By Barbara Drosey
When a traumatic injury occurs, the countdown to an optimal chance at survival begins. With hemorrhage being the main cause of death within 24 hours postinjury, how bleeding is managed in those initial hours can greatly affect outcomes. It is within this critical window that Sage Myers, MD, MSCE, and her research team are trialing an intervention to prevent uncontrolled bleeding in children following traumatic injury.
Tranexamic acid (TXA), an antifibrinolytic agent, is standard of care for traumatically injured adults. A large multicenter, randomized controlled trial called CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Hemorrhage) found that, when administered within three hours of a hemorrhagic injury, TXA decreased the need for blood transfusion and resulted in reduced mortality due to bleeding in adults. While TXA is approved for use in children to treat bleeding disorders such as hemophilia and as a prophylactic measure prior to some surgical procedures, there is no definitive evidence base for use in children who present with traumatic injury.
Expanding the Standard
Dr. Myers, an emergency department physician at Children’s Hospital of Philadelphia and assistant professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, is CHOP’s lead principal investigator for the Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children (TIC-TOC). The pilot feasibility study will enroll 40 patients across four sites: CHOP; UC Davis Health, Sacramento, California; Primary Children's Hospital, Salt Lake City, Utah; and Nationwide Children's Hospital, Columbus, Ohio. TIC-TOC is the precursor to a larger study that will enroll participants from hospitals in the United States and abroad to build an evidence base for TXA for the treatment of traumatic injury in children — for point of comparison, the CRASH-2 study included more than 20,000 adult participants.
TIC-TOC aims to discover if there is a benefit for moving the adult clinical care standard of TXA into the pediatric age range. Inclusion criteria are focused on types of injuries, such as penetrating torso trauma, blunt torso trauma, or head trauma, that are likely to result in hemorrhage with the potential to cause death or permanent disability. Investigators will collect specific outcomes measurements related to total transfused blood products, intracranial hemorrhage progression, neurocognitive function, venothromboembolic events, and seizures.
“We don't know what the effects of TXA will be in children [following traumatic injury],” Dr. Myers said. “Children are very different than adults in many ways, not just physiologically but in the types of injuries that they get.”
With funding from the National Heart, Lung, and Blood Institute, the TIC-TOC trial is part of the Pediatric Emergency Care Applied Research Network (PECARN), supported by cooperative agreements between seven academic medical centers and the Health Resources Services Administration, Maternal and Child Health Bureau, and Emergency Medical Services for Children Program. The network provides the leadership and infrastructure to conduct large multicenter studies, support collaborative research, and collect and disseminate findings through its data coordinating center.
An Exceptional Trial
The random and unexpected nature of emergency medicine make clinical trials in this specialty challenging. Children may arrive at the emergency room without their parents if they were not together when their injury occurred, or parents may have been in the same accident and are also receiving care. The FDA allows an exception from informed consent within prescribed circumstances, and TIC-TOC’s case for exception has a lot to do with the crucial timing of administering TXA.
“TXA has to be given within three hours of the injury,” Dr. Myers said. “That may seem like a long time, but in actuality, it takes a while for first responders to get to the scene, stabilize the patient, and bring them to the hospital. There will definitely be children who could have been randomized but who arrive outside of the window that would allow us to enroll them.”
As a requirement of its exception to informed consent status, the TIC-TOC study leaders will inform and educate people in the community most likely to be affected by the trial. Dr. Myers’ plan involves conducting focus groups and surveys with people who could be within the recruitment pool. The public is provided information about the clinical trial, as well as a mechanism to preemptively opt out of participating.
“People are generally open to the idea and positive about having something that could possibly help save lives and improve outcomes for injured children,” Dr. Myers said.
It’s important to note that exception from informed consent does not mean a child would participate in the study against a parent or guardian’s wishes.
“If a child is enrolled with exception from informed consent, we will discuss the situation with the parents [or guardians] at the soonest possible time,” Dr. Myers said. “They would be provided all the clinical trial information, and always have the opportunity to opt out of their child’s participation in the study. If the patient was receiving TXA at that point, we would stop administering the medicine and continue to monitor for side effects or adverse events.”
Community members may visit the TIC-TOC website to learn more details about the trial and learn how to opt out.
With strong evidence of the benefits of TXA in adults combined with good safety data in children for its currently approved use, Dr. Myers is cautiously optimistic.
“We have no medicine that stops bleeding in children and no medicine that will decrease the amount of hemorrhage children have, and hemorrhage is what kills children in the first 24 hours following traumatic injury,” Dr. Myers said. “The potential to have a medicine would be amazing, but we’ve had drugs in the past that worked for adults and did not have the same effect for children. Whatever the outcome, we always keep moving forward, and always keep looking for better ways to treat children.”
For more information about the TIC-TOC trial, or to contact the study team about opting out, click here.