Dabigatran Etexilate in Children with Venous Thromboembolism: Results of the Open-Label, Phase IIb/III, Randomized Diversity Clinical Trial

Background: In children, current standard of care (SOC) with heparins or vitamin K antagonists is limited by the need for parenteral administration and frequent monitoring. Dabigatran etexilate (DE), a direct oral anticoagulant, is an effective oral treatment for venous thromboembolism (VTE) in adults and may be an effective and safe alternative to SOC for treating acute VTE in children. Aims: The DIVERSITY trial evaluated the efficacy and safety of DE versus SOC, and the appropriateness of a DE dosing algorithm, in children with VTE aged from birth to < 18 years. Methods: This was an open-label, randomized, active-controlled, multicenter, phase IIb/III trial (NCT01895777; consent obtained and ethics committee approved). Children (12 to < 18 years, 2 to < 12 years, birth to < 2 years) with an objectively confirmed VTE diagnosis and initially treated with unfractionated heparin or low-molecular-weight heparin were randomized (2:1) to DE (capsules, and child-friendly pellets and oral suspension, dosed using an age- and body-weight-adjusted dosing algorithm) or SOC, and treated for up to 3 months. The primary composite efficacy endpoint was the proportion of children with complete thrombus resolution, and freedom from recurrent VTE or VTE-related death. Safety endpoints included bleeding events and adverse events (AEs), and pharmacokinetic/pharmacodynamic (PK/PD) relationships. Results: Of 267 children in the randomized set, 35 were aged < 2 years (13 SOC, 22 DE; of these, 14 were < 6 months [3 SOC, 11 DE]), 64 were 2 to < 12 years (21 SOC, 43 DE), and 168 were 12 to < 18 years (56 SOC, 112 DE). Overall, similar proportions of children treated with SOC and DE met the composite efficacy endpoint (38/90 [42.2%] vs 81/177 [45.8%]; Mantel Hänszel-weighted difference -0.04; 90% confidence interval [CI] -0.14 to 0.07; p < 0.0001 for non-inferiority), and major bleeding events were comparable (2/90 [2.2%] and 4/176 [2.3%]; hazard ratio 0.94; 95% CI 0.17-5.16; p = 0.95). Across the three age groups (12 to < 18 years, 2 to < 12 years, birth to < 2 years), DE was comparable with SOC for the combined efficacy endpoint, which was achieved by 33.9-57.1% of children treated with SOC and 42.0-59.1% treated with DE. Similar numbers of children experienced major bleeding events, reported by between 0.0-3.6% of children treated with SOC and 1.8-4.5% treated with DE. In the overall population, the incidence of AEs in children treated with SOC and DE was 66.7% and 76.7%, respectively, and serious AEs were reported by 20.0% and 12.5% of all children, respectively. Across the three main age groups, the frequency of serious AEs was comparable for SOC and DE (reported by 19.0-23.1% and 9.1-14.4% of children, respectively). Dabigatran PK/PD relationships for three laboratory coagulation parameters (activated partial thromboplastin time [aPTT], diluted thrombin time [dTT], and ecarin clotting time [ECT]) were comparable across the three main age groups and were also similar in infants aged < 6 months (Figure). There was a linear relationship between total dabigatran plasma concentration for both dTT and ECT, and a nonlinear relationship with aPTT. These PK/PD relationships were similar to those observed in adults (data not shown). Conclusions: This randomized trial confirmed that an age- and weight-adjusted dabigatran dosing algorithm was appropriate in children aged from birth to < 18 yrs. Dabigatran, given as either capsules or child-friendly pellets or oral suspension, was comparable with SOC in terms of efficacy for acute VTE treatment across all age groups and, notably, in vulnerable children aged < 2 yrs. Disclosures Halton: Boehringer Ingelheim: Other: Member of a paediatric expert working group. Brandao:Boehringer Ingelheim: Other: Member of a paediatric expert working group. Luciani:Boehringer Ingelheim: Other: Member of a paediatric expert working group. Bomgaars:Boehringer Ingelheim: Other: Member of a paediatric expert working group. Chalmers:Shire/Takeda: Honoraria; CSL Behring: Honoraria; Bristol-Myers Squibb: Honoraria; Sobi: Honoraria; Roche: Honoraria; Grifols: Honoraria; Boehringer Ingelheim: Other: Member of a paediatric expert working group. Mitchell:Boehringer Ingelheim: Other: Member of a paediatric expert working group. Sharathkumar:Takeda: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy; Kedrion: Consultancy. Svirin:Takeda: Consultancy, Other: Personal fees; CSL Behring: Consultancy, Other: Personal fees. Tartakovsky:Boehringer Ingelheim: Current Employment. Simetzberger:Boehringer Ingelheim: Current Employment. Huang:Boehringer Ingelheim: Current Employment. Sun:Boehringer Ingelheim: Current Employment. Kreuzer:Boehringer Ingelheim: Current Employment. Gropper:Boehringer Ingelheim: Current Employment. Brueckmann:Boehringer Ingelheim: Current Employment. Albisetti:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Other: Member of a paediatric expert working group. OffLabel Disclosure: dabigatran etexilate in paediatric VTE

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