Traumatic Brain Injury
Conditions
Keywords
Trauma, Brain Injury
Brief summary
The ProTECT study will determine if intravenous (IV) progesterone (started within 4 hours of injury and given for a total of 96 hours), is more effective than placebo for treating victims of moderate to severe acute traumatic brain injury.
Interventions
DRUGProgesterone
Following a one hour loading dose of 0.714 mg/kg per infusion pump through a dedicated IV line, the study drug (progesterone or placebo) will be administered as a continuous intravenous infusion at 0.5 mg/kg/hr for 71 hours, then tapered over an additional 24 hours. To simplify the infusion protocol, a weight based dosing table will be used by the on-sight pharmacy to mix the correct dose for a 10 cc/hour continuous infusion over the 71 hour steady state period followed by three additional 8-hour decrements (7.5 cc/hr-5.0 cc/hr-2.5 cc/hr) to zero, for a total treatment duration of 96 hour. The progesterone/placebo will be combined with a 20% Intralipid mixture for infusion.
DRUGPlacebo
Placebo stock solution is the ethanol diluent required for dissolving progesterone. The volume of placebo to be mixed with intralipid is based on the mg/kg/hr volume. Using an infusion pump through a dedicated IV line - a one hour loading dose of placebo plus intralipid is administered as a continuous intravenous infusion for 71 hours, then tapered over an additional 24 hours.
Sponsors
Medical University of South Carolina
Neurological Emergencies Treatment Trials Network (NETT)
David Wright
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Moderate to severe brain injury (GCS 12-4) * Age 18 years or older * Blunt, closed head injury * Study drug initiated within 4 hours of injury
Exclusion criteria
* Non-Survivable injury * Bilateral dilated unresponsive pupils * Severe intoxication (ETOH \> 250 mg %) * Spinal cord injury with neurological deficits * Inability to perform activities of daily living prior to injury * Cardiopulmonary arrest * Status epilepticus on arrival * Systolic blood pressure (SBP) \< 90 on arrival or for at least 5 minutes prior to enrollment * O2 Sat \< 90 on arrival or for at least 5 minutes prior to enrollment * Prisoner or ward of state * Pregnant * Active breast or reproductive organ cancers * Known allergy to progesterone or intralipid components (egg yolk) * Known history of clotting disorder * Active thromboembolic event * Concern for inability to follow up at 6 months * Anyone listed in the Opt out registry
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Favorable Outcome as Determined by the Glasgow Outcome Scale-Extended (GOSE) | 6 months post randomization | A measure of functional recovery: A GOS-E score of 1 indicates death, 2 indicates a vegetative state, 3 or 4 indicates severe disability, 5 or 6 indicates moderate disability, and 7 or 8 indicates good recovery. Favorable outcome was defined via stratified dichotomy based on the severity of the initial injury. For subjects with a severe injury, a GOS-E of 3 or higher were considered to be a favorable outcome; for subjects with moderate-to-severe injury, a GOS-E of 5 or higher was considered to be a favorable outcome; for subjects with a moderate injury, a GOS-E of 7 or higher was considered to be a favorable outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Potentially Associated Adverse Events: Phlebitis/Thrombophlebitis | within 6 months | Phlebitis/Thrombophlebitis (not due to infiltration or misplacement of the IV) |
| Mortality | 6 months | — |
| Potentially Associated Adverse Events: Pulmonary Embolism | within 6 months | Pulmonary embolism - Events were defined based on either positive chest computed tomography (CT) scanning or ventilation/perfusion lung scan (V/Q). |
| Potentially Associated Adverse Events: Acute Ischemic Stroke | within 6 months | Acute ischemic stroke - Events were defined based on either positive computed tomography (CT) scanning, magnetic resonance imaging (MRI), or neurologist diagnosis of cerebrovascular accident (CVA) |
| Potentially Associated Adverse Events: Deep Venous Thrombosis (DVT) | within 6 months | DVT - Events were defined based on a positive Doppler ultrasound exam |
| Disability Rating Scale | 6 months | A measure of functional impairment, with complete recovery scored a 0 and vegetative state scored a 29. |
| Potentially Associated Adverse Events: Sepsis | within 6 months | Sepsis - Events must have met Centers for Disease Control and Prevention (CDC) definition of sepsis. The definition includes that a patient ≤1 year of age has at least 1 of the following clinical signs or symptoms with no other recognized cause: fever (\>38°C rectal), hypothermia (\<37°C rectal), apnea, or bradycardia, and blood culture not done or no organisms detected in blood and no apparent infection at another site and physician institutes treatment for sepsis. |
