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