AUTHOR
Halinder S. Mangat, MD, Assistant Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Mangat reports no financial relationships relevant to this field of study.
EDITOR IN CHIEF
Matthew E. Fink, MD, Professor and Chairman, Department of Neurology, Weill Cornell Medical College, Neurologist-in-Chief, New York-Presbyterian Hospital
PEER REVIEWER
M. Flint Beal, MD, Anne Parrish Titzel Professor, Department of Neurology and Neuroscience, Weill Cornell Medical Center
Administration of progesterone after acute traumatic brain injury does not improve neurological outcome nor reduce mortality.
Wright DW, et al. Very early administration of progesterone for acute traumatic brain injury (ProTECT III trial). N Engl J Med 2014;371:2457-2466.
Skolnick BE, et al. A clinical trial of progesterone for severe traumatic brain injury (SYNAPSE trial). N Engl J Med 2014;371:2467-2476.
The ProTECT trial studied the benefit of parenteral progesterone administered within 4 hours after moderate or severe non-penetrating traumatic brain injury (TBI).1 In the study, 882 patients were randomized 1:1. The two groups were similar in demographics, cause, and severity of injury. Progesterone was administered as a continuous infusion over 96 hours. Based on severity of injury, mortality and functional outcome (measured by GOS-E) were similar in the two groups. Incidence of thrombophlebitis was slightly higher in the group receiving progesterone; this was the most commonly observed adverse effect.
The SYNAPSE trial enrolled only patients with severe non-penetrating TBI.2 Progesterone was administered within 8 hours, and the infusion continued for 120 hours. In this trial, 1195 patients were randomized. GOS (and GOS-E) outcomes and mortality were similar in the two groups. Dose of progesterone was identical in the two trials and was weight-based.
Commentary
TBI remains a major global health problem, exacting a huge social and economic price. However, in spite of significant advances in the management of severe TBI, there is no pharmacological agent that has been shown to treat the deleterious effects of TBI and improve outcome. The Brain Trauma Foundation has developed guidelines for the management of severe TBI.1 The main tenets of the guidelines are reduction of intracranial pressure and ensuring adequate cerebral perfusion while avoiding hypoxia and hypotension. There is scant Level I evidence supporting the various interventions even though several randomized clinical trials have been conducted to evaluate a variety of therapies, including steroids and hypothermia.
Progesterone has been shown to have a multitude of neurotrophic effects while limiting toxic neuronal injury by blocking excitotoxic pathways. Importantly, Phase 2 trials showed significant reduction in mortality as well as improvement in functional outcome in patients who received progesterone after suffering a TBI.
Both the trials were based on the Phase 2 PROTECT data for dosing and duration of treatment.2 Supporting data were also available from another single-center trial.3 While patients were treated within 4 hours in the PROTECT trial, patients in the SYNAPSE trial were treated within 8 hours. Yet, the outcomes were similar in the two trials and comparable to placebo therapy. No benefit was seen with progesterone therapy.
While pilot data seemed to suggest benefit, the size of the ProTECT Phase 2 trial was small, enrolling a total of 50 patients. The statistical significance of the mortality benefit was not very robust, while patients with moderate injury had improved functional outcome. Meanwhile, the trial by Xiao et al enrolled 159 patients and demonstrated improved functional outcome. However, the differences in the mortality and GOS at 3 and 6 months were marginal, while the differences in Functional Independence Measure (FIM) scores were more pronounced at 6 months. The targeted 50% favorable outcome in the current trials appears over-reaching based on these data. In addition, the mortality in the pilot trial placebo group patients was significantly higher than that in the current trials, as well as mortality documented from retrospective cohort studies.4 This may also partly explain the loss of the earlier-observed marginal mortality benefit. Many of the beneficial mechanisms of progesterone were studied in rodents and extrapolated to benefit humans also. No data in large animals were available. We have learned from past failed trials that rodent data do not translate to benefit in human trials.
Many of the above-cited points are also emphasized in the editorial accompanying the articles.5 Failed Phase 3 trials must make us look very closely at pilot data. The editorial cites unrecognized bias and modest benefit in pilot data. Whether this is due to single-center data or increasing need for a therapy to improve outcome after TBI, it needs to be minimized.
In summary, these trials demonstrate the failure of progesterone to provide benefit in improving outcome after TBI. Nevertheless, we must learn that to avoid failure in future trials, robust pilot trials must be undertaken, demonstrate significant benefit, and perhaps be preceded by preclinical data from large animals. We must avoid letting our enthusiasm cloud our judgments and observations.
References
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Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS. Bratton SL, et al. Guidelines for the management of severe traumatic brain injury. VI. Indications for intracranial pressure monitoring. J Neurotrauma 2007;24(Suppl 1):S37-44.
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Wright DW, et al. ProTECT: A randomized clinical trial of progesterone for patients with acute severe traumatic brain injury. Ann Emerg Med 2007;49:391-402.
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Xiao G, et al. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: A randomized clinical trial. Crit Care 2008;12:R61.
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Gerber LM, et al. Marked reduction in mortality in patients with severe traumatic brain injury. J Neurosurg 2013;119:1583-1590.
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Schwamm LH. Progesterone for traumatic brain injury — Resisting the sirens’ song. N Engl J Med 2014;371:2522-2523.
