- Based on favorable results from phase 2 studies, two phase 3 trials were initiated to compare the neurosteroid progesterone to placebo in the treatment of traumatic brain injury (TBI).
- Neither study showed improvement over placebo, and the PROTECT III trial was halted early because of futility. Side-effect profiles were similar between progesterone and placebo groups in the studies.
- Researchers suggest that study protocols may have to be changed dramatically in the search for an effective treatment for TBI.
The attempt to identify a single effective treatment to improve outcomes for those who incur a traumatic brain injury (TBI) continues to frustrate researchers. Two recently published phase 3 trials failed to replicate results of earlier phase 2 studies that had shown a favorable response to the neurosteroid progesterone.
The annual cost of TBI nationally has been estimated at around $76.5 billion, and survivors of severe TBI usually need 5 to 10 years of intensive therapy and often must live with significant disability. No pharmacologic treatment has been shown to improve post-TBI outcomes. However, animal studies and two single-center clinical trials have fueled interest in progesterone for this indication, with the latter studies showing decreased mortality and improved functional outcomes compared with placebo.
Two phase 3 trials were initiated based on the phase 2 results. The Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (PROTECT III) trial examined the efficacy of early administration of progesterone for treatment of TBI ranging from severe to moderate. The Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (SYNAPSE) trial examined progesterone in a sample of only patients with severe TBI.
The PROTECT III trial, conducted at 49 trauma centers, enrolled adults with severe, moderate-to-severe, or moderate TBI who had a score of 4 to 12 on the Glasgow Coma Scale (GCS), which ranges from 3 to 15, with lower scores corresponding to a lower level of consciousness. Among the exclusion criteria were a determination that the injury was not survivable or that the patient had hypotension, spinal cord injury, active myocardial infarction, ischemic stroke, or several other major complicating comorbidities.
Progesterone or placebo was initiated within 4 hours after injury, with a 1-hour leading dose, 71 hours of maintenance infusion, and a 24-hour infusion taper. The leading dose was 14.3 mL, followed by 10 mL/hour for 71 hours and then a taper by 2.5 mL/hour every 8 hours. The primary outcome was functional recovery as measured by the Extended Glasgow Outcome Scale (GOS-E) at 6 months after randomization, with the criterion for functional recovery based on the severity of each patient’s initial injury.
The SYNAPSE trial enrolled patients with severe TBI only, with the requirement of a GCS score of 8 or lower. Exclusion criteria were similar to those used in the PROTECT III trial. Treatment was initiated within 8 hours after injury.
Dosing in the first hour was 0.71 mg/kg of body weight, followed by 0.50 mg/kg for 119 hours. The primary outcome was the Glasgow Outcome Scale (GOS) score 6 months after the initial injury.
A total of 882 patients were randomized in the PROTECT III trial, with 53.5% having a moderate-to-severe brain injury. After the second interim analysis took place, the trial was stopped because of futility; 51% of progesterone patients had achieved favorable outcomes, compared with 55.5% of placebo patients. The overall 6-month mortality rate was 17.2%, with no significant difference between the two patient groups. Progesterone had an acceptable safety profile in the study, although phlebitis and thrombophlebitis were more common in the progesterone group than in the placebo group.
A total of 1,195 patients were randomized in the SYNAPSE trial. There was no significant difference between treatment groups in the primary outcome of GOS score at 6 months. Favorable outcomes were achieved in 50.4% of progesterone patients and 50.5% of placebo patients. There were no significant differences in adverse events between the two patient groups.
The authors of the PROTECT III trial wrote, “The PROTECT III trial joins a growing list of negative or inconclusive trials in the arduous search for a treatment for TBI.” They cited several possible explanations that have been offered for this, including limited preclinical development work, delayed initiation of treatment, and heterogeneity of the brain injuries incurred by patients.
The authors of the SYNAPSE trial wrote, “TBI is a complex, heterogeneous disorder, in which the primary injury initiates a variety of secondary injury cascades. These cascades involve processes that may not be responsive to monotherapy.…”
Researchers in these two trials suggest that the search for an effective treatment for TBI may require new research paradigms, including adaptive clinical trial designs in early phases and rigorous preclinical trials in animals that better simulate human trials.
In an accompanying editorial to the two progesterone trials, Lee H. Schwamm, M.D., of the Department of Neurology, TeleStroke and Acute Stroke Services at Massachusetts General Hospital, wrote that the failed phase 3 results reflect deficiencies in the studies that preceded these trials. He stated that although the benefit seen in the phase 2 trials of progesterone was modest, investigators and funders were convinced enough to pursue phase 3 studies.
Schwamm suggested “a radical change in the culture of investigation and its funding,” including more rigorous reporting of preclinical data, as well as coordinated phase 2 trials that use standardized outcomes.
For the PROTECT III trial, lead author David W. Wright, M.D., reported receiving royalties from a patent related to progesterone for the treatment of TBI.
Skolnick BE, Maas AI, Narayan RK, et al. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med 2014; 371:2467–2476. E-mail: email@example.com.
Wright DW, Yeatts SD, Silbergleit R, et al. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med 2014; 371:2457–2466. E-mail: firstname.lastname@example.org.