TBI Endpoints Development (TED)

Principal Investigator: MANLEY, GEOFFREY T
Program: PH-TBI
Proposal Number: PT130798
Award Number: W81XWH-14-2-0176
Funding Mechanism: Traumatic Brain Injury Endpoints Development Award
Partnering Awards:
Award Amount: $17,109,805.00


Traumatic brain injury (TBI) is a major medical problem. It is a condition that results from a bump, blow, or jolt to the head or a penetrating head injury that disrupts the normal function of the brain. Each year in the United States, at least 1.7 million people suffer TBI; it is a contributing factor in a third of all injury-related US deaths. In the military, TBI is one of the most common causes of injury and disability in active duty service members. Risk of mild TBI (mTBI) during combat deployment was estimated at 15%-20% during the Operation Enduring Freedom and Operation Iraqi Freedom conflicts, and has been termed these conflicts' signature injury. Researchers use broad categories to describe TBI from "mild," a brief change in mental status or consciousness, to "severe," i.e., an extended period of unconsciousness. TBI has a very wide variety of symptoms and post-injury conditions that affect the physical (balance, coordination), cognitive (attention, memory, information processing speed, executive functions), and emotional/psychological/mental/social (mood, stress, depression, anxiety, social participation, and subjective well-being/quality of life) aspects of a person's life. Researchers have been actively working on better ways to diagnose and treat TBI, but at present, we have no "cures" for TBI, or even very good ways to diagnose if it has happened, or its severity. Doctors and research scientists agree that we need a more accurate way to understand if someone has TBI and whether and which drugs or medical devices might work to help or heal those affected by TBI. The best way to investigate and answer these questions is to carefully and safely enroll people with different kinds of TBI, from the military, civilian, and sports settings, in medical studies that are designed to assess their physical, psychological/emotional/cognitive functioning and the hidden anatomical and physiological effects that TBI may cause, and protect them from harm while they undergo these studies. In the TBI trials we are conducting, participants are asked sets of questions about their cognitive and emotional/psychological states and are given a variety of motor and other tests to check their physical function. These are called clinical outcome assessments (COAs). In addition, we know from existing research that when people have a TBI, the anatomy of their brain changes in obvious, but also subtle, ways, and their cells may release chemicals that signify that their body is reacting to the injury, even though they may not show outward signs. These imaging and blood-based signs are called biomarkers.

This project will help to confirm which of the many available COAs as well as imaging techniques (Magnetic Resonance Imaging [MRI], Computed Tomography Scan [CT or CAT Scan], Positron Emission Tomography [PET] scanning), and blood biomarkers are the most promising to move onto advanced study, with the ultimate aim of helping doctors to diagnose and treat TBI. Our review of the outcomes of our studies will be undertaken with the guidance of the US Food and Drug Administration (FDA), and patient advocacy groups, so that all of the relevant stakeholders are in agreement and reach consensus as to the most important targets for diagnosis and treatment. The FDA may then "qualify" one or more of these COAs and biomarkers to serve as Drug Development Tools for future studies that may investigate future drugs or therapies for TBI.

Our studies have been approved by ethics boards that ensure the safety and privacy of our enrolled study subjects and will be monitored for safety. Study subjects will not receive experimental treatments. Those study subjects who may undergo brain imaging will receive standard imaging tests that have been deemed safe over many decades of study. Finally, the blood samples that may be taken are in such small quantities that there is no risk to the study subjects. The combined power of the information gained from the many subjects that will be enrolled in this study will give doctors, researchers, and regulators better tools for clinical trials in TBI.

Identification, treatment, and prevention of mTBI in future conflicts is a priority for the health of the force. TBI is also prevalent during non-combat activities, because duties such as training and living in dangerous environments place service members at risk of mTBI. Finally, activities such as contact sports and other recreational activities place participants at high risk for TBI. Post-active duty, the known long-term consequences of TBI are of concern to the Department of Veterans Affairs and all Americans. There are very few therapies that limit follow-on injury in the immediate aftermath of sustaining a TBI, or that can help someone to rehab once the immediate danger is past, and prevent long-term consequences such as post-traumatic stress disorder or post-concussive syndrome. The TBI Endpoints Development project aims are designed to benefit our broader scientific understanding of brain injury, which will help all those affected by it to benefit from improved care.