Clinical trial NCT01895777: Open Label Study Comparing Efficacy and Safety of Dabigatran Etexilate to Standard of Care in Paediatric Patients With Venous Thromboembolism (VTE)
Official title: Open-label, Randomized, Parallel-group, Active-controlled, Multi-centre Non-inferiority Study of Dabigatran Etexilate Versus Standard of Care for Venous Thromboembolism Treatment in Children From Birth to Less Than 18 Years of Age
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Venous Thromboembolism
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2013-07-11
Enrollment: 267
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion criteria:

* 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).
* Clinical indication for at least 3 month of treatment with anticoagulants for the VTE episode defined under the above inclusion criterion.
* 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.

Exclusion criteria:

* 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.
* Further exclusion criteria apply

Primary outcomes:
measure: Composite Primary Endpoint
timeFrame: From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days.
Secondary outcomes:
measure: Freedom From Major Bleeding Events (MBEs)
timeFrame: From first administration of trial medication until last administration of trial medication +6 days (residual effect period). Up to 97 days.
measure: Steady State Plasma Concentrations of Total Dabigatran at Visit 3
timeFrame: From the time of randomisation until visit 3
measure: Steady State Plasma Concentrations After at Least 3 Days Following Any Dabigatran Etexilate Dose Adjustment
timeFrame: From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days.
measure: Frequency of Dose Adjustment During the Treatment Phase
timeFrame: From first administration of trial medication until last administration of trial medication +6 days (residual effect period).
measure: 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
timeFrame: From first administration of trial medication until last administration of trial medication +6 days (residual effect period).
measure: Freedom From Thrombus Progression at End of Therapy Compared With Baseline
timeFrame: From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days.
measure: All Bleeding Events
timeFrame: From first administration of trial medication until last adminstration of trial medication +6 days (residual effect period). Up to 97 days.
measure: All-cause Mortality
timeFrame: From first administration of trial medication until last administration of trial medication +6 days (residual effect period). Up to 97 days.
measure: All Components of the Primary Efficacy Endpoint
timeFrame: From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days.
measure: Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Capsules)
timeFrame: Assessment at the last study visit at day 84 (+- 7 days), or at day of early termination.
measure: Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Pellets)
timeFrame: Assessment at the last study visit at day 84 (+- 7 days), or at day of early termination.
measure: Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Oral Liquid Formulation - OLF)
timeFrame: Assessment at the last study visit at day 84 (+- 7 days), or at day of early termination.
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California Davis
state: California
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: St. Joseph's Children's Hospital
state: Florida
city: Des Moines
country: United States
facility: Blank Children's Hospital
state: Iowa
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Spokane
country: United States
facility: Providence Sacred Heart Medical Center and Children's Hospital
state: Washington
city: Caba
country: Argentina
facility: Hospital General de Niños Pedro de Elizalde
city: Innsbruck
country: Austria
facility: Medical University of Innsbruck
city: Wien
country: Austria
facility: AKH - Medical University of Vienna
city: Bruxelles
country: Belgium
facility: Brussels - UNIV Saint-Luc
city: Gent
country: Belgium
facility: UNIV UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven
city: Campinas
country: Brazil
facility: HMCP - Hospital e Maternidade Celso Pierro - PUC-Campinas
city: Campinas
country: Brazil
facility: Faculdade de Ciencias Medicas da UNICAMP
city: Sao Paulo
country: Brazil
facility: PenSI - Pesquisa e Ensino em Saude Infantil
city: Sao Paulo
country: Brazil
facility: Instituto de Crianca / Hospital das Clínicas-FMUSP
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: CHU Sainte-Justine
state: Quebec
city: Brno
country: Czechia
facility: University Hospital Brno
city: Hradec Kralove
country: Czechia
facility: General Univ.hosp Hradec Kralove
city: Olomouc
country: Czechia
facility: University Hospital Olomouc
city: Ostrava
country: Czechia
facility: University Hospital Ostrava
city: Plzen-Lochotin
country: Czechia
facility: University Hospital Plzen, Plzen-Lochotin
city: Prague
country: Czechia
facility: University Hospital Motol
city: Copenhagen
country: Denmark
facility: Rigshospitalet, København, Børneonkologisk Afsnit 5002
city: Tampere
country: Finland
facility: TaUH, Pediatric Early Phase Trial Unit
city: Brest cedex
country: France
facility: HOP de la Cavale Blanche
city: Essen
country: Germany
facility: Universitätsklinikum Essen AöR
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Athens
country: Greece
facility: "Aghia Sophia" Children's Hospital
city: Debrecen
country: Hungary
facility: University Debrecen Hospital
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center, Jerusalem 91031
city: Roma
country: Italy
facility: Università degli Studi "La Sapienza"
city: Torino
country: Italy
facility: Ospedale Infantile Regina Margherita
city: Vilnius
country: Lithuania
facility: Children Intensive Care Hosp,Anaesthesiology Dept,Vilnius
city: México D.F
country: Mexico
facility: Instituto Nacional de Pediatría
city: Nuevo León
country: Mexico
facility: Hospital Universitario Dr Jose Eleuterio Gonzalez
city: Bergen
country: Norway
facility: Haukeland Universitetssykehus
city: Oslo
country: Norway
facility: Oslo Universitetssykehus HF, Rikshospitalet
city: Kazan
country: Russian Federation
facility: Children Rep.Clin.Hosp of MoH,Cardio Vas.surgery Dept, Kazan
city: Kemerovo
country: Russian Federation
facility: Science Res.Instit.CV Diseases,Scientific Res.Dept,Kemerovo
city: Moscow
country: Russian Federation
facility: Izmilovskaya Child City ClinHosp,Haematological Dept, Moscow
city: Moscow
country: Russian Federation
facility: Child.CityClin.Hos.na.ZA Bashlyaeva MoscowHealth Dep,Cardiol
city: St. Petersburg
country: Russian Federation
facility: St.Petersburg State Pediatric Univ.Ministry of Healthcare RF
city: Tyument
country: Russian Federation
facility: Reg Clin.Hosp.#1,Healthcare Tyumen Region,Cardiovas.Surgery
city: Yekaterinburg
country: Russian Federation
facility: Childr.CityClin.Hos#9,pediatric&Neonatal Neurol.Ekaterinburg
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Niño Jesus
city: Göteborg
country: Sweden
facility: Sahlgrenska US, Göteborg
city: Solna
country: Sweden
facility: Karolinska Univ. sjukhuset
city: Zürich
country: Switzerland
facility: Universitäts-Kinderspital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital
city: Adana
country: Turkey
facility: Cukurova Universitesi Tip Fakultesi Cocuk Sagligi
city: Ankara
country: Turkey
facility: Hacettepe Universitesi Tip Fakultesi
city: Antalya
country: Turkey
facility: Akdeniz Universitesi Tip Fakultesi
city: Istanbul
country: Turkey
facility: Istanbul Universitesi Cerrahpasa Tip Fakultesi
city: Istanbul
country: Turkey
facility: Istanbul Saglik Bilimleri Uni. Kanuni Sultan Suleyman EAH
city: Izmir
country: Turkey
facility: Ege Universitesi Tip Fakultesi Cocuk Hematolojisi Bilim Dali
city: Konya
country: Turkey
facility: Necmettin Erbakan Universitesi Meram Tip Fakultesi
city: Dnipropetrovsk
country: Ukraine
facility: Reg.Children Hosp.Dnipropetrovsk
city: Vinnytsya
country: Ukraine
facility: Reg.Children Hosp,Vinnytsia
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.