Dabigatran Etexilate for the Treatment of Acute Venous Thromboembolism in Children: Results of an Open-Label, Phase 2b/3, Randomised Clinical Trial

Abstract

Background: Dabigatran etexilate, a direct oral anticoagulant, may be an effective and safe alternative for treating acute venous thromboembolism (VTE) in children. Methods: This open-label, randomised (2:1), phase 2b/3 trial evaluated the efficacy and safety of standard of care (SOC) versus dabigatran using a paediatric dabigatran dosing algorithm (age- and weight-adjusted nomogram) in children with acute VTE aged 12 to <18 years, 2 to <12 years, and birth to <2 years requiring anticoagulation therapy for ≥3 months. Primary composite efficacy endpoint: proportion of children with complete thrombus resolution, and freedom from recurrent VTE or VTE-related death. Secondary endpoints: safety (determined by major bleeding events), and pharmacokinetic/pharmacodynamic relationships. Findings: While target enrolment was 141 children, 90 randomised to SOC and 177 to dabigatran were analysed. Similar proportions of children treated with SOC and dabigatran met the composite efficacy endpoint (38/90 [42·2%] vs 81/177 [45·8%]; Mantel-Hanszel weighted difference, –0·04; 90% 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%]; HR 0·94; 95% CI 0·17 to 5·16; p=0·95). Incidence of adverse events was 66·7% and 76·7% for SOC and dabigatran, respectively, and 20·0% and 12·5% for serious adverse events. Dabigatran pharmacokinetic/pharmacodynamic relationships were similar to those for adults. Interpretation: This randomized trial confirmed that an age- and weight-adjusted dabigatran dosing algorithm was appropriate in children aged birth to <18 years. Dabigatran was non-inferior to SOC in terms of efficacy for acute VTE treatment, with similar pharmacokinetic/pharmacodynamic relationships to adults. Trial Registration: EudraCT No.: 2013-002114-12 Funding: Boehringer Ingelheim; DIVERSITY, NCT01895777. Conflict of Interest: JH is a member of a paediatric expert working group for Boehringer Ingelheim and has received honoraria from Boehringer Ingelheim for congress presentation.LRB is a member of a paediatric expert working group for Boehringer Ingelheim and has received advisory board fees from Boehringer Ingelheim.ML is a member of a paediatric expert working group for Boehringer Ingelheim.LB is a member of a paediatric expert working group for Boehringer Ingelheim and reports fees to her institution from Janssen Pharmaceuticals.EC is a member of a paediatric expert working group for Boehringer Ingelheim and reports personal fees from Roche, Sobi, Bristol-Myers Squibb, CSL Behring, and Shire/Takeda.LGM is a member of a paediatric expert working group for Boehringer Ingelheim and has received a research grant from Bristol-Myers Squibb.IN declares no competing interests.AS has received consulting fees from Takeda, CSL Behring, Bayer, and Kedrion.PS reports personal fees from Takeda and CSL Behring.KG declares no competing interests.IT, MS, FH, ZS, JK, SG, PR, and MB are all employees of Boehringer Ingelheim.DIVERSITY manuscript to submit_4June2020MA is a member of a paediatric expert working group for Boehringer Ingelheim and has received advisory board fees from Daiichi Sankyo. Ethical Approval: The design of this study (including the definition of endpoints and SOC comparators) is based upon the European Medicines Agency’s Paediatric Committee’s recommendations. This committee has previously reviewed and approved the principal design elements and endpoints of this trial.