The Journal of the American Medical Association (JAMA) has just published the practice-changing findings of the NIH-funded multinational Kids-DOTT randomized clinical trial.

This landmark trial, led by Neil Goldenberg, M.D., Ph.D., associate dean for research, and the Clinical Coordinating Center team in the Johns Hopkins All Children’s Institute for Clinical and Translational Research, involved an Investigators Group that Goldenberg assembled over a decade ago, focused on the emerging pediatric challenge of venous thromboembolism (VTE—also known as “blood clots,” including deep vein thrombosis (DVT) and pulmonary embolism (PE)). The Kids-DOTT Investigators Group represents over 50 collaborating institutions from throughout the United States, Canada, Europe and Australia.

The trial also involved a Data Coordinating Center team at the University of Colorado-affiliated academic research organization CPC Clinical Research, led in recent years by Marc Bonaca, M.D., M.P.H., and previously by the late Will Hiatt, M.D. Over the past several months since some of the key findings were presented at the “late-breaking oral abstract” session of the International Society on Thrombosis and Haemostasis 2021 annual meeting, the Kids-DOTT trial has already begun to change clinical practice in the treatment of a growing number of young patients affected by DVT and PE worldwide.

“This milestone for Johns Hopkins All Children’s, Hopkins Medicine and the pediatric field is at the intersection of discovery, innovation and collaboration,” says Goldenberg, also the Perry Family Endowed Professor in Clinical and Translational Research and a professor of pediatrics and medicine at the Johns Hopkins University School of Medicine. “In order to achieve major advances in children’s health, it’s the collaboration piece that’s paramount. The success of the Kids-DOTT trial and its impact on the care of young patients with VTE, could not have been realized without the tremendous commitment and partnership of a large team of physician researchers, clinical research nurses and study coordinators from around the world, and the courage and trust of the many patients and families who participated in the trial for the benefit of future children and young adults with VTE. Above all, it is our patients and families who inspire us to continue to advance children’s health through research.”

What Was Found

The researchers found that a six-week course of treatment with anti-clotting medications (called “anticoagulants”) for acute, provoked VTE in patients under 21 years old was just as effective, and at least as safe, as the historical conventional duration of anticoagulant treatment of three months.

Why It’s Important

VTE occurs in only about 1 in 10,000 children overall. However, VTE occurs in 1 in 200 hospitalized children, and about 1 in 50 children hospitalized with critical illnesses, making it one of the most common hospital-acquired pediatric conditions. In addition, for more than the past year, children’s hospitals have been seeing a spike in VTE attributable to acute COVID-19 infection, especially among those who develop the multisystem inflammatory syndrome in children (known as MIS-C).

The historical routine duration of anticoagulant treatment, three months, was based on trials from the 1990s comprised of adult VTE patients (most of whom were over age 40), and little evidence existed for the optimal treatment of children. Goldenberg and his collaborators around the world sought to establish for how long patients under 21 years of age (the age range for patients treated at most children’s hospitals in the United States) should be treated with anticoagulant medications.

By showing through a rigorous, multinational randomized clinical trial that a shortened, six-week course of anticoagulant therapy for VTE in patients under 21 years of age is as effective, and at least as safe, as the previous standard three-month course, the Kids-DOTT (Duration of Therapy for Thrombosis) trial calls for cutting the conventional duration of therapy in half. This is anticipated to result in significant savings in health care costs for the treatment of VTE in young patients, as well as substantial benefits in overall well-being of affected children and their parents — much less time having to be concerned about bleeding risks, and being able to return to normal age-appropriate physical activities and sports much sooner (which is particularly important in the “other ongoing epidemic” apart from COVID-19 — that of childhood obesity).

Not all patients under 21 years of age fit the criteria of the Kids-DOTT trial, and therefore, for safely and effectively cutting the prior conventional duration of treatment in half. Kids-DOTT focused on those with “provoked” VTE (VTE that are accompanied by an identifiable risk factor for developing blood clots, such as recent hospitalization or surgery, severe infection, placement of a central venous catheter in children with underlying medical conditions, or use of estrogen-containing oral contraceptives.