| Potentially Associated Adverse Events: Pneumonia | within 6 months | Events must have met Centers for Disease Control and Prevention (CDC) definition of pneumonia. There are three specific types of pneumonia: clinically defined pneumonia, pneumonia with specific laboratory findings, and pneumonia in immunocompromised patients. There are specific algorithms to identify each pneumonia, which include x-ray findings, fever with no other cause, leukopenia or leukocytosis, altered mental status with no other cause (adults \>70 years old), new onset of purulent sputum, change in character of sputum, increase respiratory secretions, increase suctioning requirements, new onset or worsening cough, dyspnea, tachypnea, rales, bronchial breath sounds, or worsening gas exchange, increased oxygen requirements, or increased ventilator demand). Also, labs can identify pneumonia such as positive growth in blood culture, positive Gram stain, and histopathologic exam evidence. |
| Potentially Associated Adverse Events: Central Nervous System (CNS) Infection | within 6 months | CNS infection - Events must have met Centers for Disease Control and Prevention (CDC) definition of CNS infection. The definition includes intracranial infection, Meningitis, ventriculitis, and spinal abscess without meningitis. |
| Potentially Associated Adverse Events: Myocardial Infarction (MI) | within 6 months | Myocardial infarction - Events were defined based on serial cardiac enzyme elevation consistent with MI and/or new ST elevation on electrocardiogram (ECG) consistent with MI. Potentially associated adverse events (those events which are included as outcome measures) were specifically defined per the protocol, and the classification of an event as a PAAE was determined by the site. The reported name of the associated event, however, was subject to clinical judgement and case details; these were then further coded by the Principal Investigator. Since these data points do not share the same definition, there is no reason to expect perfect concordance. (For example, the potentially associated adverse event of myocardial infarction may include MedDRA codes other than myocardial infarction.) |
| Potentially Associated Adverse Events: Unexplained Increased Liver-enzyme Level | within 6 months | Unexplained increased liver enzymes (e.g. not due to liver injury ) - Events were defined based on aspartate transaminase (AST) and alanine transaminase (ALT) levels \> 500 U/L and/or total bilirubin levels \> 2.0 mg/dL. |
Countries
United States
Participant flow
Recruitment details
A total of 882 patients underwent randomization at 49 trauma centers in the United States between April 5, 2010, and October 30, 2013. 442 patients were randomized to Progesterone Arm and 440 were randomized to Placebo Arm.
Participants by arm
| Arm | Count |
|---|---|
| Progesterone | 442 |
| Placebo | 440 |
| Total | 882 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Became a ward of the state | 2 | 1 |
| Overall Study | Death | 83 | 69 |
| Overall Study | Lost to Follow-up | 9 | 9 |
| Overall Study | Withdrawal by Subject | 14 | 14 |
Baseline characteristics
| Characteristic | Progesterone | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 39 years STANDARD_DEVIATION 18 | 38 years STANDARD_DEVIATION 17 | 39 years STANDARD_DEVIATION 18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 61 Participants | 64 Participants | 125 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 347 Participants | 343 Participants | 690 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 34 Participants | 33 Participants | 67 Participants |
| Index GCS score at randomization Moderate | 129 participants | 125 participants | 254 participants |
| Index GCS score at randomization Moderate to severe | 234 participants | 238 participants | 472 participants |
| Index GCS score at randomization Severe | 79 participants | 77 participants | 156 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) Asian | 20 Participants | 22 Participants | 42 Participants |
| Race (NIH/OMB) Black or African American | 70 Participants | 64 Participants | 134 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 6 Participants | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 13 Participants | 13 Participants | 26 Participants |
| Race (NIH/OMB) White | 330 Participants | 331 Participants | 661 Participants |
| Region of Enrollment United States | 442 participants | 440 participants | 882 participants |
| Sex: Female, Male Female | 118 Participants | 114 Participants | 232 Participants |
| Sex: Female, Male Male | 324 Participants | 326 Participants | 650 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 332 / 442 | 330 / 440 |
| serious Total, serious adverse events | 246 / 442 | 251 / 440 |
Outcome results
Primary
Favorable Outcome as Determined by the Glasgow Outcome Scale-Extended (GOSE)
A measure of functional recovery: A GOS-E score of 1 indicates death, 2 indicates a vegetative state, 3 or 4 indicates severe disability, 5 or 6 indicates moderate disability, and 7 or 8 indicates good recovery. Favorable outcome was defined via stratified dichotomy based on the severity of the initial injury. For subjects with a severe injury, a GOS-E of 3 or higher were considered to be a favorable outcome; for subjects with moderate-to-severe injury, a GOS-E of 5 or higher was considered to be a favorable outcome; for subjects with a moderate injury, a GOS-E of 7 or higher was considered to be a favorable outcome.
