Posttraumatic Epilepsy, Traumatic Brain Injury
Conditions
Keywords
Brain Injuries, Pregnanolone, Epilepsy
Brief summary
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
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.
Interventions
DRUGAllopregnanolone injection
Allopregnanolone intravenous solution in 0.9% sodium chloride injection with 6% sulfobutyl ether β-cyclodextrin sodium
DRUGPlacebo injection
Placebo intravenous solution, 0.9% sodium chloride injection with 6% sulfobutyl ether β-cyclodextrin sodium
Sponsors
United States Department of Defense
Michael A. Rogawski, MD, PhD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Extended Glasgow Outcome Scale (GOS-E) Score | 6 months after injury | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Allopregnanolone Allopregnanolone injection (intravenous solution) continuous infusion for 5 days
Allopregnanolone injection: Allopregnanolone intravenous solution in 0.9% sodium chloride injection with 6% sulfobutyl ether β-cyclodextrin sodium | 7 |
| Placebo Placebo injection (intravenous solution) continuous infusion for 5 days
Placebo injection: Placebo intravenous solution, 0.9% sodium chloride injection with 6% sulfobutyl ether β-cyclodextrin sodium | 6 |
| Total | 13 |
Baseline characteristics
| Characteristic | Allopregnanolone | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 31.1 years STANDARD_DEVIATION 13.1 | 28.8 years STANDARD_DEVIATION 13 | 26.2 years STANDARD_DEVIATION 13.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 9 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 12 Participants | 5 Participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 7 Participants | 11 Participants | 4 Participants |
| TBI Severity Moderate | 2 Participants | 2 Participants | 0 Participants |
| TBI Severity Severe | 5 Participants | 11 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 7 | 0 / 6 |
| other Total, other adverse events | 7 / 7 | 6 / 6 |
| serious Total, serious adverse events | 7 / 7 | 6 / 6 |
Outcome results
Primary
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.
Time frame: 6 months after injury
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allopregnanolone | Extended Glasgow Outcome Scale (GOS-E) Score | 4.2 GOS-E Score | Standard Deviation 1.9 |
| Placebo | Extended Glasgow Outcome Scale (GOS-E) Score | 4.3 GOS-E Score | Standard Deviation 1.8 |