Two new studies published by the New England Journal of Medicine show that progesterone has little-to-no clinical benefit when administered to patients after severe traumatic brain injury, contradicting the findings of several previous studies that were optimistic about the drug’s efficacy in treating this particular progressive disorder ( doi:10.1056/NEJMoal1411090 and doi:10.1056/NEJMoa1404304 ).

“Progesterone has been shown to have broad neuroprotective properties in multiple animal species and in a variety of models of neurologic injury,” said Dr. Brett E. Skolnick of North Shore University Hospital, Manhasset, N.Y., who led the analysis of the Severe Traumatic Brain Injury (SYNAPSE) trial.

“A total of 20 research groups working with four species and 22 different models have found neuroprotective effects of progesterone in more than 180 experimental pharmacologic studies [and] two phase II randomized, controlled clinical trials with progesterone showed a clinical benefit,” he said.

For SYNAPSE – a multinational, placebo-controlled, prospective, randomized phase III clinical trial – investigators looked at 10,519 male and female patients, aged 16-70 years, admitted to level 1 or equivalent centers in 21 countries around the world. All individuals had nonpenetrating traumatic brain injury (TBI), Glasgow Coma Scale (GCS) scores of 8 or less, a Marshall classification score of II or higher, at least one reactive pupil, body weight of 99-298 pounds, and clinical indication for monitoring intracranial pressure. All subjects also underwent treatment within 8 hours of injury, and dosing continued for 120 hours.

Recruitment lasted from July 2010 to September 2013, with the final 6-month follow-up occurring in March 2014. Of the subjects who were randomized and went through full treatment and procedure, 591 received intravenous administration of progesterone, and 588 received a placebo. The primary outcome measure was GOS score at 6 months after initial injury, and secondary outcome measure was defined as GOS score at 3 months, mortality at 1 month and 6 months, and the GOS-E (Extended GOS) score.

Between the progesterone and placebo cohorts, there was no significant difference in the primary outcome: 189 subjects (32%) vs. 1,883 (31.1%) were in “good recovery,” 109 (18.4%) vs. 114 (19.4%) had “moderate disability,” 162 (27.4%) vs. 160 (27.2%) had “severe disability,” and 131 (22.2%) vs. 131 (22.3%) were in a “dead or vegetative state” 6 months after injury, respectively. Both adjusted and unadjusted data showed statistical insignificance (adjusted OR, 0.96).

Furthermore, mortality rates between both groups were similar, and the difference in proportion of subjects who received favorable GOS – with “good recovery” or “moderate disability,” as defined by the investigators – between the progesterone and placebo cohorts was negligible: 50.4% for progesterone vs. 50.5% for placebo.

“TBI is a complex, heterogeneous disorder, in which the primary injury initiates a variety of secondary injury cascades,” the authors noted. “These cascades involve various processes that may not be responsive to monotherapy [and] suggest that a successful therapeutic agent should influence rather than a single cascade. On the basis of the experimental data, progesterone would appear to be an appropriate candidate for this pluripotential role.”

The second study, “Progesterone for Traumatic Brain Injury: Experimental Clinical Treatment” (PROTECT III), was a double-blind, multicenter clinical trial with 882 patients randomized into cohorts receiving either progesterone or a placebo.

Subjects were randomized from April 2010 to October 2013, and were included on the basis of adults who had either severe, moderate to severe, or moderate TBI caused by a blunt mechanism, and a GOS of 4-12. Subjects were enrolled if they could begin treatment within 4 hours of initial injury. The median age of the patients was 35 years; 73.7% of subjects were men, 15.2% were black, and the mean Injury Severity Score was 24.4 on a scale of 0-75, with higher scores indicating greater severity of symptoms. The most common cause of TBI in subjects was motor vehicle accident.

Primary outcome measure was defined as the GOS-E score at 6 months after injury (1 = death, 2 = vegetative state, 3 or 4 = severe disability, 5 or 6 = moderate disability, and 7 or 8 = good recovery), while secondary outcomes measure “included mortality, the Disability Rating Scale score, the rates of nine prespecified adverse events that were considered to be potentially associated with treatment, and the rates of all reported adverse events and serious adverse events.” Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome at 6 months after injury.

The progesterone cohort comprised 442 subjects, while the remaining 440 received placebos. Investigators found that 213 (48.2%) of the progesterone subjects had favorable outcomes at 6 months after injury, and 232 (52.7%) were favorable in the placebo group; therefore, a total of 445 patients (50.5% of total population) had optimal response to treatment, and no significant difference between the two treatment options.

“Despite extensive preclinical data and two promising single-center trials, progesterone was not associated with any benefit over placebo, as measured by the GOS-E score at 6 months, in this large, multicenter clinical trial,” wrote lead author Dr. David W. Wright of Emory University, Atlanta, and his associates.

“The PROTECT III trial joins a growing list of negative or inconclusive trials in the arduous search for a treatment for TBI. To date, no treatment has succeeded at the confirmatory trial stage,” the researchers noted.

The SYNAPSE trial was funded by BHR Pharma, a division of Besins Healthcare. PROTECT III was funded by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke and the National Center for Advancing Translational Sciences; the Emory Emergency Neurosciences Laboratory at Emory University, Atlanta; and Grady Memorial Hospital, Atlanta. Several coauthors for each study had their own disclosures, as well.


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