Why Did the Phase III Clinical Trials for Progesterone in TBI Fail? An Analysis of Three Potentially Critical Factors

Introduction: Progesterone Treatment Showed Promise in Preclinical Research

Although in many animal models of CNS injury, acute-stage treatment with progesterone demonstrated multifactorial benefits in the repair of the damaged brain, the Phase III translation to effective clinical outcome was disappointing. Over 300 preclinical studies listed on PubMed in both male and female subjects demonstrate that, given within the first few days after a traumatic brain injury (TBI), progesterone can modulate the expression of inflammatory cytokines, reduce levels of glutamate toxicity, attenuate both vasogenic and intracellular cerebral edema, prevent apoptosis and necrosis, restore the functions of the blood–brain barrier, and improve functional outcomes on sensory, cognitive, and motor behaviors. At the cellular level, giving progesterone early in the injury cascade can stimulate glial cells to increase myelin formation and restore metabolic function through its effects on the mitochondrial transition pore, and modify calcium channel activity to stabilize cellular metabolism, reducing the cytochemical cascade that can lead to further cell death in the days, weeks, and months after injury.

Progesterone is also known to have growth-promoting properties in the central nervous system. In preclinical experiments, it stimulates the expression and release of neurotrophic factors such as brain-derived neurotrophic factor, nerve growth factor, and insulin-like growth factor, which repair the damaged brain by stimulating neurogenesis, protecting against axonal degeneration, and enhancing synaptogenesis. Many genes involved in the expression of trophic factors and the inhibition of inflammatory cytokines can be regulated by progesterone, because it works through multiple receptor mechanisms throughout the brain. In laboratory experiments, progesterone and its metabolites consistently produce these beneficial effects in the brain and spinal cord after traumatic contusion injuries, nerve crush injuries, diffuse axonal injury, stroke, hemorrhage, cytotoxic injury, and even in degenerative neuropathologies. For a more detailed understanding of how progesterone and its metabolites modulate the cascade of mechanisms leading to both neuronal loss and repair over the course of brain insult, see , and .

Despite a few reports in the preclinical literature showing no benefits of progesterone treatment ( ), with no known toxic effects and so much experimental data supporting its neuroprotective properties, why did this well-known and well-established drug show no translational promise in Phase III clinical trials?