Recently, our team completed an NINDS-funded, Phase IIa double-blinded, placebo-controlled pilot clinical trial that examined the pharmacokinetics, safety, and activity of progesterone, a steroid found to have powerful neuroprotective effects in multiple animal models of brain injury. Our pilot study demonstrated a 50% reduction in death among severe TBI patients and less disability among moderate TBI patients treated with progesterone. Based on these promising results and supportive preclinical data, we are conducting a large, phase III clinical trial (ProTECT III) to definitively assess the safety and efficacy of this treatment for adults with moderate to severe acute TBI. The study is slated to begin August 2008.
WHY Progesterone: Although progresterone is widely considered a sex steroid, it is also a potent neurosteroid. Progesterone is naturally synthesized in the CNS. A large and growing body of animal studies indicate that early administration of progesterone after TBI reduces cerebral edema, neuronal loss, and behavioral deficits in laboratory animals. Certain properties of progesterone make it an ideal therapeutic candidate. First, in contrast to most drugs tested to date, progesterone rapidly enters the brain and reaches equilibrium with the plasma within an hour of administration. Second, unlike other experimental agents, progesterone has a long history of safe use in humans. Finally, the findings of our pilot clinical trial (presented in the Preliminary Data Section, below) indicate that progesterone has consistent and predictable pharmacokinetic properties, is unlikely to produce harm, and may be efficacious for treating acute TBI in humans.
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traumatic brain injury, progesterone, clinical trial, neuroprotection, one mind tbi
ProTECT III - Progesterone for Traumatic Brain Injury: Experimental Clinical Treatment: Phase III Clinical Trial
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Created 3 years ago by Anonymous
- Stein DG
- Dialogues Clin Neurosci
- 2011 28
Although progesterone is critical to a healthy pregnancy, it is now known to have other important functions as well. Recent research demonstrates that this hormone is also a potent neurosteroid that can protect damaged cells in the central and peripheral nervous systems and has rapid actions that go well beyond its effects on the classical intranuclear progesterone receptor. Based on years of preclinical research demonstrating its safety and effectiveness in animal models of central nervous system injury the hormone was recently tested in two Phase II clinical trials for traumatic brain injury (TBI). A US National Institutes of Health-sponsored, nationwide Phase III clinical trial is now evaluating progesterone for moderate-to-severe TBI in 1200 patients. An industry-sponsored Phase III international trial is also under way, and planning for a trial using progesterone to treat pediatric brain injury has begun. Preclinical data suggest that progesterone may also be effective in stroke and some neurodegenerative disorders.
- Wright DW
- Ann Emerg Med
- 2007 20
STUDY OBJECTIVE: Laboratory evidence indicates that progesterone has potent neuroprotective effects. We conducted a pilot clinical trial to assess the safety and potential benefit of administering progesterone to patients with acute traumatic brain injury. METHODS: This phase II, randomized, double-blind, placebo-controlled trial was conducted at an urban Level I trauma center. One hundred adult trauma patients who arrived within 11 hours of injury with a postresuscitation Glasgow Coma Scale score of 4 to 12 were enrolled with proxy consent. Subjects were randomized on a 4:1 basis to receive either intravenous progesterone or placebo. Blinded observers assessed patients daily for the occurrence of adverse events and signs of recovery. Neurologic outcome was assessed 30 days postinjury. The primary safety measures were differences in adverse event rates and 30-day mortality. The primary measure of benefit was the dichotomized Glasgow Outcome Scale-Extended 30 days postinjury. RESULTS: Seventy-seven patients received progesterone; 23 received placebo. The groups had similar demographic and clinical characteristics. Laboratory and physiologic characteristics were similar at enrollment and throughout treatment. No serious adverse events were attributed to progesterone. Adverse and serious adverse event rates were similar in both groups, except that patients randomized to progesterone had a lower 30-day mortality rate than controls (rate ratio 0.43; 95% confidence interval 0.18 to 0.99). Thirty days postinjury, the majority of severe traumatic brain injury survivors in both groups had relatively poor Glasgow Outcome Scale-Extended and Disability Rating Scale scores. However, moderate traumatic brain injury survivors who received progesterone were more likely to have a moderate to good outcome than those randomized to placebo. CONCLUSION: In this small study, progesterone caused no discernible harm and showed possible signs of benefit.