Time frame: 6 months post randomization
Population: The primary analysis was conducted according to intention to treat.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Progesterone | Favorable Outcome as Determined by the Glasgow Outcome Scale-Extended (GOSE) | Favorable Outcome | 213 participants |
| Progesterone | Favorable Outcome as Determined by the Glasgow Outcome Scale-Extended (GOSE) | Unfavorable | 201 participants |
| Progesterone | Favorable Outcome as Determined by the Glasgow Outcome Scale-Extended (GOSE) | Missing Data | 28 participants |
| Placebo | Favorable Outcome as Determined by the Glasgow Outcome Scale-Extended (GOSE) | Favorable Outcome | 232 participants |
| Placebo | Favorable Outcome as Determined by the Glasgow Outcome Scale-Extended (GOSE) | Unfavorable | 184 participants |
| Placebo | Favorable Outcome as Determined by the Glasgow Outcome Scale-Extended (GOSE) | Missing Data | 24 participants |
Comparison: Test of null hypothesis (equal proportions of subjects with favorable outcome in progesterone and placebo arms) versus alternative hypothesis (unequal proportions of subjects with favorable outcome in progesterone and placebo arms). Standard multiple imputation methods are used to account for missing data. The primary outcome measure is based on the stratified dichotomy approach.p-value: 0.3595% CI: [0.85, 1.06]Regression, Generalized linear
Secondary
Disability Rating Scale
A measure of functional impairment, with complete recovery scored a 0 and vegetative state scored a 29.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Progesterone | Disability Rating Scale | 2.9 units on a scale | Standard Deviation 4.6 |
| Placebo | Disability Rating Scale | 3.3 units on a scale | Standard Deviation 5.1 |
Secondary
Mortality
Time frame: 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Progesterone | Mortality | Subjects with events | 83 participants |
| Progesterone | Mortality | Subjects without events | 359 participants |
| Placebo | Mortality | Subjects with events | 69 participants |
| Placebo | Mortality | Subjects without events | 371 participants |
Comparison: The Cox proportional hazards model is used to compare these curves after adjustment for age, sex and injury severity.95% CI: [0.86, 1.63]
Secondary
Potentially Associated Adverse Events: Acute Ischemic Stroke
Acute ischemic stroke - Events were defined based on either positive computed tomography (CT) scanning, magnetic resonance imaging (MRI), or neurologist diagnosis of cerebrovascular accident (CVA)
Time frame: within 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Progesterone | Potentially Associated Adverse Events: Acute Ischemic Stroke | Subjects with events | 6 participants |
| Progesterone | Potentially Associated Adverse Events: Acute Ischemic Stroke | Subjects without events | 436 participants |
| Placebo | Potentially Associated Adverse Events: Acute Ischemic Stroke | Subjects with events | 13 participants |
| Placebo | Potentially Associated Adverse Events: Acute Ischemic Stroke | Subjects without events | 427 participants |
Secondary
Potentially Associated Adverse Events: Central Nervous System (CNS) Infection
CNS infection - Events must have met Centers for Disease Control and Prevention (CDC) definition of CNS infection. The definition includes intracranial infection, Meningitis, ventriculitis, and spinal abscess without meningitis.
Time frame: within 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Progesterone | Potentially Associated Adverse Events: Central Nervous System (CNS) Infection | Subjects with events | 5 participants |
| Progesterone | Potentially Associated Adverse Events: Central Nervous System (CNS) Infection | Subjects without events | 437 participants |
| Placebo | Potentially Associated Adverse Events: Central Nervous System (CNS) Infection | Subjects with events | 3 participants |
| Placebo | Potentially Associated Adverse Events: Central Nervous System (CNS) Infection | Subjects without events | 437 participants |
Secondary
Potentially Associated Adverse Events: Deep Venous Thrombosis (DVT)
DVT - Events were defined based on a positive Doppler ultrasound exam
Time frame: within 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Progesterone | Potentially Associated Adverse Events: Deep Venous Thrombosis (DVT) | Subjects with events | 50 participants |
| Progesterone | Potentially Associated Adverse Events: Deep Venous Thrombosis (DVT) | Subjects without events | 392 participants |
| Placebo | Potentially Associated Adverse Events: Deep Venous Thrombosis (DVT) | Subjects with events | 40 participants |
| Placebo | Potentially Associated Adverse Events: Deep Venous Thrombosis (DVT) | Subjects without events | 400 participants |
Secondary
Potentially Associated Adverse Events: Myocardial Infarction (MI)
Myocardial infarction - Events were defined based on serial cardiac enzyme elevation consistent with MI and/or new ST elevation on electrocardiogram (ECG) consistent with MI. Potentially associated adverse events (those events which are included as outcome measures) were specifically defined per the protocol, and the classification of an event as a PAAE was determined by the site. The reported name of the associated event, however, was subject to clinical judgement and case details; these were then further coded by the Principal Investigator. Since these data points do not share the same definition, there is no reason to expect perfect concordance. (For example, the potentially associated adverse event of myocardial infarction may include MedDRA codes other than myocardial infarction.)
