Open Label Study Comparing Efficacy and Safety of Dabigatran Etexilate to Standard of Care in Paediatric Patients With Venous Thromboembolism (VTE)

NCT01895777 | Completed Phase 3 Results

• 2 other identifiers: 1160.1062013-002114-12
• Study Type: interventional
• Target: 267
• Locations: 26 countries
• Sites: 65

Brief Summary

The main objectives of this large phase IIb/III paediatric study are to assess the efficacy and safety of dabigatran etexilate relative to standard of care and to document the appropriateness of the proposed dabigatran etexilate dosing algorithm for use in patients from birth to less than 18 years of age.

Conditions

Venous Thromboembolism

Outcome Measures

Primary Outcomes (1)

• Composite Primary Endpoint

  The primary endpoint was the combined endpoint of the proportions of patients with: * Complete thrombus resolution * Freedom from recurrent VTE * Freedom from mortality related to VTE. The events outlined in the above combined primary endpoint were assessed by radiologists or other such qualified clinicians using an appropriate method such as ultrasound, echocardiography, venography, or CT scan, based on the location of the thrombus and the test used to perform the baseline assessment. The primary efficacy endpoint contained 3 components. Each component was evaluated separately, and only if the criteria for all 3 components were satisfied, the primary endpoint was considered achieved.

  From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days.

Secondary Outcomes (12)

• Freedom From Major Bleeding Events (MBEs)

  From first administration of trial medication until last administration of trial medication +6 days (residual effect period). Up to 97 days.

• Steady State Plasma Concentrations of Total Dabigatran at Visit 3

  From the time of randomisation until visit 3

• Steady State Plasma Concentrations After at Least 3 Days Following Any Dabigatran Etexilate Dose Adjustment

  From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days.

• Frequency of Dose Adjustment During the Treatment Phase

  From first administration of trial medication until last administration of trial medication +6 days (residual effect period).

• Frequency of Patients Switching the Type of Anti-coagulation Therapy Including Dabigatran Etexilate to Standard of Care Treatment and Switching From One Standard of Care Treatment to Another

  From first administration of trial medication until last administration of trial medication +6 days (residual effect period).

Study Arms (2)

dabigatran etexilate

EXPERIMENTAL

Dabigatran etexilate capsules, pellets or liquid formulation given BID in an open label fashion for 3 months

Drug: dabigatran etexilate

standard of care

ACTIVE COMPARATOR

Low molecular weight heparin, vitamin K antagonist or fondaparinux prescribed in an open label fashion for 3 months (these medications will not supplied in this study as IMP)

Drug: standard of care

Interventions

dabigatran etexilate DRUG

Age and weight appropriate capsule dose (combination of 50 mg, 75 mg and 110 mg capsules) or pellets or oral liquid formulation

dabigatran etexilate

standard of care DRUG

Low molecular weight heparin, vitamin K antagonist or fondaparinux prescribed in an open label fashion for 3 months (these medications will not supplied in this study as IMP)

standard of care

Eligibility Criteria

• Age: Up to 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male or female subjects 0 to less than 18 years of age at the time of informed consent / assent
• Documented diagnosis of clinically stable VTE (e.g. DVT, PE, central line thrombosis, sinus vein thrombosis) per investigator judgment, initially treated (minimum of 5 to 7 days, but not longer than 21 days) with parenteral anticoagulation therapy, such as unfractionated heparin (UFH) or a low molecular weight heparin (LMWH).
• Written informed consent provided by the patient's parent or legal guardian and assent provided by the patient (if applicable) at the time of informed consent form (ICF) signature according to local regulations.

You may not qualify if:

• Conditions associated with an increased risk of bleeding
• Renal dysfunction (eGFR \< 50 mL/min/1.73m\^2 using the Schwartz formula) or requirement for dialysis. eGFR retesting during the screening period is allowed (once).
• Active infective endocarditis
• Subjects with a heart valve prosthesis requiring anticoagulation.
• Hepatic disease:
• Active liver disease, including known active hepatitis A, B or C or, Persistent alanine aminotransferase (ALT) or aspartate transaminase (AST) or alkaline phosphatase (AP) \> 3 × upper limit of normal (ULN) within 3 months of screening
• Pregnant or breast feeding females. Females who have reached menarche and are not using a medically accepted contraceptive method per local guidelines. Acceptable methods of birth control must be used in a correct and consistent manner
• Patients in stratum 3 (0 to \< 2 years) with gestational age at birth \< 37 weeks or with body weight lower than the 3rd percentile
• Anemia (hemoglobin \< 80g/L) or thrombocytopenia (platelet count \< 80 x 109/L) at screening. Transfusions during the screening period are allowed, provided that a satisfactory hemoglobin or platelet level is attained prior to visit 2
• Patients who have taken prohibited or restricted medication within one week of the first dose of study medication other than medication for prior VTE treatment and P-glycoprotein inhibitors..
• Patients who have received an investigational drug in the past 30 days prior to screening
• Patients who are allergic/sensitive to any component of the study medication including solvent
• Patients or parents/legal guardians considered unreliable to participate in the trial per investigator judgment or any condition which would present a safety hazard to the patient based on investigator judgment
• Patients or parents/legal guardians who are unwilling or unable to undergo or permit repeat of the baseline imaging tests required to confirm thrombus resolution at study day 84 (or eEOT, whichever comes first) or in whom repeating such imaging tests at these pre-specified time points may not be medically in the patient's best interest. Examples may include unwarranted radiation exposure as a result of a repeat CT scan at day 84 for a patient with an isolated case of pulmonary embolism evaluated at baseline solely by a CT scan. In such cases, the baseline radiological assessment (e.g. CT) may be supplemented with an acceptable non-radiological assessment at baseline (e.g. MRI) which could then be repeated at day 84 hence alleviating any potential unwarranted radiation exposure.

