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

Venous Thromboembolism Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01895777
• Other study ID #: 1160.106
• Secondary ID: 2013-002114-12
• Status: Completed
• Phase: Phase 3
• Start date: September 25, 2013
• Est. completion date: November 14, 2019

Study information

• Verified date: June 2020
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 267
• Est. completion date: November 14, 2019
• Est. primary completion date: October 16, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 17 Years

Eligibility

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

Related Conditions & MeSH terms

• Thromboembolism
• Venous Thromboembolism

Intervention

Drug:
• dabigatran etexilate
Age and weight appropriate capsule dose (combination of 50 mg, 75 mg and 110 mg capsules) or pellets or oral liquid formulation
• standard of care
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)

Locations

Country	Name	City	State
Argentina	Hospital General de Niños Pedro de Elizalde	Caba
Austria	Medical University of Innsbruck	Innsbruck
Austria	AKH - Medical University of Vienna	Wien
Belgium	Brussels - UNIV Saint-Luc	Bruxelles
Belgium	UNIV UZ Gent	Gent
Belgium	UZ Leuven	Leuven
Brazil	Faculdade de Ciencias Medicas da UNICAMP	Campinas
Brazil	HMCP - Hospital e Maternidade Celso Pierro - PUC-Campinas	Campinas
Brazil	Instituto de Crianca / Hospital das Clínicas-FMUSP	Sao Paulo
Brazil	PenSI - Pesquisa e Ensino em Saude Infantil	Sao Paulo
Canada	CHU Sainte-Justine	Montreal	Quebec
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	The Hospital for Sick Children	Toronto	Ontario
Czechia	University Hospital Brno	Brno
Czechia	General Univ.hosp Hradec Kralove	Hradec Kralove
Czechia	University Hospital Olomouc	Olomouc
Czechia	University Hospital Ostrava	Ostrava
Czechia	University Hospital Plzen, Plzen-Lochotin	Plzen-Lochotin
Czechia	University Hospital Motol	Prague
Denmark	Rigshospitalet, København, Børneonkologisk Afsnit 5002	Copenhagen
Finland	TaUH, Pediatric Early Phase Trial Unit	Tampere
France	HOP de la Cavale Blanche	Brest cedex
Germany	Universitätsklinikum Essen AöR	Essen
Germany	Universitätsklinikum Münster	Münster
Greece	"Aghia Sophia" Children's Hospital	Athens
Hungary	University Debrecen Hospital	Debrecen
Israel	Shaare Zedek Medical Center, Jerusalem 91031	Jerusalem
Italy	Università degli Studi "La Sapienza"	Roma
Italy	Ospedale Infantile Regina Margherita	Torino
Lithuania	Children Intensive Care Hosp,Anaesthesiology Dept,Vilnius	Vilnius
Mexico	Instituto Nacional de Pediatría	México D.F
Mexico	Hospital Universitario Dr Jose Eleuterio Gonzalez	Nuevo León
Norway	Haukeland Universitetssykehus	Bergen
Norway	Oslo Universitetssykehus HF, Rikshospitalet	Oslo
Russian Federation	Children Rep.Clin.Hosp of MoH,Cardio Vas.surgery Dept, Kazan	Kazan
Russian Federation	Science Res.Instit.CV Diseases,Scientific Res.Dept,Kemerovo	Kemerovo
Russian Federation	Child.CityClin.Hos.na.ZA Bashlyaeva MoscowHealth Dep,Cardiol	Moscow
Russian Federation	Izmilovskaya Child City ClinHosp,Haematological Dept, Moscow	Moscow
Russian Federation	St.Petersburg State Pediatric Univ.Ministry of Healthcare RF	St. Petersburg
Russian Federation	Reg Clin.Hosp.#1,Healthcare Tyumen Region,Cardiovas.Surgery	Tyument
Russian Federation	Childr.CityClin.Hos#9,pediatric&Neonatal Neurol.Ekaterinburg	Yekaterinburg
Spain	Hospital Infantil Universitario Niño Jesus	Madrid
Sweden	Sahlgrenska US, Göteborg	Göteborg
Sweden	Karolinska Univ. sjukhuset	Solna
Switzerland	Universitäts-Kinderspital	Zürich
Taiwan	Taichung Veterans General Hospital	Taichung
Thailand	King Chulalongkorn Memorial Hospital	Bangkok
Turkey	Cukurova Universitesi Tip Fakultesi Cocuk Sagligi	Adana
Turkey	Hacettepe Universitesi Tip Fakultesi	Ankara
Turkey	Akdeniz Universitesi Tip Fakultesi	Antalya
Turkey	Istanbul Saglik Bilimleri Uni. Kanuni Sultan Suleyman EAH	Istanbul
Turkey	Istanbul Universitesi Cerrahpasa Tip Fakultesi	Istanbul
Turkey	Ege Universitesi Tip Fakultesi Cocuk Hematolojisi Bilim Dali	Izmir
Turkey	Necmettin Erbakan Universitesi Meram Tip Fakultesi	Konya
Ukraine	Reg.Children Hosp.Dnipropetrovsk	Dnipropetrovsk
Ukraine	Reg.Children Hosp,Vinnytsia	Vinnytsya
United States	Boston Children's Hospital	Boston	Massachusetts
United States	University of Virginia Health System	Charlottesville	Virginia
United States	Blank Children's Hospital	Des Moines	Iowa
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of Miami	Miami	Florida
United States	University of California Davis	Sacramento	California
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	St. Joseph's Children's Hospital	Tampa	Florida
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Belgium,  Brazil,  Canada,  Czechia,  Denmark,  Finland,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Lithuania,  Mexico,  Norway,  Russian Federation,  Spain,  Sweden,  Switzerland,  Taiwan,  Thailand,  Turkey,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Freedom From Major Bleeding Events (MBEs)	Freedom from major bleeding events (MBEs), defined as either fatal bleeding, clinically overt bleeding associated with a decrease in haemoglobin of at least 20 g/L in a 24-hour period, bleeding that is retroperitoneal, pulmonary, intracranial or otherwise involves the central nervous system, or bleeding that requires intervention in an operating suite.	From first administration of trial medication until last administration of trial medication +6 days (residual effect period). Up to 97 days.
Secondary	Steady State Plasma Concentrations of Total Dabigatran at Visit 3	Descriptive statistics for steady state plasma concentrations of total dabigatran etexilate at visit 3	From the time of randomisation until visit 3
