The Kids-DOTT Trial: Novel Aspects of the ‘Parallel Cohort RCT‘ Design and Its Application to the Investigation of Duration of Anticoagulant Therapy for Pediatric Venous Thromboembolism.

Abstract Abstract 4169 The randomized controlled trial (RCT) is the gold-standard clinical trial design by which safety and efficacy of new medical therapies are evaluated in comparison to placebo or established treatments. Randomization serves as a primary means of ensuring equal distribution of confounding factors, minimizing selection bias, and upholding key assumptions of the statistical analysis. In some circumstances, when prognostic heterogeneity is hypothesized but evidence is not definitive, lack of equipoise among experts in the field may preclude randomization in a particular subgroup. In traditional RCT designs, patients in this subpopulation are then excluded from trial participation. However, these patients often constitute an important subgroup of the disease population. By taking advantage of existing RCT infrastructure, efforts to evaluate such patients in a parallel cohort arm – using a “parallel-cohort RCT” design – would provide an efficient means of generating multi-center prospective data on natural history, toward the development of future RCTs involving these subgroups. A current example of the parallel-cohort RCT design is the Kids-DOTT trial, an ongoing investigator-initiated multi-center randomized trial of the duration of anti-thrombotic therapy for venous thrombosis in children. The target population is children with first-episode acute VTE (excluding pulmonary embolism) in whom a reversible prothrombotic clinical risk factor has been identified and comprehensive laboratory assessment reveals no severe or multi-trait thrombophilia. Children meeting eligibility criteria and in whom no persistent occlusive thrombosis at the six-week follow-up time point are randomized to shortened-duration (six weeks) versus conventional-duration (three months) anticoagulant therapy (Figure 1). The primary endpoint is the cumulative incidence (i.e., risk) of recurrent VTE at two years, and will be compared between the two arms. Secondary outcomes include cumulative incidence of post-thrombotic syndrome (PTS) at two years and of major hemorrhage during anticoagulant therapy. The primary hypothesis of the study is that shortened-duration anticoagulation is non-inferior to conventional-duration therapy. The study also evaluates two groups of patients in parallel cohorts (Figure 1). The first group is comprised of patients with a persistent occlusive thrombosis following the first six weeks of anticoagulation; this cohort is allocated to a conventional course of anticoagulation. The second parallel cohort in the Kids-DOTT trial consists of patients with persistent antiphospholipid antibodies, who are allocated to a course of anticoagulation ranging from 3 months to lifelong. For each of these subpopulations, there was lack of equipoise toward inclusion in the randomization to shortened- versus conventional-duration therapy, due to perception of possible increased recurrence risk. The specific aims involving the parallel cohorts are to determine whether: (1) persistent thrombotic veno-occlusion is a prognostic indicator of recurrent VTE and/or PTS, among children treated with a three month conventional course of anticoagulation (comparison of randomization arm B vs. parallel cohort arm C in Figure 1); and (2) duration of therapy influences risk of recurrent VTE and/or PTS among children with persistent APA, when anticoagulated for a minimum duration of three months (within parallel cohort arm D in Figure 1). In this way, the parallel-cohort RCT model of the Kids-DOTT trial provides additional efficiency in trial design, maximizing the information gained from subpopulations of interest that are excluded from randomization. Broader application of the parallel-cohort RCT design should be considered, particularly in rare disease areas, where efforts to maximize inclusion of the diseased population are critical to trial feasibility and applicability. Disclosures: Off Label Use: The presentation refers to the use of anticoagulants as a drug class in general in the treatment of venous thromboembolism (VTE) in children. Despite their use in the standard care for pediatric VTE, all anticoagulants remain off-label for this indication in children.

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