Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. [Clinical study on the therapeutic effects and mechanism of progesterone in the treatment for acute severe head injury].
Severe traumatic brain injury (TBI) has been increasing with greater incidence of injuries from traffic or sporting accidents. Although there are a number of animal models of TBI using progesterone for head injury, the effects of progesterone on neurologic outcome of acute TBI patients remain unclear. The aim of the present clinical study was to assess the longer-term efficacy of progesterone on the improvement in neurologic outcome of patients with acute severe TBI.
                A total of 159 patients who arrived within 8 hours of injury with a Glasgow Coma Score </= 8 were enrolled in the study. A prospective, randomized, placebo-controlled trial of progesterone was conducted in the Neurotrauma Center of our teaching hospital. The patients were randomized to receive either progesterone or placebo. The primary endpoint was the Glasgow Outcome Scale score 3 months after brain injury. Secondary efficacy endpoints included the modified Functional Independence Measure score and mortality. In a follow-up protocol at 6 months, the Glasgow Outcome Scale and the modified Functional Independence Measure scores were again determined.
                Of the 159 patients randomized, 82 received progesterone and 77 received placebo. The demographic characteristics, the mechanism of injury, and the time of treatment were compared for the two groups. After 3 months and 6 months of treatment, the dichotomized Glasgow Outcome Scale score analysis exhibited more favorable outcomes among the patients who were given progesterone compared with the control individuals (P = 0.034 and P = 0.048, respectively). The modified Functional Independence Measure scores in the progesterone group were higher than those in the placebo group at both 3-month and 6-month follow-up (P < 0.05 and P < 0.01). The mortality rate of the progesterone group was significantly lower than that of the placebo group at 6-month follow-up (P < 0.05). The mean intracranial pressure values 72 hours and 7 days after injury were lower in the progesterone group than in the placebo group, but there was no statistical significance between the two groups (P > 0.05). Instances of complications and adverse events associated with the administration of progesterone were not found.
                Our data suggest that acute severe TBI patients with administration of progesterone hold improved neurologic outcomes for up to 6 months. These results provide information important for further large and multicenter clinical trials on progesterone as a promising neuroprotective drug.
                ACTRN12607000545460. Laboratory evidence indicates that progesterone has potent neuroprotective effects. We conducted a pilot clinical trial to assess the safety and potential benefit of administering progesterone to patients with acute traumatic brain injury.
                This phase II, randomized, double-blind, placebo-controlled trial was conducted at an urban Level I trauma center. One hundred adult trauma patients who arrived within 11 hours of injury with a postresuscitation Glasgow Coma Scale score of 4 to 12 were enrolled with proxy consent. Subjects were randomized on a 4:1 basis to receive either intravenous progesterone or placebo. Blinded observers assessed patients daily for the occurrence of adverse events and signs of recovery. Neurologic outcome was assessed 30 days postinjury. The primary safety measures were differences in adverse event rates and 30-day mortality. The primary measure of benefit was the dichotomized Glasgow Outcome Scale-Extended 30 days postinjury.
                Seventy-seven patients received progesterone; 23 received placebo. The groups had similar demographic and clinical characteristics. Laboratory and physiologic characteristics were similar at enrollment and throughout treatment. No serious adverse events were attributed to progesterone. Adverse and serious adverse event rates were similar in both groups, except that patients randomized to progesterone had a lower 30-day mortality rate than controls (rate ratio 0.43; 95% confidence interval 0.18 to 0.99). Thirty days postinjury, the majority of severe traumatic brain injury survivors in both groups had relatively poor Glasgow Outcome Scale-Extended and Disability Rating Scale scores. However, moderate traumatic brain injury survivors who received progesterone were more likely to have a moderate to good outcome than those randomized to placebo.
                In this small study, progesterone caused no discernible harm and showed possible signs of benefit. To evaluate the therapeutic effects of Progesterone (PG) on the patients with acute severe traumatic brain injury, and investigate it's neuroprotective mechanisms.
                Fifth-six patients with acute severe traumatic head injury were divided randomly into two groups: 26 cases were treated with PG and 30 cases were control. Neurological outcome of the patients were assessed using Glasgow Coma Scale (GCS), Glasgow Outcome Scale (GOS), verbal and motor functions scale and Karnofsky Performance Scale (KPS). The serum concentrations of PG, TNF-alpha and 15-F(2t)-isoprostane were measured at day 1, 5 and 10 after trauma.
                In the two groups, There were no significant difference in the mortality, GCS of acute healing phase, GOS and verbal and motor functions at 10th days after treatment (P>0.05); After follow-up for 3 months, GOS, verbal functions and KPSin the PG treatment group were better than those in the control group (P<0.05); In addition, there was no difference of motor functions in the two groups (P>0.05). At 5th day after trauma, serum 15-F(2t)-isoprostane and TNF-alpha levels increased in the control group, but decreased at 10th day after trauma. Compared with the control group serum PG levels increased, serum 15-F(2t)-isoprostane and TNF-alpha levels reduced significantly in the PG treatment group at 5th and 10th day after injury (P<0.05).
                It indicated that successive early application of PG will benefit the patients with acute severe head injury by improving the recovery and reducing the disability, which may be related to its alleviating inflammatory and lipid peroxidation response.
Current clinical evidence from three small RCTs indicates progesterone may improve the neurologic outcome of patients suffering TBI. This evidence is still insufficient and further multicentre randomised controlled trials are required.