Progesterone treatment does not decrease serum levels of biomarkers of glial and neuronal cell injury in moderate and severe TBI subjects: A secondary analysis of the Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (ProTECT) III trial.

Early treatment of moderate/severe traumatic brain injury (TBI) with progesterone does not improve clinical outcomes. This is in contrast with findings from preclinical 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), 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 hours post-injury and before administration of study drug), and at 24 and 48 hours post-injury. Serum progesterone levels were measured at 24 and 48 hours 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 hours 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 hours. When examined as a continuous variable, baseline biomarker levels did not modify the association between progesterone treatment and neurologic outcome (p of interaction term>0.39 for all biomarkers). We conclude that progesterone treatment does not decrease the levels of biomarkers of glial and neuronal cell death during the first 48 hours post-injury.