In pediatric patients, 5-10% of VTE are unprovoked, and such patients require longer than three months of anticoagulant medication, rather than only six weeks. The Kids-DOTT trial did not randomize to shortened vs. conventional therapy those children whose blood clots were completely blocking blood flow in the involved veins by repeat ultrasound at the six-week follow-up mark; when this is the case for future patients, the historical conventional duration of anticoagulation should still be considered as the standard. Lastly, because few patients with cancer or whose VTE involved pulmonary embolism were enrolled in the trial, the findings of the Kids-DOTT trial also do not apply to patients with these conditions. Yet, the vast majority of patients younger than 21 years of age with VTE do not have cancer, pulmonary embolism, or complete occlusion at six weeks follow-up, and for this reason the findings of the Kids-DOTT trial are far-reaching.

“This collaborative effort involving the NIH, academic experts, the Johns Hopkins Clinical Coordinating Center, and the Colorado Prevention Center (CPC) Data Coordinating Center enabled the team to answer this question in an area where research has been traditionally very challenging,” says Marc Bonaca, M.D., M.P.H., executive director of CPC Clinical Research and head of the Data Coordinating Center for the randomized trial. “We are very proud to have contributed to this important scientific endeavor and look forward to ongoing collaborations as more is learned from this rich and important dataset. We hope Kids-DOTT continues as an ongoing network enabling investigators to answer important questions in this space.”

How It Started

Goldenberg conceived of the idea for the Kids-DOTT study in 2002, sketching it out on a napkin in a cafeteria at a hospital in Paris where he was doing an elective. He was a resident in Internal Medicine and Pediatrics at the University of South Florida Morsani College of Medicine in Tampa. Goldenberg had developed an interest in VTE at McGill University in Montreal where, as a medical student, he conducted a three-hospital investigation of coagulation markers and angiogenic factors in adults with VTE and cancer.

After finishing his residency, Goldenberg moved on to fellowship in hematology, oncology and bone marrow transplantation at Children’s Hospital Colorado and the University of Colorado, where he also completed a Ph.D. in Clinical Investigation. As a fellow, he conducted early research on prognostic biomarkers for long-term outcomes of VTE in children that was published in the New England Journal of Medicine. His fellowship research, coupled with a five-year Career Development Award from the National Heart, Lung, and Blood Institute, laid the groundwork for Kids-DOTT and culminated in the completion of the trial’s pilot/feasibility phase.

The first patient was enrolled in 2008, the final patient was enrolled in 2019, and data collection on the primary outcomes was completed in 2021.

How it Innovated

As Goldenberg and his team developed the Kids-DOTT trial, they used an innovative approach to clinical trial design. In a traditional randomized clinical trial design, patients who are ineligible for randomization are excluded from study participation. However, these patients often constitute an important subgroup of the disease population. By extending existing trial infrastructure, efforts to evaluate such patients in parallel cohort arms provided an efficient means of generating multicenter prospective data in patients for whom there were significant gaps in medical knowledge, laying the foundation for potential future trials involving these VTE subgroups of interest.

“The database from this study is a treasure that will allow us to gain many more insights on blood clots in children from secondary analyses of the data, for example by looking at specific patient subgroups, further outcomes, or blood samples that have been collected,” says Christoph Male, M.D., M.Sc., the European lead for the trial and associate professor of pediatrics at the Medical University of Vienna and chair of the pediatric arm of the of the International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee.

An additional innovation in Kids-DOTT was its analytic approach. Since keeping a patient on anticoagulant medication involves a continuous tradeoff between the risk of bleeding related to anticoagulation and the risk of developing more blood clots (each of which potentially can be life-threatening), Goldenberg and colleagues (including University of Colorado-based biostatistician-leader John Kittelson, Ph.D., as well as Hiatt — an adult vascular disease multicenter trialist) planned an innovative approach to analyzing the data. Rather than adopting the usual approach of focusing primarily on the difference in rates of new blood clots between the two treatment approaches and then considering the difference in rates of bleeding secondarily, they simultaneously measured the trade-off between the two risks — much like savvy patients do inherently, when considering whether there is evidence to indicate a “net benefit” in continuing anticoagulant medication in patients like them.

