Allopregnanolone for the Treatment of Traumatic Brain Injury

This is a double-blind, placebo-controlled, randomized, dose-finding, two-stage adaptive, clinical trial study comparing allopregnanolone to placebo when administered intravenously for 5 days beginning within 8 hours after injury. Test products to be administered are low and high dose allopregnanolone (Products L and H, respectively) and placebo (Product P) intravenous solutions. The products are administered during a 4-day treatment period followed by a 1-day dose de-escalation period. Stage 1 of the study will assess safety and confirm that dosing with Products L and H achieve the target steady-state plasma concentrations set for each of these products. Dosing will be adjusted in Stage 1, if necessary. Stage 2 will initially allocate subjects equally to Products L, H and P but will then use adaptive randomization to allocate subjects between Products L and H to optimized the probability of yielding a better 3-month Glasgow Outcome Score Extended (GOS-E) score.

Inclusion criteria

• English or Spanish speaking person
• Moderate to severe closed or blunt traumatic brain injury [post resuscitation Glasgow Coma Score (GCS) 3-12 with abnormal head CT scan if GCS is 9-12]
• Less than 8 hours from injury to study initiation
• Able to participate for the full term of the study

Exclusion criteria

• Subjects with life expectancy of less than 24 hours
• Isolated epidural hematoma
• Hypoxia (pulse oximetry saturation ≤90% for 15 or more minutes before enrollment)
• Hypotension (systolic blood pressure ≤90 mm Hg on 2 or more reliable measurements before enrollment)
• Cardiopulmonary arrest prior to randomization
• Spinal cord injury with motor deficits
• Bilateral non-reactive pupils with Glasgow Coma Scale 3
• Body weight >120 kg
• Pregnancy
• Active breast or reproductive organ cancer
• Allergy to progesterone
• History of thromboembolic events
• Receipt of activated Factor VII before enrollment
• Any disease that is unstable or which could jeopardize the safety of the subject including severe renal impairment (creatinine clearance <50 ml/min)
• Prisoner/ward of the state
• Known treatment with another investigational drug therapy or procedure within 30 days of injury