Sponsors & Collaborators

• Boehringer Ingelheim: lead

Study Sites (65)

University of California Davis

Sacramento, California, 95817, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

St. Joseph's Children's Hospital

Tampa, Florida, 33607, United States

Location

Blank Children's Hospital

Des Moines, Iowa, 50309, United States

Location

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

University of Virginia Health System

Charlottesville, Virginia, 22908, United States

Location

Providence Sacred Heart Medical Center and Children's Hospital

Spokane, Washington, 99204, United States

Location

Hospital General de Niños Pedro de Elizalde

CABA, C1270AAN, Argentina

Location

Medical University of Innsbruck

Innsbruck, 6020, Austria

Location

AKH - Medical University of Vienna

Vienna, 1090, Austria

Location

Brussels - UNIV Saint-Luc

Brussels, 1200, Belgium

Location

UNIV UZ Gent

Ghent, 9000, Belgium

Location

UZ Leuven

Leuven, 3000, Belgium

Location

HMCP - Hospital e Maternidade Celso Pierro - PUC-Campinas

Campinas, 13059-740, Brazil

Location

Faculdade de Ciencias Medicas da UNICAMP

Campinas, 13083-970, Brazil

Location

PenSI - Pesquisa e Ensino em Saude Infantil

São Paulo, 01227-200, Brazil

Location

Instituto de Crianca / Hospital das Clínicas-FMUSP

São Paulo, 05403-000, Brazil

Location

Children's Hospital of Eastern Ontario

Ottawa, Ontario, K1H 8L1, Canada

Location

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

CHU Sainte-Justine

Montreal, Quebec, H3T 1C5, Canada

Location

University Hospital Brno

Brno, 61300, Czechia

Location

General Univ.hosp Hradec Kralove

Hradec Králové, 500 05, Czechia

Location

University Hospital Olomouc

Olomouc, 77900, Czechia

Location

University Hospital Ostrava

Ostrava, 70852, Czechia

Location

University Hospital Plzen, Plzen-Lochotin

Plzen-Lochotin, 304 60, Czechia

Location

University Hospital Motol

Prague, 15006, Czechia

Location

Rigshospitalet, København, Børneonkologisk Afsnit 5002

Copenhagen, 2100, Denmark

Location

TaUH, Pediatric Early Phase Trial Unit

Tampere, 33520, Finland

Location

HOP de la Cavale Blanche

Brest, 29609, France

Location

Universitätsklinikum Essen AöR

Essen, 45147, Germany

Location

Universitätsklinikum Münster

Münster, 48149, Germany

Location

"Aghia Sophia" Children's Hospital

Athens, 11527, Greece

Location

University Debrecen Hospital

Debrecen, 4032, Hungary

Location

Shaare Zedek Medical Center, Jerusalem 91031

Jerusalem, 9103102, Israel

Location

Università degli Studi "La Sapienza"

Roma, 00161, Italy

Location

Ospedale Infantile Regina Margherita

Torino, 10126, Italy

Location

Children Intensive Care Hosp,Anaesthesiology Dept,Vilnius

Vilnius, 08406, Lithuania

Location

Instituto Nacional de Pediatría

México D.F, 04530, Mexico

Location

Hospital Universitario Dr Jose Eleuterio Gonzalez

Nuevo León, 64460, Mexico

Location

Haukeland Universitetssykehus

Bergen, N-5021, Norway

Location

Oslo Universitetssykehus HF, Rikshospitalet

Oslo, N-0372, Norway

Location

Children Rep.Clin.Hosp of MoH,Cardio Vas.surgery Dept, Kazan

Kazan', 420138, Russia

Location

Science Res.Instit.CV Diseases,Scientific Res.Dept,Kemerovo

Kemerovo, 650002, Russia

Location

Izmilovskaya Child City ClinHosp,Haematological Dept, Moscow

Moscow, 105077, Russia

Location

Child.CityClin.Hos.na.ZA Bashlyaeva MoscowHealth Dep,Cardiol

Moscow, 125373, Russia

Location

St.Petersburg State Pediatric Univ.Ministry of Healthcare RF

Saint Petersburg, 194100, Russia

Location

Reg Clin.Hosp.#1,Healthcare Tyumen Region,Cardiovas.Surgery

Tyument, 625023, Russia

Location

Childr.CityClin.Hos#9,pediatric&Neonatal Neurol.Ekaterinburg

Yekaterinburg, 620134, Russia

Location

Hospital Infantil Universitario Niño Jesus

Madrid, 28009, Spain

Location

Sahlgrenska US, Göteborg

Gothenburg, 41345, Sweden

Location

Karolinska Univ. sjukhuset

Solna, 171 65, Sweden

Location

Universitäts-Kinderspital

Zurich, 8032, Switzerland

Location

Taichung Veterans General Hospital

Taichung, 407, Taiwan

Location

King Chulalongkorn Memorial Hospital

Bangkok, 10330, Thailand

Location

Cukurova Universitesi Tip Fakultesi Cocuk Sagligi

Adana, 1330, Turkey (Türkiye)

