By Dana Sand 14C
Thirty years ago, Don Stein came across some clinical reports that appeared to show that women recover better from stroke and trauma than men.
Stein had been pursuing a better treatment for traumatic brain injury (TBI) since witnessing its devastating consequences while interning at VA Medical Center near the University of Oregon with psychiatric and brain-injured patients during his first year of graduate school.
Intrigued by the reports, Stein decided to study this phenomenon in rats. Sure enough, he found that female rats recovered better from severe brain injury than their male counterparts.
“It turns out that where the female rat was in her estracycle determined the outcome, so we could measure progesterone and estrogen levels,” says Stein, Asa Griggs Candler Professor of Emergency Medicine at the Emory University School of Medicine and director of the department’s Brain Research Laboratory. “What we found, much to our surprise, was that when the female was high in progesterone at the time of her injury, the outcome was much better than with the same injury when she was high in estrogen.”
The brains of these animals showed much less swelling and damage, so Stein took it a step further. With positive results from administering progesterone to male rats, Stein knew that his findings had the potential to transform dramatically how brain injuries are treated. Rather than the standard treatments postdamage, progesterone offered a much better prognosis by changing the way patients’ brains react to trauma. Stein continued his research and sought clinicians to begin human trials.
“There are probably more than 200 publications from all around the world showing beneficial effects of progesterone in about 20 different kinds of injury models and four species, including people,” Stein says. “This kind of international . . . corroboration of your work is very important to a scientist. It says that other people have been able to apply what we’ve learned in our laboratory and try the use of progesterone in different types of central-nervous-system injuries and have found it quite successful.”
This work moved from the laboratory—although a good portion of it still goes on in the lab—to a 100-subject Phase II clinical trial that the NIH awarded the research team in 2001. This initial safety study, on which clinical researcher David Wright collaborated, found a 50-percent reduction in mortality in the treated group. Now the researchers have moved to a Phase III clinical trial, the ProTECT III study led by Wright, using progesterone to treat TBI in humans.
According to Wright, associate professor of emergency medicine and director of emergency neurosciences at Emory’s School of Medicine, the epicenter of the current double-blind study is at Grady Memorial Hospital in Atlanta, with about 40 other Level 1 trauma sites enrolling a total of 1,140 patients throughout the US.
More than 70 percent of these patients have blunt head injuries due to vehicular accidents. Because of the potential severity of the injuries, the Food and Drug Administration (FDA) granted Wright and the other clinicians an exception to enrolled consent. With only four hours postinjury to administer progesterone, the time window is small. According to Wright, after a patient is enrolled, they are given an intravenous (IV) fusion for four days; a one-hour bolus, or increased dosage of the drug; three days of steady infusion; and, finally, an eight-hour taper of the treatment. Each patient is followed to see his or her outcome six months after treatment.
“P1 is the research we’re doing now, which is a clinical trial to prove that a drug that works in animals works in humans. That’s quite a task because so far there’s been no drug that’s ever worked for TBI despite hundreds of clinical compounds and trials,” Wright explains. “There’s also P2, which is convincing people to change their practice. It’s likely to be so incredibly safe that it will be quickly adopted by clinicians.”
The study, which began in 2009, is a little over halfway to completion. With no signs of any serious side effects and positive results during the first interim analysis by an independent data safety monitoring board, Stein and Wright are optimistic. If the study continues on this path, progesterone will become a standard of practice treatment for TBI in the near future.
The ProTECT III study, aside from leading to a potential new treatment, is revolutionizing the way researchers look at progesterone and TBI worldwide.
“There have been many different trials for components of traumatic brain injury. There are trials to look at depression, epilepsy, growth, and many factors,” Stein says. “But in terms of neuroprotective trials—trials that actually try to shut down the injury and repair the damaged brain pharmacologically—there haven’t been that many.”
The international outreach for ProTECT III has attracted postdocs and graduate students who are interested in brain injury and stroke from around the world, including China, India, Israel, and Italy.
“I think this work would have gone far more slowly had it not been for the very extensive numbers of foreign or international postdocs who have come here, and certainly moving the understanding of how progesterone works at the mechanistic level would have never happened without this close collaboration,” Stein says.
One of these collaborators is Rachida Guennoun, a senior researcher at the French Institute for Health and Medical Research. Guennoun studies the neuroprotective effects and mechanisms of actions of progesterone and has worked with Stein on six publications and counting. Stein visits her lab in Paris annually, and Guennoun came to Emory in 2003. Guennoun says their collaboration has shown that progesterone has significant neuroprotective qualities, and its effects may be mediated by biological mechanisms.
Emory's work on progesterone also has attracted the interest of BHR Pharma, a French-Belgian pharmaceutical company that produces the majority of the world’s natural progesterone.
“They approached us, and to disclose this, after much discussion and negotiation, they licensed our technologies and continue to work with us to move progesterone forward as a potential treatment,” Stein says. “In order to do this, they are funding another separate Phase III clinical trial that is in 21 countries around the globe.”
With the license from Emory to access all prior data from Stein, Wright, and the NIH, the company developed a formulation of the drug in a stable oil and water mixture that can sit on the shelf for three years. BHR Pharma began its SyNAPSe trial in 2010 and has enrolled more than 800 of its expected 1,200 patients thus far. If the study is successful, the FDA has agreed to register the new drug immediately, meaning it could be available for hospital use next year.
“The goal is not just to get the FDA to approve this, but to get it approved everywhere around the world,” says Thomas MacAllister, president and chief executive officer of BHR Pharma. “Severe brain injury is certainly a problem in the Western world, but if you can think about countries like India and China that are still rapidly developing and don’t have the seatbelt laws, for example, you can just imagine it’s essentially an epidemic.”
MacAllister also emphasizes the benefit this drug has based on the targeted age group. While the studies have no upper age limit for patients, 50 to 60 percent of those enrolled are under the age of 35.
“These are people that are getting half of their lives back. They have another 35, 40, 50 years potentially of productive and high-quality living,” MacAllister says. “There is nothing out there in modern medicine that can compare to this in terms of its societal impact.”
As the TBI work goes forward, BHR Pharma and Emory plan to address several populations that are not yet being reached by the current IV progesterone treatment. In an offshoot of the current study, BHR Pharma is developing a nasal spray to address the majority of brain-injured patients who do not suffer from severe TBI. This version of the drug could reach people with military and sports-related injuries using similar mechanisms, and the company will begin trials next year.
Iqbal Sayeed, lab director of the Brain Research Lab and assistant professor at the Department of Emergency Medicine at Emory, says he is collaborating with the Emory Institute of Drug Development to develop a “novel, water-soluble form (pro-drug) of progesterone which can be stored and transported as a powder or liquid and administered immediately to stroke and TBI patients in emergency field conditions.”
With the advancement of progesterone trials, other Emory researchers are developing studies with colleagues, both domestic and abroad, for progesterone in the treatment of stroke as well as a 22-center trial for children with severe TBI. With an award from the National Institute of Neurological Disorders and Stroke Cooperative Program in Translational Research, designed to meet FDA requirements for an investigational new drug application to test progesterone in human stroke, and a planning grant partnered with the Pediatric Trials Network funded by the National Institute of Child Health and Human Development, respectively, these two studies are set to begin later this year.
Dana Sand 14C is an Emory College student co-majoring in journalism and anthropology and an editorial intern for the Office of International Affairs.