Secondary	Steady State Plasma Concentrations After at Least 3 Days Following Any Dabigatran Etexilate Dose Adjustment	Descriptive statistics for steady state plasma concentrations of total dabigatran etexilate 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.
Secondary	Frequency of Dose Adjustment During the Treatment Phase	Frequency of dose adjustments (i.e. number of patients with dose adjustment), temporary and permanent discontinuation from therapy, and number of patients with laboratory monitoring requirements for dose	From first administration of trial medication until last administration of trial medication +6 days (residual effect period).
Secondary	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	Frequency of patients switching the type of anti-coagulation therapy including Dabigatran etexilate (DE) to standard of care (SoC) treatment and switching from one standard of care treatment to another.; For DE arm, only the switch from DE to SoC was counted, while for the SoC arm, all switches among SoC treatments were counted.	From first administration of trial medication until last administration of trial medication +6 days (residual effect period).
Secondary	Freedom From Thrombus Progression at End of Therapy Compared With Baseline	Freedom from thrombus progression at end of therapy compared with baseline, based on adjudication-confirmed data.	From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days.
Secondary	All Bleeding Events	The number of participants with bleeding events includes major bleeding events (MBEs), clinically relevant non-major (CRNM) bleeding, minor bleeding events, any bleeding events, and the numbers of the combined endpoint of major and CRNM bleeding events was presented, based on adjudication-confirmed data.	From first administration of trial medication until last adminstration of trial medication +6 days (residual effect period). Up to 97 days.
Secondary	All-cause Mortality	Patients being alive at the end of observational period will be censored for all-cause mortality at the date of patients' last date known to be alive, or the date of data cut-off whichever comes first.	From first administration of trial medication until last administration of trial medication +6 days (residual effect period). Up to 97 days.
Secondary	All Components of the Primary Efficacy Endpoint	Patients with VTE-related death occurring between randomisation to Day 84 + 7 days were considered as not meeting the endpoint. The presence of recurrent VTE(s) was examined throughout the trial, and only the date of first occurrence was used for analysis. Assessment of index VTE status (best overall response) was scheduled on Day 84 ± 7 days (Visit 8) for patients who were alive without an early consent withdraw. In the case a Patient discontinued trial medication prematurely due to any reason the index VTE assessment took place at the early end of treatment visit.	From the time of randomisation until Week 12, 84 days after randomisation including a visit window of 7 days.
Secondary	Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Capsules)	Acceptability was defined as the overall ability and willingness of the patient to use the medicinal product. Questions regarding acceptability were to be answered by the patient and/or parent/caregiver (as applicable) and by the investigator/site staff.; Investigator questionnaire capsules: What is your impression about the patient's acceptability of DE intake? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad).; Parents questionnaire capsules: How acceptable was the DE treatment for the child? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad).; Patients questionnaire capsules: Was taking the study capsules easy or difficult? The score is 1 (Very easy), 2 (easy), 3 (neither easy nor difficult), 4 (difficult) and 5 (very difficult).; Scores refers to the end of treatment.	Assessment at the last study visit at day 84 (+- 7 days), or at day of early termination.
Secondary	Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Pellets)	Acceptability was defined as the overall ability and willingness of the patient to use the medicinal product. Questions regarding acceptability were to be answered by the patient and/or parent/caregiver (as applicable) and by the investigator/site staff.; Investigator questionnaire pellets: What is your impression about the patient's acceptability of DE intake? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad).; Parents questionnaire pellets: Do you think that spitting occurs? The score is 1 (Never), 2 (sometimes) and 3 (often).; Scores refers to the end of treatment.	Assessment at the last study visit at day 84 (+- 7 days), or at day of early termination.
Secondary	Assessment of the Acceptability of an Age-appropriate Formulation at End of Therapy (Oral Liquid Formulation - OLF)	Acceptability was defined as the overall ability and willingness of the patient to use the medicinal product. Questions regarding acceptability were to be answered by the patient and/or parent/caregiver (as applicable) and by the investigator/site staff.; Investigator questionnaire flavoured OLF: What is your impression about the patient's acceptability of DE intake? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad).; Investigator questionnaire unflavoured OLF: What is your impression about the patient's acceptability of DE intake? The score is 1 (good), 2 (satisfactory), 3 (not satisfactory) and 4 (bad).; Parents questionnaire flavoured OLF.: Do you think spitting occurs? The score ranges form 1 (never), 2 ( sometimes) to 3 (often).; Parents questionnaire unflavoured OLF:Do you think spitting occurs? The score ranges form 1 (never), 2 ( sometimes) to 3 (often).; Scores refers to the end of treatment.	Assessment at the last study visit at day 84 (+- 7 days), or at day of early termination.