Very early administration of progesterone for acute traumatic brain injury

Abstract

Background: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI.

Methods: We conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score.

Results: A total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes.

Conclusions: This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900.).

Figure 1. Distribution of Extended Glasgow Outcome Scale (GOS-E) Scores, Stratified According to Initial Injury Severity

The GOS-E is an ordinal scale on which each increment represents a better quality of recovery. A GOS-E score of 1 indicates death, 2 a vegetative state, 3 or 4 severe disability, 5 or 6 moderate disability, and 7 or 8 good recovery. Each cell corresponds to a score on the GOS-E; the width of the cell indicates the proportion of patients with equivalent scores, and the number and percentage of patients are shown within the cell. The diagonal line between the two study groups indicates the favorable-outcome dichotomization in each severity stratum.

Figure 2. Adjusted Relative Benefit in Predefined Subgroups, as Assessed According to the Stratified Dichotomy of the GOS-E Score

Models were adjusted for initial injury severity, sex, and age, as specified for the primary analysis. The significance of the interaction effect between study assignment and the corresponding subgroup is provided. Other prespecified subgroups that were considered according to the statistical analysis plan were based on the Rotterdam computed tomographic classification, score on the Injury Severity Scale, score on the Abbreviated Injury Scale head-injury component, time from injury to infusion, pupillary response, and medical histories (neurologic, cardiovascular, pulmonary, gastrointestinal, metabolic, renal, reproductive, psychiatric, social, hematologic, oncologic, and related to the eyes, ears, nose, and throat). The statistical analysis plan limited the reporting of these additional subgroups to those with both clinical and statistical significance.