The city of Atlanta will soon serve as the national epicenter for a groundbreaking National Institutes of Health (NIH)-sponsored Phase III trial for the treatment of traumatic brain injuries using the hormone progesterone.
The national study, called ProTECT III, is a multicenter, randomized, double-blind study, which will enroll 1,140 patients over five years at 17 medical centers in 15 states. Atlanta’s Grady Memorial Hospital will serve as the lead center, led by Emory University School of Medicine faculty researchers, as well as faculty from the Morehouse School of Medicine.
The initial NIH award is for three years and a total of approximately $14.5 million, in order to demonstrate target feasibility to conduct the trial. If milestones are met during the first three years, the trial could be extended for three more years with additional funding of approximately $14 million.
David Wright, MD, associate professor of emergency medicine, Emory School of Medicine, is the national study’s lead investigator. Michael Frankel, MD, Emory professor of neurology, and Jeffrey Salomone, MD, Emory associate professor of surgery, Division of Trauma Surgery, will serve as site principal investigators of the clinical trial at Grady. The trial will be conducted through the Neurological Emergencies Treatment Trials (NETT) network coordinated by the University of Michigan. Data analysis will occur at the Medical University of South Carolina.
Every 15 seconds, someone in the United States sustains a significant traumatic brain injury. Approximately 2 million adults and children in the United States suffer from traumatic brain injuries each year – leading to 50,000 deaths and 80,000 new cases of long-term disability, according to the Centers for Disease Control and Prevention. Despite the enormity of the problem, scientists have failed to identify effective medications to improve outcomes following a traumatic brain injury.
Emory researchers, however, concluded in an earlier pilot clinical trial that giving progesterone to trauma victims shortly following brain injury appears to be safe and may reduce the risk of death and long-term disability. Their previous three-year study, called ProTECT I (Progesterone for Traumatic brain injury–Experimental Clinical Treatment), enrolled 100 participants at Grady Memorial Hospital. It was designed to evaluate whether progesterone can be administered intravenously in a safe and reliable way.
“We found evidence that progesterone is not only safe for use in patients suffering from traumatic brain injuries,” says Wright. “We also found a 50 percent reduction in mortality in those patients treated with progesterone. Even though this was a small pilot study, we found signs that progesterone improved functional outcomes and reduced disability in patients with moderate brain injury.
“By expanding our test sites to 17 major trauma centers across 15 states and enrolling more than 1,000 patients, we hope to confirm these preliminary findings and determine if progesterone benefits victims of acute traumatic brain injury,” says Wright.
Progesterone is naturally present in small but measurable amounts in the brains of males and females. Human brain tissue is loaded with progesterone receptors. Laboratory studies suggest that progesterone is critical for the normal development of neurons in the brain and exerts protective effects on damaged brain tissue.
Donald G. Stein, PhD, Asa G. Candler Professor of Emergency Medicine, Emory School of Medicine, and director of Emory’s Department of Emergency Medicine Brain Research Laboratory, pioneered discoveries regarding the effect of progesterone following traumatic brain injury – first discovering the neuro-protective properties of progesterone in the laboratory more than 25 years ago.
“The results that we are now seeing, and hope to continue validating, are an incredible and gratifying reward for more than 25 years of concentrated research,” says Stein. “My work first started when I began to notice evidence that women tended to respond to treatment and recover better than men after suffering from brain injury and stroke. Many people do not realize that it’s not just a female hormone; both men and women produce progesterone directly in the brain, as well as other tissue.
“Ultimately, we learned that progesterone basically does in brain injuries what it also does during fetal development – protect cells and tissue,” says Stein. “To now witness the translation of this laboratory research into a treatment that may have life-saving benefits is breathtaking.”
Exception from Informed Consent (EFIC)
As part of the trial, patients who are enrolled in the study may be provided the progesterone hormone without consent of family members or next-of-kin, in large part because success of the drug is highly dependent on being administered to the patient as quickly as possible after sustaining a brain injury.
According to Wright, researchers normally get permission (consent) before a person participates in a clinical study. If that person is unconscious, such as in a traumatic brain injury (TBI), they will be unable to consent for themselves. In these cases researchers will ask for permission from a person’s legal guardian (usually next of kin). However, since TBI must be treated quickly, there might not be enough time to locate and talk to someone about the study before the medication is started.
“In ProTECT III, a person might very well be enrolled in the study without a legal guardian’s or family member’s consent,” explains Wright. “The U.S. Food and Drug Administration (FDA) has, in fact, created a set of special rules, called “Exception from Informed Consent” (EFIC). These rules allow research studies in certain emergency situations to be conducted without consent.”
EFIC applies only when all of the following apply:
A. The person is in a life-threatening situation
B. Current treatments are unproven or unsatisfactory
C. The study might provide direct benefit to the person
D. It is not possible to obtain informed consent from: 1) the person because of his or her medical condition or 2) the person’s guardian because there is a very short amount of time required to treat the medical condition.
“No new treatment for severe TBI has been approved in over 30 years,” says Wright. “With such promising success in laboratory testing and in our previous clinical trial, we certainly hope to conclude that this national trial – along with standard medical trauma care – works better than standard medical care alone in reducing brain damage caused from a TBI. If progesterone helps brain injury patients get better, it will be a nothing short of incredible for patients who suffer such debilitating injuries in the future.”
Emory University has licensed technology for the use of progesterone in traumatic brain injury to Besins Healthcare SA. Wright and Stein are inventors of novel technology related to this research and under Emory policies are eligible to receive a portion of any royalties or fees from this technology that are received by Emory. Stein is also a consultant to BHR Pharma, LLC, the R&D affiliate of Besins. These relationships have been reviewed and managed by Emory University in compliance with its conflict of interest policies.