Rationale and design of a phase III safety trial of idarucizumab in children receiving dabigatran etexilate for venous thromboembolism

Background: The incidence of venous thromboembolism (VTE) in children has been increasing. Anticoagulants are the mainstay of treatment but are associated with bleeding events that may be life-threatening. Idarucizumab is a fragment antigen-binding (fab) that provides immediate, complete, and sustained reversal of dabigatran's anticoagulant effects in adults. Objective and Methods: This phase III, open-label, single-arm, multicenter, multinational trial will assess the safety of idarucizumab in children participating in two ongoing trials investigating dabigatran etexilate. Eligible patients will be children with VTE (aged 0-<= 18 years; n = similar to 5) with life-threatening or uncontrolled bleeding (group A), and children who require emergency surgery/urgent procedures for a condition other than bleeding (group B). Patients will receive idarucizumab up to 5 g as two consecutive intravenous infusions over 5-10 minutes each, as two 10-15-minute drips or as two bolus injections (15 minutes apart) and will be monitored for 30 days. 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. Secondary endpoints will be the reversal of dabigatran anticoagulant effects assessed by changes in diluted thrombin time and ecarin clotting time, time to achieve complete reversal and the duration of the reversal and bleeding severity (group A). The formation of anti-drug antibodies at 30 days post-dose and cessation of bleeding will also be assessed. Conclusion: This study will report the safety of idarucizumab in children with VTE who require rapid reversal of the anticoagulant effects of dabigatran.