Progesterone Treatment Does Not Decrease Serum Levels of Biomarkers of Glial and Neuronal Cell Injury in Moderate and Severe Traumatic Brain Injury Subjects: A Secondary Analysis of the Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (ProTECT) III Trial

Abstract

Early treatment of moderate/severe traumatic brain injury (TBI) with progesterone does not improve clinical outcomes. This is in contrast with findings from pre-clinical studies of progesterone in TBI. To understand the reasons for the negative clinical trial, we investigated whether progesterone treatment has the desired biological effect of decreasing brain cell death. We quantified brain cell death using serum levels of biomarkers of glial and neuronal cell death (glial fibrillary acidic protein [GFAP], ubiquitin carboxy-terminal hydrolase-L1 [UCH-L1], S100 calcium-binding protein B [S100B], and Alpha II Spectrin Breakdown Product 150 [SBDP]) in the Biomarkers of Injury and Outcome-Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (BIO-ProTECT) study. Serum levels of GFAP, UCHL1, S100B, and SBDP were measured at baseline (≤4 h post-injury and before administration of study drug) and at 24 and 48 h post-injury. Serum progesterone levels were measured at 24 and 48 h post-injury. The primary outcome of ProTECT was based on the Glasgow Outcome Scale-Extended assessed at 6 months post-randomization. We found that at baseline, there were no differences in biomarker levels between subjects randomized to progesterone treatment and those randomized to placebo (p > 0.10). Similarly, at 24 and 48 h post-injury, there were no differences in biomarker levels in the progesterone versus placebo groups (p > 0.15). There was no statistically significant correlation between serum progesterone concentrations and biomarker values obtained at 24 and 48 h. When examined as a continuous variable, baseline biomarker levels did not modify the association between progesterone treatment and neurological outcome (p of interaction term >0.39 for all biomarkers). We conclude that progesterone treatment does not decrease levels of biomarkers of glial and neuronal cell death during the first 48 h post-injury.

Keywords: adult brain injury; biomarkers; head trauma; traumatic brain injury.

FIG. 1.

Temporal changes in biomarker levels in subjects randomized to progesterone treatment versus placebo. This is a graphical display of biomarker levels in the progesterone versus placebo arms during the first 48 hours post-injury. The gray line represents smoothed conditional means for each plot. GFAP, glial fibrillary acidic protein; S100B, S100 calcium-binding protein B; SBDP150, Alpha II Spectrin Breakdown Product 150; UCH-L1, ubiquitin carboxy-terminal hydrolase-L1.

FIG. 2.

Changes in biomarker levels during the first 48 h after injury. Twenty-four hour GFAP values were slightly higher than baseline (0-4 hours after injury) values, however 48 hour values were lower than baseline and 24 hour values. In contrast, UCH-L1, S100B, and SBDP values were highest at baseline and were progressively lower at 24 and 48 hours. GFAP, glial fibrillary acidic protein; S100B, S100 calcium-binding protein B; SBDP150, Alpha II Spectrin Breakdown Product 150; UCH-L1, ubiquitin carboxy-terminal hydrolase-L1.

FIG. 3.

Correlation between steady-state progesterone and biomarker level. The correlation between steady state progesterone concentrations and biomarker values obtained at 24 and 48 hours in progesterone arm were not statistically significant. GFAP, glial fibrillary acidic protein; S100B, S100 calcium-binding protein B; SBDP150, Alpha II Spectrin Breakdown Product 150; UCH-L1, ubiquitin carboxy-terminal hydrolase.