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

Abstract

Essentials There is no data on the use of idarucizumab in children with venous thromboembolism (VTE).We present the design of a trial that will assess the safety of idarucizumab in children with VTE.Patients will be recruited from two ongoing trials in children treated with dabigatran for VTE.Idarucizumab provides additional re‐assurance when rapid reversal of dabigatran effects is needed. BackgroundThe 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 MethodsThis 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 = ~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 antidrug antibodies at 30 days post‐dose and cessation of bleeding will also be assessed.ConclusionThis study will report the safety of idarucizumab in children with VTE who require rapid reversal of the anticoagulant effects of dabigatran. Clinical trial registration: NCT02815670.

Andexanet Alfa Versus Prothrombin Complex Concentrates/Blood Products as Apixaban/Rivaroxaban Reversal Agents: A Survey Among Pediatric Hematologists

“…With the recent FDA approval of dabigatran (an oral direct thrombin inhibitor) for pediatric use, studies to assess the efficacy and safety of idarucizimab reversal in children are also needed. 30 Our survey did not include questions directed to the use of dabigatran reversal since idarucizumab is the only evidence-based option.…”

How I treat pediatric venous thromboembolism in the DOAC era

“…Although idarucizumab and andexanet-α are approved by the US Food and Drugs Administration for adults for reversal of dabigatran and rivaroxaban/apixaban, respectively, it is neither approved nor tested for children. 65 , 66 , 67 There are only 2 published case reports of using idarucizumab and andexanet-α for children, for overdose and bleeding reversal. 68 , 69 Interestingly, a recent survey of pediatric hematologists assessing preferences for reversal of bleeding associated with DOACs reported prothrombin complex concentrates as the preferred option.…”

New Anticoagulants in Neonates, Children, and Adolescents

“…46 Promising candidates for this are currently the reversal agent idarucizumab/Praxbind and Ondexxya/andexanet alfa-currently, there are just anecdotal reports of its use in children; therefore, it can only be used off-label for the time being. 47 For rivaroxaban, the antidote Ondexxya (andexanet alfa) was granted EMA-approval for use in adults in 2019. 48 Though the three phase III trials we described here evaluated adverse events, we still lack knowledge of possible pediatric DDI and DFI.…”