What’s Next

The JAMA publication reports the findings of the randomized controlled trial (involving over 400 patients across 42 of the 51 centers that participated in the overall study), while the results of the parallel cohorts (involving more than 100 additional patients) will be the subject of subsequent publications. 

Additionally, the trial has compiled a unique biobank of more than 10,000 blood-derived specimens of plasma, DNA and RNA, maintained in the state-of-the-art, College of American Pathologists-accredited Johns Hopkins All Children’s Pediatric Biorepository.

Goldenberg and his team are applying for NIH funding to follow up on how the Kids-DOTT findings are disseminated and adopted into practice globally, and to monitor the degree to which the favorable outcomes measured in Kids-DOTT continue to be observed in subsequent real-world experience. This is just one of many avenues of investigation ahead for the multinational Kids-DOTT Investigators Group, who are presently collaborating on multiple secondary manuscripts that leverage the study’s breadth of data and biospecimens to address numerous additional important questions in the field of pediatric VTE.

“Imagine the impact on pediatric investigators in this field, on reading the results and believing that prospective trials are feasible. And imagine the positive impact on patients and families, who will be immensely benefited from a research endeavor that resulted in cutting by half the time required to treat children with acute venous thrombosis,” says Leonardo Brandao, M.D., M.Sc., a hematologist at The Hospital for Sick Children in Toronto, a professor of in the Department of Pediatrics at the University of Toronto and the Canadian lead for the trial. “I dare say that the entire scientific community will benefit from the recent large-scale trials published in the field of pediatric thrombosis, particularly Kids-DOTT. The immediate legacy of Kids-DOTT will go beyond its practice-changing findings, as it signals that it is a very auspicious time to be a part of pediatric thrombosis.”

Kids-DOTT milestones

• 2002: Initial trial concept developed (by then-medical-resident in Pediatrics and Internal Medicine at the University of South Florida, Neil Goldenberg, M.D., Ph.D., while on a one-month elective in Paris, France)
• 2004: Thrombosis Studies Award from the Hemophilia and Thrombosis Research Society of North America
• 2007-2013: K23 Career Development Award from U.S. National Institutes of Health, National Heart, Lung and Blood Institute
• 2008: First patient participant enrolled in the trial
• 2009-2013: Investigator-Initiated Study Award from Eisai, Inc.
• 2010: Publication of the innovative Kids-DOTT “parallel-cohort” randomized controlled trial design in the medical journal Contemporary Clinical Trials
• 2013: Publication of the innovative “bivariate endpoint” analytic design of the Kids-DOTT trial in the Journal on Thrombosis and Haemostasis (official medical journal of the International Society on Thrombosis and Haemostasis)
• 2013-2017: Johns Hopkins All Children’s Foundation Institutional Research Award
• 2015: Publication of the Kids-DOTT pilot/feasibility phase findings in the Journal of Thrombosis and Haemostasis (official medical journal of the International Society on Thrombosis and Haemostasis)
• 2015-2016: Bridge Award from the American Society of Hematology2016-2022: U01 Cooperative Research Agreement Award from U.S. National Institutes of Health, National Heart, Lung and Blood Institute, for Kids-DOTT Clinical Coordinating Center
• 2019: Last patient participant enrolled in the trial
• 2021: Last follow-up visit conducted for primary endpoints; primary database locked and analyzed; primary findings presented at late-breaking oral abstract session of the International Society on Thrombosis and Haemostasis annual meeting
• 2022: Primary findings published in Journal of the American Medical Association; last follow-up visits being conducted for secondary endpoints; multiple secondary manuscripts in development by the Kids-DOTT Investigators Group