Progesterone Promising in Traumatic Brain Injury

Caroline Cassels

October 04, 2006

October 4, 2006 — Progesterone given soon after traumatic brain injury (TBI) is safe, appears to cut the risk of death by 50%, and reduces subsequent disability, a small pilot study suggests.

Funded by the National Institute of Neurological Disorders and Stroke, the 3-year, randomized, double-blind, placebo-controlled phase 2 trial, known as Progesterone for the Traumatic Brain Injury — Experimental Clinical Treatment (ProTECT), found at 30-day follow-up that intravenous (IV) progesterone administered over 3 days reduced the overall death rate by 50% compared with placebo. Furthermore, there was a significant improvement in the functional outcome and level of disability among patients with moderate brain injury.

"Determining the safety of progesterone was a primary outcome of this study, and it was shown to be safe with no adverse events. But perhaps the most exciting finding is that for the first time in 30 years we may actually have a drug that can improve patients' outcome after head injury. Currently there isn't a single agent that shows improvement in outcome for head injury patients," the study's lead author, David Wright, MD, from Emory University in Atlanta, Georgia, told Medscape.

The study is published in the October 2006 issue of the Annals of Emergency Medicine.

World-First

Progesterone has been used extensively in animal models of TBI, but this is the first time it has ever been used to treat TBI in humans, said Dr. Wright.

Based on the strength of the preclinical data, which demonstrated the hormone has the ability to reduce edema, prevent neuronal loss, and improve functional outcomes, the investigators decided to apply it in the clinical setting.

A total of 100 adult TBI patients presenting at an urban level 1 trauma center within 11 hours of injury were enrolled in the study. All subjects had a postresuscitation Glasgow Coma Scale (GCS) score of 4 to 12 and were enrolled with proxy consent. Average enrollment time was 5.9 hours after injury. Subjects were then randomized on a 4:1 basis to receive either IV progesterone or placebo.

A total of 77 patients received progesterone and 23 placebo. At 30 days postinjury, the death rate among the progesterone group was 13% compared with 30% among those on placebo.

Furthermore, there were no differences in the rate of adverse events among those who received progesterone vs placebo.

Stops damage before it starts

While the majority of patients with severe TBI in both placebo and progesterone groups had poor outcomes as measured by the Glasgow Outcomes Scale and the Disability Rating Scale, the study demonstrated that progesterone significantly improved functional outcome and level of disability among patients with moderate TBI.

"Since this was a safety study, we were delighted to see not only that progesterone is safe but that it may also be effective. Even though it was a small study, we were able to see a decrease in disability and an improvement in functional outcome both on the Disability Rating Scale and the Glasgow Outcome Scale, the classic TBI outcome measures. However, this is a small study, and therefore we need a bigger study to confirm these results," he said.

According to Dr. Wright, IV infusion of progesterone has never been used before in head injury and only twice before in other clinical areas. "We felt it was important to use this formulation to achieve steady blood levels as soon after injury as possible to coat the brain during this critical time."

Previously it was thought traumatic brain injury followed the stroke paradigm — that is, brain damage occurred and treatment was aimed at recovery. However, it is now known that the majority of TBI damage is sustained after the initial injury when the cytotoxic secondary cascade occurs and continues to damage the brain — in some cases up to a year after injury. Therefore, said Dr. Wright, successful therapy lies in finding an agent that can intervene and stop brain damage before it occurs.

Next Steps

Preclinical studies indicate progesterone may have the ability to interrupt this complex cycle at multiple levels by modulating excitotoxicity, reconstituting the blood-brain barrier, reducing cerebral edema, downregulating the inflammatory cytokine cascade, decreasing apoptosis, and enhancing recovery from cortical, cerebral, and spinal cord injury.

Dr. Wright and his team are currently planning a large, multicenter, phase 3 clinical trial of 1000 patients to test progesterone's efficacy. They also hope to study the effects of progesterone in animal models of blast-related injury, a major cause of disability among soldiers involved in the current Iraq and Afghanistan conflicts.

In addition, he said, eventually his team plans to look at the potential effect of progesterone in pediatric TBI, which is currently the leading cause of death due to injury among US children.

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