Phase 3, single‐arm, multicenter study of dabigatran etexilate for secondary prevention of venous thromboembolism in children: Rationale and design

Abstract

BackgroundAnticoagulant therapy for venous thromboembolism (VTE) in children is largely based on treatment recommendations for adults. However, differences in both physiology (ie, renal maturation and drug excretion) and developmental hemostasis must be considered when treating children, as such differences could affect dose appropriateness, safety and efficacy.ObjectivesTo address these concerns, a study was designed to evaluate the safety of dabigatran etexilate in children requiring secondary thrombus prevention in whom an initial VTE was associated with an identified risk factor that persisted after the acute VTE treatment period. We report herein the rationale and design of the study.Patients/MethodsThis phase 3, open‐label, single‐arm, multicenter, multinational, prospective cohort study will be conducted in ≥100 children aged 0 to <18 years at ~100 specialist sites worldwide. Children will be treated with dabigatran etexilate for 12 months, or for a shorter duration if their identified VTE risk factor resolves, as per current American College of Chest Physicians recommendations. A nomogram will be used to determine starting doses for each patient.ResultsThe primary outcomes of the study will be VTE recurrence, bleeding events, overall mortality, and VTE‐related mortality. Secondary outcomes will include occurrence of post‐thrombotic syndrome, the pharmacokinetics of dabigatran, and the need for dose adjustments during treatment. Data on adverse events during the study will also be collected.ConclusionThis study will evaluate the safety of dabigatran etexilate for the secondary prevention of VTE in children, in addition to providing further data to guide pediatric dosing with dabigatran.

Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children

“…The trial design has been described in detail previously. 18 In brief, this open-label, single-arm, safety prospective cohort, phase 3 clinical trial (NCT02197416) (supplemental Figure 1, available on the Blood Web site) is a part of a Pediatric Investigational Plan agreed upon with the EMA Pediatric Committee, and a postmarketing requirement agreed upon with the US FDA. The main objective was to assess the safety of dabigatran etexilate for secondary prevention of VTE; all study outcomes were considered safety related.…”

“…The main objective was to assess the safety of dabigatran etexilate for secondary prevention of VTE; all study outcomes were considered safety related. The current analysis includes the data set and target enrollment 18 that fulfills the requirements of the European Union (EU) Pediatric Investigational Plan agreed with the EMA Pediatric Committee, while recruitment continued in order to fulfill additional US FDA requirements. The trial was conducted in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice, and was approved by all investigational site ethics committees.…”

“…An age-and weight-adjusted nomogram according to Hayton, 19 derived from estimated renal function, was used to dose dabigatran and achieve comparable exposure to adult populations treated with dabigatran. 18 Only 1 dabigatran dose modification (up-or down-titration) according to the nomogram was allowed. Different formulations of dabigatran were administered depending upon the age of the child; capsules were given to those aged 8 to ,18 years, pellets to those aged ,8 years (or those aged 8 to ,12 years unable to swallow capsules); oral solution was offered for those aged from .3 months to ,12 months who were unable to swallow pellets (but ultimately no patient in this trial required oral solution).…”

Treatment of Venous Thromboembolism in Special Populations with Direct Oral Anticoagulants

“…75 In addition, an interim analysis of a single-arm, prospective cohort, phase III study demonstrated a favorable safety profile of dabigatran used for up to 12 months in approximately 200 children aged 0 to <18 years who required anticoagulation for the secondary prevention of VTE and with a persistent risk factor for VTE. 76,77 The phase III EINSTEIN Junior trial evaluated rivaroxaban (20 mg o.d. equivalent adjusted according to body weight following at least 5 days of initial heparin therapy) versus standard of care anticoagulation therapy for the treatment of acute VTE in approximately 500 children and neonates.…”

A systematic review of adherence to anticoagulation regimens in pediatric patients

“…8 Anticoagulant choices currently include oral vitamin K antagonists or agents (broadly abbreviated as VKA herein), subcutaneously injected low molecular weight heparin (LMWH), and with an expanding market share for the newer direct oral anticoagulants (DOACs). [9][10][11] Treatment regimens differ by dose interval, delivery route, and/or necessity for therapeutic monitoring.…”