Rationale and Design of a Phase III Safety Trial of Idarucizumab in Children Receiving Dabigatran Etexilate for the Treatment and Secondary Prevention of Venous Thromboembolism

Introduction: The frequency of venous thromboembolism (VTE) is increasing in children. Dabigatran etexilate (DE), the prodrug of the direct thrombin inhibitor dabigatran is approved for use in adults for the treatment and secondary prevention of VTE. However, DE is not approved for the use in children and is currently being evaluated for the treatment and secondary VTE prevention within ongoing pediatric DE trials. With the increasing use of oral anticoagulants for VTE treatment and prevention in adults, agents that can rapidly reverse anticoagulant effects in patients who require emergency surgery/urgent procedure, or who have a rare event of life-threatening or uncontrolled bleeding, will complement treatment strategies for managing bleeds or urgent interventions in patients receiving dabigatran. Idarucizumab is a humanized monoclonal antibody fragment that provides immediate, complete and sustained reversal of the anticoagulation effects of dabigatran. The safety and efficacy of idarucizumab have been confirmed in adult patients receiving DE; however, the safety of idarucizumab in children with VTE remains to be established. The present trial will investigate the safety of idarucizumab in children with VTE who have participated in two ongoing clinical trials investigating DE.

Methods: A phase III, open-label, single arm, global multicenter safety trial (approximately 25-40 sites; approximately 10 countries) is planned in children (aged < 18 years; n = ~5) recruited within the ongoing dabigatran pediatric clinical program for treatment or secondary prevention of VTE. Children who require a rapid reversal of anticoagulation will be eligible for trial inclusion: those with life-threatening/uncontrolled bleeding (group A) and those without bleeding but needing emergency surgery/urgent procedures (group B). Patients will receive a single intravenous dose of idarucizumab (up to 5 g, calculated according to the patient's body weight, administered in two equally divided infusions or injections given not more than 15 minutes apart) and will be monitored for 30 days.

Results: The primary endpoint will be the safety of idarucizumab assessed by the occurrence of drug-related adverse events (including immune reactions) and all-cause mortality. The secondary endpoints will be the percentage change of coagulation tests (diluted thrombin time [dTT] and ecarin clotting time [ECT]) at 30 minutes post-dose versus pre-dose, the time to achieve complete reversal, duration of complete reversal of dabigatran's anticoagulant effect sustained at 24 hours post-dose based on coagulation tests (dTT and ECT), and the formation of antidrug antibodies at 30 days post-dose. Cessation of bleeding, bleeding status and other clinical conditions that may contribute to bleeding (group A patients only) will also be assessed. Data will be reported using descriptive statistics and all treated patients will be included in the safety analysis.

Conclusion: This trial will report the safety of idarucizumab in children with VTE who require the rapid, complete and sustained reversal of the anticoagulant effects of dabigatran.