A clinical trial of progesterone for severe traumatic brain injury.

BACKGROUND: Progesterone has been associated with robust positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 randomized, controlled trials. We investigated the efficacy and safety of progesterone in a large, prospective, phase 3 randomized clinical trial. METHODS: We conducted a multinational placebo-controlled trial, in which 1195 patients, 16 to 70 years of age, with severe TBI (Glasgow Coma Scale score, ≤8 [on a scale of 3 to 15, with lower scores indicating a reduced level of consciousness] and at least one reactive pupil) were randomly assigned to receive progesterone or placebo. Dosing began within 8 hours after injury and continued for 120 hours. The primary efficacy end point was the Glasgow Outcome Scale score at 6 months after the injury. RESULTS: Proportional-odds analysis with covariate adjustment showed no treatment effect of progesterone as compared with placebo (odds ratio, 0.96; confidence interval, 0.77 to 1.18). The proportion of patients with a favorable outcome on the Glasgow Outcome Scale (good recovery or moderate disability) was 50.4% with progesterone, as compared with 50.5% with placebo. Mortality was similar in the two groups. No relevant safety differences were noted between progesterone and placebo. CONCLUSIONS: Primary and secondary efficacy analyses showed no clinical benefit of progesterone in patients with severe TBI. These data stand in contrast to the robust preclinical data and results of early single-center trials that provided the impetus to initiate phase 3 trials. (Funded by BHR Pharma; SYNAPSE ClinicalTrials.gov number, NCT01143064.).

Found in translation: The rationale behind the early development of glibenclamide in large hemispheric infarction.

Many reasons have been put forth to explain the inability to translate neuroprotection in animal stroke models to humans. Following our determination that glibenclamide is an anti-edema drug, not a neuroprotective drug, and the revelation that the "gold standard" middle cerebral artery occlusion used for animal studies models large hemispheric infarction, a subpopulation of ischemic stroke that develops clinically relevant edema that contributes significantly to poor outcomes, we designed an innovative approach to studying the drug in patients with large hemispheric infarction. The approach included careful selection of the relevant patient population, which gave us a high degree of confidence to move forward into humans. Initial human studies showed drug effects consistent with the animal studies. The considerations leading to the development plan are described.