Johns Hopkins All Children’s Hospital Researcher Plays Key Role toward Landmark FDA Drug Approval for Anticoagulant in Children

Venous thromboembolism (VTE) is a disorder that includes deep vein thrombosis and pulmonary embolism. A deep vein thrombosis (DVT) occurs when a blood clot forms in a deep vein, usually in the lower leg, thigh, or pelvis. A pulmonary embolism (PE) occurs when a clot breaks loose and travels through the bloodstream to the lungs.

Image of constricted artery. Credit: Getty Images

In 2008, Johns Hopkins professor of pediatrics and medicine Neil Goldenberg, MD, PhD (at the time, a faculty member of University of Colorado School of Medicine) submitted an investigator-initiated trial (IIT) award application to the pharmaceutical company that oversaw research and development of the low molecular weight heparin anticoagulant, dalteparin sodium, in the United States. Dalteparin had first gained approval by the US Food and Drug Administration (FDA) in 1994 for the prevention of venous thromboembolism (VTE) in adults with cancer.

Dr. Goldenberg’s IIT proposal was to study the dosing, safety, and efficacy of dalteparin for VTE treatment in children, as a sub-study of his NIH NHLBI K23 grant-funded randomized trial investigating the optimal duration of therapy for thrombosis in patients <21 years of age (the Kids-DOTT trial), in which multiple anticoagulant agents were being studied simultaneously. The IIT grant was awarded.

The next year, Goldenberg was contacted by the company’s US medical & scientific affairs leaders, stating that they needed to design and conduct a pediatric study of dalteparin for treatment of VTE in cancer patients, as part of the post-marketing commitment to FDA under the recent expanded approval of the drug for VTE treatment in adults with cancer. They asked Goldenberg to help, including co-developing the protocol and serving as the chair of the trial’s Steering Committee.

Nearly 10 years (and several changes in pharmaceutical company leadership) later, the phase 2 trial was completed. During this time, due to challenges in accrual, FDA agreed to an expansion of the trial to include children without cancer, and also agreed to accept the Kids-DOTT sub-study data (conducted under the IIT award) on dose-finding, safety, and efficacy as supportive data to the phase 2 results. In May 2019, dalteparin became the first FDA-approved anticoagulant for children.

At the recent joint American Society of Hematology (ASH) FDA symposium on New and Late-Breaking Drug Approvals, held at the 2019 ASH Annual Meeting, experts including Goldenberg, other clinical trialists and clinicians, and FDA officers and reviewers convened to offer clinical and regulatory perspectives on the recently approved indications. These included givosiran for patients with the rare disease acute hepatic porphyria (approved Nov 2019), crizanlizumab and voxelotor for patients with sickle cell disease (approved Nov 2019), and dalteparin for pediatric patients with venous thromboembolism (approved May 2019).  Goldenberg provided the perspectives of both a clinician expert and clinical trialist, emphasizing the challenges of completing clinical trials in pediatric rare/infrequent diseases, and the importance of academic engagement in the design, conduct, and oversight of pharmaceutical industry-sponsored trials.

In a recent interview with the Johns Hopkins Institute for Clinical and Translational Research (JH ICTR) communications team, Goldenberg (who is based at Johns Hopkins All Children’s Hospital, and directs the Johns Hopkins All Children’s Hospital Institute for Clinical and Translational Research) remarked: “Most often, academically-initiated clinical trials of developed drugs take place as an ‘after thought’ to pharmaceutical company-driven trials conducted in a given population or age group—particularly in pediatric trials. In this case, although it didn’t quite happen in the other direction, the academically-initiated study certainly made key contributions to the pharma-driven trial and its resultant FDA approval.” Perhaps we should call it serendipity…by design.

And what has become of the original IIT? The Kids-DOTT trial (NCT00687882) progressed from NIH K23 funding to an ASH Bridge Award in 2015 and dual NIH NHLBI U01 awards in 2016. Recently, on December 31, 2019, the trial completed its enrollment of 608 patients <21 years old with VTE from the U.S., Canada, Austria, the Netherlands, and Australia. Next month, the central biorepository for the trial—the Johns Hopkins All Children’s Pediatric Biorepository—is slated to receive its final shipments of biospecimens collected from patients on study at the trial participating sites. Follow-up on the trial continues, and reporting of the trial’s main findings is anticipated in April 2021.

For more information visit:

NIH-Sponsored Multinational Trial Led by Johns Hopkins Faculty Member at Johns Hopkins All Children’s Successfully Completes Enrollment

Perspectives on 2019’s New Hematology Drug Approvals