The last days and hours of 2019 marked not only the end of a decade, but also the completion of patient enrollment in a landmark randomized clinical trial on the duration of anti-clotting medication (anticoagulant) therapy for venous thromboembolism (VTE) in patients under 21 years old — the Kids-DOTT trial.
VTE, which includes blood clots in the deep veins of the legs, arms, other areas of the body, including those that travel to (or originate in) the arteries of the lungs, occurs in only about 1 in 10,000 children — clearly, an infrequent health condition. However, among hospitalized children, VTE occurs in 1 in 200 children with critical illnesses, making it one of the most common hospital-acquired pediatric conditions. Another all-too-common scenario for pediatric VTE is the use of estrogen-containing oral contraceptive pills in adolescent females who are overweight or have a history of VTE in family members who are middle-aged or younger.
When VTE occurs in adults, the standard of care is a three-month course of anti-clotting medicine (anticoagulants), based on landmark clinical trials performed in the 1990s, mostly among adults over 40 years of age. The same standard of care has been applied in pediatric patients with VTE, but in the absence of such trials performed in children.
The Kids-DOTT trial began enrollment in 2007 during its pilot/feasibility phase, funded by a grant from the National Heart Lung and Blood Institute (NHLBI) of the National Institutes of Health (NIH) to the trial’s leader, Neil Goldenberg, M.D., Ph.D., Professor of Pediatrics and Medicine at Johns Hopkins University School of Medicine and associate dean for research at Johns Hopkins All Children’s in St. Petersburg, Florida (at the time, an Assistant Professor of Pediatrics and Medicine at the University of Colorado and associate director of the Mountain States Regional Hemophilia and Thrombosis Center).
Having successfully met its pilot/feasibility milestones, the study then continued into its definitive trial phase, first through research grant funding from the Johns Hopkins All Children’s Foundation in 2013 and a Bridge Award from the American Society of Hematology in 2015, and subsequently through paired large cooperative clinical trial (U01) grants awarded by NHLBI in 2016.
The Kids-DOTT trial design is innovative in that it incorporates both a randomized trial as well as two parallel observational cohort arms that track outcomes in patient subgroups that don’t meet criteria for randomization. This provides efficiency in a relatively low-frequency health condition like pediatric VTE by taking advantage of the infrastructure of a large randomized trial and its “economy of scale” to establish much-needed data on natural history in subpopulations of interest for future randomized trials.
Additional innovations of the trial include: its use of a nested pilot/feasibility phase with pre-specified criteria to be met prior to continuing seamlessly into the rest-of-trial phase of the definitive study; its use of real-time centralized remote monitoring of all eligibility and randomization criteria of enrollees across more than 50 participating centers; and its establishment of a multinational “biobank” of blood samples for future discovery of disease biomarkers.
With a total enrollment of 607 patients altogether in the randomized trial and parallel cohorts, Kids-DOTT is the largest trial ever conducted in the field of pediatric thromboembolism. With a follow-up period of one year for patient outcomes, followed by database closure and analysis procedures, the main results of the trial are anticipated to be reported in Spring 2021.
“While the Kids-DOTT story is still being written, it’s clear that its main heroes are the children, young adults, and parents who have generously participated in the trial for the benefit of future young patients with VTE,” Goldenberg says. “The other heroes who too often go unrecognized are the experienced, highly-trained clinical research professionals who work closely with the physician-investigators, patients and parents at each of the participating centers in the trial — as well as those at the coordinating center at Johns Hopkins All Children’s who support their peers at all participating centers — to ensure the safety of the patient participants and the integrity of the trial.”