Despite promising results in preclinical data and single-center trials, a multinational Phase III trial of progesterone administered to patients with traumatic brain injury showed no clinical benefit, according to a research published Dec. 10 in The New England Journal of Medicine.
Despite promising results in preclinical data and single-center trials, a multinational Phase III trial of progesterone administered to patients with severe acute traumatic brain injury showed no clinical benefit, according to a research published Dec. 10 in The New England Journal of Medicine.
Brett Skolnick PhD of NorthShore LIJ Health System in Manhasset, NY and colleagues report that in the trial 1195 patients with severe TBI got the treatment or placebo within 8 hours after they were injured and that the dosing continued for 120 hours.
The endpoint of the trial, known as SyNAPSe was an assessment of patients with the Glasgow Coma Scale.
But the disappointing result was that the proportion of patients with a favorable outcome was the same in both the treatment and placebo groups.
Mortality rates were similar in the two groups (109 deaths in the group getting progesterone and 95 getting the placebo) and no relevant safety issues were noted between the two groups.
The researchers note that the hypothesis that progesterone might work made sense. “Progesterone has been shown to have broad neuroprotective properties in multiple animal species an in a variety of models of neurologic injury,” the team wrote.
“A total of 20 research groups working with 4 species and 22 different models have found neuroprotective effects of progesterone in more than 180 experimental pharmacologic studies,” they said.
Attempting to account for the negative results, the authors said that in TBI “the primary injury initiates a variety of secondary injury cascades [involving] various processes that many not be responsive to monotherapy.”
“These complex injury mechanisms suggest that a successful therapeutic agent should influence several mechanisms rather than a single cascade,” the researchers said.
“The negative results of this trial should stimulate a rethinking of procedures for drug development and testing in TBI. The study was funded by BHR Pharma
In an accompanying editorial, Lee Schwamm, MD wrote that the trial showed the perils of relying on animal studies and single-site trials.
“As a neuroscience community, we must emulate Homer’s crew of the Odyssey by plugging our ears with beeswax and steeling ourselves against the temptations of the Sirens’ song if we wish to navigate past the obstacles in our path, emerge victorious, and proceed onward to new adventures, Schwamnn wrote.