Patients around the world with severe COVID-19 illness are presenting with higher rates of vascular blood clots, so researchers at Johns Hopkins All Children’s Hospital have launched a national clinical trial to study the use of anti-clotting medications to treat children with the coronavirus and related diseases.
Blood clotting is a natural reaction of the body to stop bleeding after injury, but in rare cases, the clots can block flow in blood vessels and cause a pulmonary embolism, stroke or other complications.
Faculty physicians and colleagues in the Johns Hopkins All Children’s Institute for Clinical and Translational Research are studying low-dose anticoagulation — the use of anti-clotting medications — to prevent vascular clotting in COVID-19 and related cases.
The trial — known as the COVID-19 Anticoagulation in Children (COVAC) Thromboprophylaxis trial — is designed to evaluate safety, dose requirements, and preliminary efficacy of an anticoagulant medication regimen (specifically, low molecular weight heparin) for the prevention of vascular clotting (“thrombotic”) complications in children hospitalized with COVID-19-related illness. The trial will enroll not only children hospitalized with the respiratory illness who have tested positive for the SARS-CoV-2 (the virus that causes COVID-19), but also those hospitalized with the rapidly-emerging, COVID-related, and often severe multisystem inflammatory syndrome in children (MIS-C). Blood sample collection for research as part of the trial protocol will enable Johns Hopkins All Children’s investigators and their basic science collaborators in the Johns Hopkins All Children’s Institute for Fundamental Biomedical Research and the Johns Hopkins All Children’s Pediatric Biorepository to gain key insights into the pathophysiology of the COVID-19 disease course in children and the mechanisms underlying the COVID-related MIS-C syndrome.
“Around the world and in the United States, children have not been spared from developing severe illness related to COVID-19,” says pediatric intensivist Tony Sochet, M.D., M.H.S., the overall principal investigator for the multicenter study. “These presentations include respiratory failure related to clots in large and small arteries in the lung, but also multisystem inflammatory syndrome associated with the development of venous thromboembolism (VTE, including blood clots in the deep veins of the body, as well as clots that embolize from those veins to the lung arteries and clots that start in the arteries of the lungs).
“As in adults, the development of thrombotic disease in these children not only leads to prolonged hospitalization but also contributes to the heightened risk of death in children hospitalized for COVID-19 in both the ICU and general pediatric wards,” continues Sochet, also an assistant professor of anesthesia and critical care medicine at Johns Hopkins University School of Medicine, who is based in St. Petersburg, Florida. “The COVAC trial will provide the critical evidence in support of the current standard practice of anticoagulant thromboprophylaxis in this population.”
Led by a multidisciplinary team of pediatric clinical trial experts, the study protocol, and the FDA Investigational New Drug (IND) waiver application, and two grant applications were developed and submitted—and the network of participating sites was established — in an unprecedented 10 days, as compared to what often takes several months, if not longer.
What were the secrets behind this achievement?
First, the team leveraged the combined experience and expertise of leaders from several Centers within the Johns Hopkins All Children’s Institute for Clinical and Translational Research:
- Internationally recognized pediatric antithrombotic therapy expert, clinical trialist and institute director Neil Goldenberg, M.D., Ph.D., led the development of the initial grant submission;
- Sochet and hospitalist John Morrison, M.D., Ph.D., (who directs the institute’s Center for Training, Education, Engagement and Mentorship [TEEM]) co-led the development of the trial protocol for submission to the Johns Hopkins Medicine Institutional Review Board (IRB);
- Institute Data Coordinating Center leader and lead trial biostatistician Ernest Amankwah, Ph.D., led the design of the statistical analysis plan for the grant and protocol;
- Frances Hamblin, R.N., MSHS, CCRP, JHAC ICTR Clinical Coordinating Center co-director, and Jonathan Metts, M.D., oncologist and co-director of the institute’s Center for Early Phase Trials, developed the FDA Investigational New Drug waiver (which was subsequently granted by FDA);
- Hamblin and Goldenberg registered the trial on clinicaltrials.gov, and while the NIH grant and IRB protocol were under review, the full team collaborated on the development of the trial’s web-based database; and
- The team assembled a national Steering Committee, a Clinical Endpoint Adjudication Committee, and an independent Data and Safety Monitoring Committee (DSMC), developed charters for each, and obtained DSMC approval of the trial protocol, including the data and safety monitoring plan.
The second key strategy for rapid development and launch of the multicenter trial was leveraging an existing network of collaborative centers. The COVAC trial group is mostly comprised of centers that have been participating in another Johns Hopkins All Children’s-led clinical trial, Kids-DOTT, which ranks among the largest randomized trials ever conducted in the field of pediatric thrombosis.
Dan Hanley, M.D., professor of neurology, neurosurgery, and anesthesia and critical care medicine at Johns Hopkins University School of Medicine and director of the NIH-funded Johns Hopkins-Tufts Trial Innovation Network, emphasizes that, “This is a key effort with great potential to protect children’s health in an area we know is important in the COVID-19 disease processes. It will provide an urgently needed ingredient to COVID therapies – a rigorously-conducted multicenter trial with validated data.”
The study has caught the attention of an international audience.
“Clinical trials confirming the safety of low molecular weight heparin (LMWH) thromboprophylaxis in hospitalized children have long been awaited,” says Dr. Christoph Male, 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. “The Pediatric SSC applauds Dr. Goldenberg’s, Sochet’s and Morrison’s leadership of this crucial and time-sensitive trial, given the paucity of evidence to support the current clinical use of LMWH thromboprophylaxis in hospitalized children who are at increased risk of thrombotic complications, whether due to COVID-19 or other prothrombotic states.”
“The ability to nimbly respond to rapidly-emerging child health needs by developing and implementing multicenter studies on very short timelines, with robust organizational infrastructure and oversight and the engagement of multidisciplinary colleagues from around the country inspires us to do even more of this kind of work,” says Goldenberg, who is a Johns Hopkins All Children’s-based professor of pediatrics and medicine at Johns Hopkins University School of Medicine, and associate dean for research at Johns Hopkins All Children’s Hospital. “By combining the extensive experience in pediatric multicenter clinical trial design, execution and analysis of the faculty and staff in the Johns Hopkins All Children’s Institute for Clinical and Translational Research with the field-leading clinical expertise of physicians at our hospital across a vast array of pediatric medical and surgical subspecialties, we are poised and passionate to lead further critical collaborative efforts like the COVAC trial.”
More information on the COVAC trial is available here at clinicaltrials.gov.
Disclaimer: Johns Hopkins Medicine researchers are working tirelessly to find ways to better understand and eventually eliminate COVID-19 and the virus that causes it. New research like this, especially research related to clinical therapies and drug regimens, are still early in concept and small in sample size. This will require rigorous research, testing and peer review, all of which take time, before solid conclusions for clinical care and disease prevention can be made.