Location

Hacettepe Universitesi Tip Fakultesi

Ankara, 06100, Turkey (Türkiye)

Location

Akdeniz Universitesi Tip Fakultesi

Antalya, 7058, Turkey (Türkiye)

Location

Istanbul Universitesi Cerrahpasa Tip Fakultesi

Istanbul, 34098, Turkey (Türkiye)

Location

Istanbul Saglik Bilimleri Uni. Kanuni Sultan Suleyman EAH

Istanbul, 34303, Turkey (Türkiye)

Location

Ege Universitesi Tip Fakultesi Cocuk Hematolojisi Bilim Dali

Izmir, 35040, Turkey (Türkiye)

Location

Necmettin Erbakan Universitesi Meram Tip Fakultesi

Konya, 42080, Turkey (Türkiye)

Location

Reg.Children Hosp.Dnipropetrovsk

Dnipropetrovsk, 49100, Ukraine

Location

Reg.Children Hosp,Vinnytsia

Vinnytsia, 21029, Ukraine

Location

Related Publications (4)

• Albisetti M, Tartakovsky I, Halton J, Bomgaars L, Chalmers E, Mitchell LG, Luciani M, Nurmeev I, Gorbatikov K, Miede C, Brueckmann M, Brandao LR; Study Investigators. Dabigatran for Treatment and Secondary Prevention of Venous Thromboembolism in Pediatric Congenital Heart Disease. J Am Heart Assoc. 2024 Feb 20;13(4):e028957. doi: 10.1161/JAHA.122.028957. Epub 2024 Feb 13.

  PMID: 38348778 DERIVED

• Brandao LR, Tartakovsky I, Albisetti M, Halton J, Bomgaars L, Chalmers E, Luciani M, Saracco P, Felgenhauer J, Lvova O, Simetzberger M, Sun Z, Mitchell LG. Dabigatran in the treatment and secondary prophylaxis of venous thromboembolism in children with thrombophilia. Blood Adv. 2022 Nov 22;6(22):5908-5923. doi: 10.1182/bloodadvances.2021005681.

  PMID: 36150047 DERIVED

• Halton J, Brandao LR, Luciani M, Bomgaars L, Chalmers E, Mitchell LG, Nurmeev I, Sharathkumar A, Svirin P, Gorbatikov K, Tartakovsky I, Simetzberger M, Huang F, Sun Z, Kreuzer J, Gropper S, Reilly P, Brueckmann M, Albisetti M; DIVERSITY Trial Investigators. Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial. Lancet Haematol. 2021 Jan;8(1):e22-e33. doi: 10.1016/S2352-3026(20)30368-9. Epub 2020 Dec 5.

  PMID: 33290737 DERIVED

• Albisetti M, Biss B, Bomgaars L, Brandao LR, Brueckmann M, Chalmers E, Gropper S, Harper R, Huang F, Luciani M, Manastirski I, Mitchell LG, Tartakovsky I, Wang B, Halton JML. Design and rationale for the DIVERSITY study: An open-label, randomized study of dabigatran etexilate for pediatric venous thromboembolism. Res Pract Thromb Haemost. 2018 Mar 25;2(2):347-356. doi: 10.1002/rth2.12086. eCollection 2018 Apr.

  PMID: 30046738 DERIVED

MeSH Terms

Conditions

Venous Thromboembolism

Interventions

Dabigatran; Standard of Care

Condition Hierarchy (Ancestors)

Thromboembolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Results Point of Contact

• Title: Boehringer Ingelheim, Call Center
• Organization: Boehringer Ingelheim

clintriage.rdg@boehringer-ingelheim.com

8002430127

Study Officials

• Boehringer Ingelheim

  Boehringer Ingelheim

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

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: July 4, 2013
• First Posted: July 11, 2013
• Study Start: September 25, 2013
• Primary Completion: October 16, 2019
• Study Completion: November 14, 2019
• Last Updated: July 7, 2020
• Results First Posted: July 7, 2020

Record last verified: 2020-06

Locations

DK (1); IT (2); FI (1); CA (3); ME (2); FR (1); GR (1); AR (1); RU (7); TW (1); US (9); LI (1); TH (1); UA (2); SE (2); ES (1); DE (2); IL (1); BE (3); AU (2); HU (1); CZ (6); TU (7); BR (4); NO (2); CH (1)