Allopregnanolone for the Treatment of Traumatic Brain Injury

Study Overview
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Brief Summary
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This study will provide initial data on the safety and effectiveness of allopregnanolone in improving neurobehavioral outcome and reducing mortality in adults with moderate and severe traumatic brain injury.

Detailed Description
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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.

Official Title
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A Double-blind, Placebo-controlled, Randomized Clinical Trial of Allopregnanolone for the Treatment of Traumatic Brain Injury

Conditions
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Traumatic Brain Injury, Posttraumatic Epilepsy

Intervention / Treatment
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* Drug: Allopregnanolone injection
* Drug: Placebo injection


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Allopregnanolone<br>Allopregnanolone injection (intravenous solution) continuous infusion for 5 days | Drug: Allopregnanolone injection<br>* Allopregnanolone intravenous solution in 0.9% sodium chloride injection with 6% sulfobutyl ether β-cyclodextrin sodium<br>* Other names: Product H (allopregnanolone intravenous solution, high dose);|
| Placebo Comparator: Placebo<br>Placebo injection (intravenous solution) continuous infusion for 5 days | Drug: Placebo injection<br>* Placebo intravenous solution, 0.9% sodium chloride injection with 6% sulfobutyl ether β-cyclodextrin sodium<br>* Other names: Product P (placebo);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extended Glasgow Outcome Scale (GOS-E) Score | GOS-E is a global scale for functional outcome that rates patient status into one of 8 levels. The minimum score is 1 and the maximum score is 8. 1 = dead; 2 = vegetative state; 3 = low severe disability; 4 = upper severe disability; 5 = low moderate disability; 6 = upper moderate disability; 7 = low good recovery; 8 = upper good recovery. GOS-E was assessed by 19 question structured interview. | 6 months after injury | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain Injuries, Pregnanolone, Epilepsy