Phase 3, single-arm, multicenter study of dabigatran etexilate for secondary prevention of venous thromboembolism in children: Rationale and design

Background: Anticoagulant therapy for venous thromboembolism (VTE) in children is largely based on treatment recommendations for adults. However, differences in both physiology (ie, renal maturation and drug excretion) and developmental hemostasis must be considered when treating children, as such differences could affect dose appropriateness, safety and efficacy. Objectives: To address these concerns, a study was designed to evaluate the safety of dabigatran etexilate in children requiring secondary thrombus prevention in whom an initial VTE was associated with an identified risk factor that persisted after the acute VTE treatment period. We report herein the rationale and design of the study. Patients/Methods: This phase 3, open-label, single-arm, multicenter, multinational, prospective cohort study will be conducted in ≥100 children aged 0 to <18 years at ~100 specialist sites worldwide. Children will be treated with dabigatran etexilate for 12 months, or for a shorter duration if their identified VTE risk factor resolves, as per current American College of Chest Physicians recommendations. A nomogram will be used to determine starting doses for each patient. Results: The primary outcomes of the study will be VTE recurrence, bleeding events, overall mortality, and VTE-related mortality. Secondary outcomes will include occurrence of post-thrombotic syndrome, the pharmacokinetics of dabigatran, and the need for dose adjustments during treatment. Data on adverse events during the study will also be collected. Conclusion: This study will evaluate the safety of dabigatran etexilate for the secondary prevention of VTE in children, in addition to providing further data to guide pediatric dosing with dabigatran

Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children

This open-label, single-arm, prospective cohort trial is the first phase 3 safety study to describe outcomes in children treated with dabigatran etexilate for secondary venous thromboembolism (VTE) prevention. Eligible children aged 12 to 3 months to 3 months to <18 years with persistent VTE risk factor(s)

Dabigatran in the treatment and secondary prophylaxis of venous thromboembolism in children with thrombophilia.

In the phase 2b/3 DIVERSITY trial (NCT01895777), 3 months\u27 treatment with dabigatran was non-inferior to standard of care (SOC) for acute venous thromboembolism (VTE) in children. In a single-arm phase 3 secondary VTE prevention study (NCT02197416), up to 12 months\u27 dabigatran was associated with favorable safety. Dabigatran is approved by the European Medicines Agency and US Food and Drug Administration for pediatric indications. We assessed primary composite efficacy (complete thrombus resolution and freedom from VTE recurrence/VTE-related death) in subgroups with thrombophilia vs those with negative/unknown thrombophilia status in DIVERSITY and safety in both studies. Thrombophilia types were similar between DIVERSITY (total population) and secondary prevention studies: factor-V-Leiden, 42% vs 33%; prothrombin mutation G20210A, 19% vs 17%; antithrombin deficiency, 15% vs 20%; protein C/S deficiency, 23% vs 25%; antiphospholipid antibodies, 18% vs 20% patients, respectively. In DIVERSITY, 36% and 22% of thrombophilia subgroup patients treated with dabigatran and SOC, respectively, met the primary endpoint (Mantel-Haenszel-weighted rate difference -0.135 [95% CI-0.36, 0.08], non-inferiority P = .0014); comparable to the total DIVERSITY population (46% vs 42%) showing dabigatran non-inferiority to SOC. Within this subgroup, numerically fewer patients experienced VTE recurrence or progression of index thrombus in the dabigatran-treatment group vs SOC. In the secondary prevention study, VTE recurrence at 12 months occurred in 2.8% of patients with thrombophilia vs 0% with negative/unknown thrombophilia. Safety profiles were consistent with those reported previously. Although they should be interpreted with caution, these exploratory findings suggest dabigatran could be an appropriate long-term anticoagulant for children with thrombophilia

Design and rationale for the DIVERSITY study: An open-label, randomized study of dabigatran etexilate for pediatric venous thromboembolism

Background The current standard of care (SOC) for pediatric venous thromboembolism (VTE) comprises unfractionated heparin (UFH), or low-molecular-weight heparin (LMWH) followed by LMWH or vitamin K antagonists, all of which have limitations. Dabigatran etexilate (DE) has demonstrated efficacy and safety for adult VTE and has the potential to overcome some of the limitations of the current SOC. Pediatric trials are needed to establish dosing in children and to confirm that results obtained in adults are applicable in the pediatric setting. Objectives To describe the design and rationale of a planned phase IIb/III trial that will evaluate a proposed dosing algorithm for DE and assess the safety and efficacy of DE versus SOC for pediatric VTE treatment. Patients/Methods An open-label, randomized, parallel-group noninferiority study will be conducted in approximately 180 patients aged 0 to <18 years with VTE, who have received initial UFH or LMWH treatment and who are expected to require ≥3 months of anticoagulation therapy. Patients will receive DE or SOC for 3 months. DE will be administered twice daily as capsules, pellets, or an oral liquid formulation according to patient age. Initial doses will be calculated using a proposed dosing algorithm. Results There will be two coprimary endpoints: a composite efficacy endpoint comprising the proportion of patients with complete thrombus resolution, freedom from recurrent VTE and VTE-related mortality, and a safety endpoint: freedom from major bleeding events. Conclusion Findings will provide valuable information regarding the efficacy and safety of DE for the treatment of pediatric VTE. ClinicalTrials.gov registration number: NCT01895777

Outcome of Patients With Recurrent Osteosarcoma Enrolled in Seven Phase II Trials Through Children\u27s Cancer Group, Pediatric Oncology Group, and Children\u27s Oncology Group: Learning From the Past to Move Forward.

PURPOSE: The use of radiographic response as the primary end point in phase II osteosarcoma trials may limit optimal detection of treatment response because of the calcified tumor matrix. We performed this study to determine if time to progression could be used as an end point for subsequent studies. PATIENTS AND METHODS: We performed a retrospective analysis of outcome for patients with recurrent/refractory osteosarcoma enrolled in one of seven phase II trials conducted by the Children’s Oncology Group and predecessor groups from 1997 to 2007. All trials used RECIST or WHO radiographic response criteria and the primary end point of response rate. The following potential prognostic factors—age, trial, number of prior chemotherapy regimens, sex, and race/ethnicity—were evaluated for their impact on event-free survival (EFS). We used data from a phase II study (AOST0221) of patients with osteosarcoma who were given inhaled granulocyte-macrophage colony-stimulating factor with first pulmonary recurrence who had an EFS as well as biologic end point to determine the historical disease control rate for patients with fully resected disease. RESULTS: In each included trial, the drugs tested were determined to be inactive on the basis of radiographic response rates. The EFS for 96 patients with osteosarcoma and measurable disease was 12% at 4 months (95% CI, 6% to 19%). There was no significant difference in EFS across trials according to number of prior treatment regimens or patient age, sex, and ethnicity. The 12-month EFS for the 42 evaluable patients enrolled in AOST0221 was 20% (95% CI, 10% to 34%). CONCLUSION: The EFS was uniformly poor for children with recurrent/refractory osteosarcoma in these single-arm phase II trials. We have now constructed baseline EFS outcomes that can be used as a comparison for future phase II trials for recurrent osteosarcoma