The administration of progesterone immediately after acute traumatic brain injury (TBI) shows no benefit in improving functional outcomes, according to two large, highly anticipated phase 3 randomized clinical trials.
Many had hoped these trials would confirm benefits of a much-needed treatment for the devastating condition.
"[This] was a stunning disappointment," David W. Wright, MD, lead author of PROTECT III (Progesterone for the Traumatic Brain Injury, Experimental Clinical Treatment), one of the two studies, told Medscape Medical News.
"Over 200 positive published studies in multiple laboratories, two pilot clinical trials, prompted immense enthusiasm for this study to finally [offer a] breakthrough and provide a positive treatment for traumatic brain injury," said Dr Wright, associate professor, vice chair for research, and director of emergency neurosciences in the Department of Emergency Medicine at Emory University School of Medicine in Atlanta, Georgia.
The two new trials are published online December 10 in the New England Journal of Medicine.
In addition to previous research in animals showing the early administration of progesterone in reducing cerebral edema and behavioral deficits after TBI, two early-phase, single-center trials involving humans further showed decreased mortality and improved outcomes compared with placebo.
With no pharmacologic therapies currently available to improve functional outcomes with acute TBI despite more than 30 clinical trials on various compounds, enthusiasm has been high that the phase 3 trials would deliver positive results.
For the double-blind, multicenter PROTECT III trial, 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) and a mean age of 35 years were randomly assigned to intravenous progesterone or placebo, initiated within 4 hours after injury and administered for a total of 96 hours.
The study was halted after enrollment of 882 of the planned 1140 patients because of futility in achieving the primary outcome of an increase of 10 percentage points in the proportion of patients with a favorable outcome according to the Extended Glasgow Outcome Scale at 6 months after injury.
Among the 882 patients, the difference in favorable outcomes between the treatment and placebo groups was not statistically significant (P = .35).
Additionally, patients in the progesterone group showed increased rates of phlebitis or thrombophlebitis (relative risk, 3.03; confidence interval [CI], 1.96 - 4.66).
The results of the second multicenter trial, SYNAPSE (the Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury), were no better.
The study involved 1195 patients aged 16 to 70 years with a Glasgow Coma Scale score of 8 or less, who were also randomly assigned to progesterone or placebo, with dosing beginning 8 hours after injury and continuing for 120 hours.
As in PROTECT III, no improved treatment effect was seen in the progesterone-treated patients compared with the placebo recipients (odds ratio, 0.96; 95% CI, 0.77 - 1.18).
In the progesterone group, 50.4% had a favorable outcome of good recovery or moderate disability on the Glasgow Outcome Scale, nearly identical to the 50.5% in the placebo group.
Mortality rates did not significantly differ between the two groups.
"Primary and secondary efficacy analyses showed no clinical benefit of progesterone in patients with severe TBI," the authors concluded.
"These data stand in contrast to the robust preclinical data and results of early single-center trials that provided the impetus to initiate phase 3 trials."
Progesterone had shown promise in addressing the complex injury mechanisms associated with acute TBI, showing anti-inflammatory properties of inhibiting the production of inflammatory cytokines, and reducing levels of inflammation-related factors, such as complement factor C3 fragments and inhibiting the activation of microglial cells, the authors explained.
"In addition, progesterone has been shown to prevent excitotoxicity and limit apoptosis by preventing bio-chemical insults, such as calcium (Ca2+) flux and nitric oxide production, and by decreasing levels of caspase 3.
"Finally, progesterone has also been shown to limit vasogenic edema through reconstitution of the blood–brain barrier and modulation of the aquaporin-4 water transporter," they write.
The disappointing results of the two trials nevertheless underscore the unique challenges of identifying true potential benefits in human traumatic brain injury, even when early data are promising, Dr Wright said.
"It's hard to dismiss all of the preclinical data," he said. "There is strong evidence that progesterone is neuroprotective in animal models."
"However, the human condition is profoundly more complex than the 'homogeneous animal model, where everything is controlled, down to the breed and hair color of the rat."
"In animal studies, even the injury is identical — 2 mm contusion mid frontal cortex — but in humans, just about any combination of injury is typically included because we do not have a better way to pathophysiologically 'define' TBI."
The current standard of gauging TBI, the Glasgow Coma Score, serves an important purpose, he added, but it "has absolutely no inference to the underlying injury type."
The authors of both studies noted the broader implications of the negative results in terms of how research efforts are executed.
"Success at translating from bench to bedside may require new paradigms, including innovative clinical-trial methods (e.g., adaptive designs and profiling of patients who have a response) in early-phase clinical trials to identify effective drug doses and timing (e.g., prehospital administration), the use of targeted outcomes based on the mechanism of injury, and rigorous preclinical multicenter trials in animals that better simulate subsequent human trials and make more accurate predictions regarding results," Dr Wright and his colleagues write.
Comprehensive Strategy Review
In an editorial on the two trials, Lee H. Schwamm, MD, associate professor of neurology, Harvard Medical School, and director of TeleStroke & Acute Stroke Services at Massachusetts General Hospital in Boston, echoed the sentiment.
"Given the negative findings of the two phase 3 trials, the investigators appropriately call for a comprehensive review of the TBI translational research strategy," Dr Schwann writes.
"I would argue that the problem lies deeper and reflects a fundamental bias in the current practice of scientific inquiry."
He referred to the widely cited article "Why Most Published Research Findings Are False," which asserts that positive research findings often turn out to be false because of unrecognized biases and the risk for false-positive findings is increased when the effect size is small, for instance, or if there is substantial professional or financial investment for a certain outcome.
In the case of the progesterone studies, the benefits observed in the earlier phase 2 trials that spurred the larger trials were in fact modest, with even the placebo group expected to show a 50% improvement, meaning the odds of a relationship were low, Dr Schwamm writes.
"With favorable-outcome rates of more than 50% observed among the participants assigned to receive placebo, neither phase 3 trial had much opportunity to show benefit."
With the costs of such failed trials high, "a radical change in the culture of investigation and its funding," is necessary to break the cycle, he added, noting the importance of collaborative research networks such as those recently implemented by the National Institute of Neurological Disorders and Stroke and more rigorous reporting and pooling of preclinical data.
As a result, "[n]egative trial results, when they do occur, will contribute more to medical progress because they will have definitively answered a question that was worth asking in the first place," he concludes.
The PROTECT III trial was supported by grants from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health and the National Center for Advancing Translational Sciences of the National Institutes of Health and by the Emory Emergency Neurosciences Laboratory in the Department of Emergency Medicine, Emory School of Medicine, and Grady Memorial Hospital. Dr Wright reports receiving royalties from a patent related to progesterone for the treatment of traumatic brain injury (US patents 7,473,687, 7,915,244, and 8,455,468), which is licensed to BHR Pharma. The SYNAPSE trial was supported by BHR Pharma, a division of Besins Healthcare. Dr Schwamm has disclosed no relevant financial relationships.
N Engl J Med. Published online December 10, 2014. PROTECT III abstract SYNAPSE abstract Editorial
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Cite this: Progesterone Fails in Traumatic Brain Injury - Medscape - Dec 11, 2014.
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