey (Türkiye)

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Related Links

• A Plain Language Trial Summary is available on novctrd.com

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Neoplasm, Residual

Interventions

midostaurin; Drug Therapy

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Therapeutics

Results Point of Contact

• Title: Study Director
• 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: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 26, 2018
• First Posted: April 30, 2018
• Study Start: July 20, 2018
• Primary Completion: February 12, 2021
• Study Completion: February 12, 2021
• Last Updated: August 21, 2023
• Results First Posted: June 18, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will share

Locations

BE (3); US (3); TW (4); BR (3); IT (18); FR (9); ES (11); CZ (2); PL (1); CH (2); AU (4); DE (38); BU (1); TU (3); PT (2); JP (20); NO (2); AR (1); IL (3)