More than 2.4 million emergency department visits, hospitalizations or deaths are related to traumatic brain injury (TBI) annually in the United States. Previous clinical studies of progesterone in laboratory animals indicated that the early administration of progesterone after experimental TBI can reduce cerebral edema, neuronal loss and behavioral deficits. This study was designed to determine the efficacy of the early administration of progesterone for the treatment of severe, moderate to severe or moderate TBI.

The Progesterone for Traumatic Brain Injury Experimental Clinical Treatment (PROTECT III) trial is a phase 3, randomized, double-blind, placebo-controlled, clinical trial including adults presenting to the emergency room with a TBI and with a Glasgow Coma Scale score of four to twelve upon admission. The study drug was infused continuously for a total treatment duration of 96 hours. The primary outcome measure was functional recovery, as determined by the extended Glasgow Outcome Scale at six months. Secondary outcome measures included mortality, the Disability Rating Scale score, and rates of pre-specified, adverse events.

Of the 17, 681 persons screened, 8, 082 patients underwent randomization. Of the patients included, 53.5% had moderate to severe injury. For the primary hypothesis, favorable outcomes occurred in 51% of the treatment group and 55.5% of the placebo group. The six-month mortality rate did not differ significantly between the treatment group and the placebo group. Phlebitis or thrombophlebitis was significantly more frequent in the treatment group than in the placebo group (relative risk=3.03).

This large, multicentered, clinical trial failed to demonstrate that progesterone improves the clinical outcome of patients with acute traumatic brain injury.