Clinical Trials of Progesterone for Adult TBI
To date, two human trials of progesterone for TBI in adults have been published.[89,90] A phase II trial was conducted by Wright et al in 2007 to gather data on drug safety and to determine the pharmacokinetics of IV progesterone in moderate-to-severely injured adult patients (age > 17 yr; Glasgow Coma Scale [GCS] scores, 4–12). One hundred patients were randomly assigned to receive either a 72-hour IV infusion of progesterone (0.71 mg/kg over 1 hr and then 0.5 mg/kg/hr given by infusion for 12 hr/d for 3 d, with a 2-day taper) or an equal volume of placebo. No serious adverse events were attributed to the study drug. Patients treated with progesterone had mortality rates less than one half of controls and had nearly identical rates of adverse events compared with controls. Moderately brain-injured patients treated with progesterone were less disabled 30 days after injury than similarly injured patients treated with placebo (p = 0.02). These findings suggested that IV progesterone is safe at the dose selected.
Another recent phase II trial demonstrated the potential of progesterone to treat brain-injured adults. This was a single-site, prospective, randomized, placebo-controlled trial of progesterone conducted in Hangzhou, China, by Xiao et al. The primary purpose of this trial was to assess the long-term efficacy of progesterone on neurologic outcome of patients with severe TBI (GCS ≤ 8). A total of 159 patients were enrolled and randomized to receive either intramuscular progesterone (1 mg/kg intramuscular Q12 for 5 d) or placebo. The primary endpoint was the GOS score 3 months after brain injury. Secondary efficacy endpoints included the modified Functional Independence Measure (FIM) score and mortality. Three months after treatment, the dichotomized GOS showed a favorable outcome for 47% of the patients given progesterone and 31% in the placebo group (p = 0.034) and an unfavorable outcome for 53% of the patients given progesterone and 70% in the placebo group (p = 0.022), with similar outcomes at 6 months. The 6-month-modified FIM scores suggested good functional outcome in the patients treated with progesterone. There were no adverse events associated with progesterone.
The Neurologic Emergencies Treatment Trials Network has commenced a large, multicenter National Institutes of Health (NIH)-funded phase III trial of progesterone for adults with moderate-to-severe TBI (Progesterone for Traumatic Brain Injury: Experimental Clinical Treatment: Phase III Clinical Trial III).[91,92] The purpose of this trial is to determine the efficacy of administering IV progesterone (initiated within 4 hr of injury, administered for 72 hr, with an additional 24-hr taper) versus placebo for treating adult victims of moderate-to-severe acute TBI (GCS score, 4–12), using the same dosing as previously discussed in the study by Wright et al. The main outcome measure is the GOS-Extended score at 6 months post injury. The total sample size was planned for 1,140 subjects. The NIH announced in January 2014 that enrollment in the trial had been stopped by the independent Data Safety Monitoring Board, when interim review indicated that it was very unlikely that progesterone would demonstrate better outcomes compared with placebo in this trial.
In addition, BHR Pharma LLC is conducting SyNAPSe (Study of the Neuroprotective Activity of Progesterone in Severe Traumatic Brain Injuries), a global, phase 3, multicenter trial in severe TBI. This study evaluates the effectiveness of its proprietary BHR-100 progesterone product as a neuroprotective agent for treating patients with severe TBI. Approximately 1,200 patients who are 16–65 years old with severe (GCS scores, 3–8), closed-head TBI are being enrolled in the study at ~150 centers worldwide. Patients are randomized in a one-to-one allocation to receive progesterone or placebo. The treatment is administered as a 5-day/120-hour, continuous IV infusion starting within 8 hours after injury. The primary study endpoint is the GOS at 6 months. This study completed enrollment, and we await the final results regarding outcome.
The stopping of the ProTECT III trial certainly has implications for the future study of progesterone treatment for pediatric TBI. It is likely that investigators will need to evaluate the results of the completed SyNAPSe study, as well as the interim results of the ProTECT III study, before moving forward to clinical trials in pediatric TBI.
Pediatr Crit Care Med. 2015;16(3):236-244. © 2015 Lippincott Williams & Wilkins