Time frame: within 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Progesterone | Potentially Associated Adverse Events: Myocardial Infarction (MI) | Subjects with events | 5 participants |
| Progesterone | Potentially Associated Adverse Events: Myocardial Infarction (MI) | Subjects without events | 437 participants |
| Placebo | Potentially Associated Adverse Events: Myocardial Infarction (MI) | Subjects with events | 5 participants |
| Placebo | Potentially Associated Adverse Events: Myocardial Infarction (MI) | Subjects without events | 435 participants |
Secondary
Potentially Associated Adverse Events: Phlebitis/Thrombophlebitis
Phlebitis/Thrombophlebitis (not due to infiltration or misplacement of the IV)
Time frame: within 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Progesterone | Potentially Associated Adverse Events: Phlebitis/Thrombophlebitis | Subjects with events | 76 participants |
| Progesterone | Potentially Associated Adverse Events: Phlebitis/Thrombophlebitis | Subjects without events | 366 participants |
| Placebo | Potentially Associated Adverse Events: Phlebitis/Thrombophlebitis | Subjects with events | 25 participants |
| Placebo | Potentially Associated Adverse Events: Phlebitis/Thrombophlebitis | Subjects without events | 415 participants |
95% CI: [1.96, 4.66]
Secondary
Potentially Associated Adverse Events: Pneumonia
Events must have met Centers for Disease Control and Prevention (CDC) definition of pneumonia. There are three specific types of pneumonia: clinically defined pneumonia, pneumonia with specific laboratory findings, and pneumonia in immunocompromised patients. There are specific algorithms to identify each pneumonia, which include x-ray findings, fever with no other cause, leukopenia or leukocytosis, altered mental status with no other cause (adults \>70 years old), new onset of purulent sputum, change in character of sputum, increase respiratory secretions, increase suctioning requirements, new onset or worsening cough, dyspnea, tachypnea, rales, bronchial breath sounds, or worsening gas exchange, increased oxygen requirements, or increased ventilator demand). Also, labs can identify pneumonia such as positive growth in blood culture, positive Gram stain, and histopathologic exam evidence.
Time frame: within 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Progesterone | Potentially Associated Adverse Events: Pneumonia | Subjects with events | 142 participants |
| Progesterone | Potentially Associated Adverse Events: Pneumonia | Subjects without events | 300 participants |
| Placebo | Potentially Associated Adverse Events: Pneumonia | Subjects with events | 140 participants |
| Placebo | Potentially Associated Adverse Events: Pneumonia | Subjects without events | 300 participants |
Secondary
Potentially Associated Adverse Events: Pulmonary Embolism
Pulmonary embolism - Events were defined based on either positive chest computed tomography (CT) scanning or ventilation/perfusion lung scan (V/Q).
Time frame: within 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Progesterone | Potentially Associated Adverse Events: Pulmonary Embolism | Subjects with events | 10 participants |
| Progesterone | Potentially Associated Adverse Events: Pulmonary Embolism | Subjects without events | 432 participants |
| Placebo | Potentially Associated Adverse Events: Pulmonary Embolism | Subjects with events | 13 participants |
| Placebo | Potentially Associated Adverse Events: Pulmonary Embolism | Subjects without events | 427 participants |
Secondary
Potentially Associated Adverse Events: Sepsis
Sepsis - Events must have met Centers for Disease Control and Prevention (CDC) definition of sepsis. The definition includes that a patient ≤1 year of age has at least 1 of the following clinical signs or symptoms with no other recognized cause: fever (\>38°C rectal), hypothermia (\<37°C rectal), apnea, or bradycardia, and blood culture not done or no organisms detected in blood and no apparent infection at another site and physician institutes treatment for sepsis.
Time frame: within 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Progesterone | Potentially Associated Adverse Events: Sepsis | Subjects with events | 9 participants |
| Progesterone | Potentially Associated Adverse Events: Sepsis | Subjects without events | 433 participants |
| Placebo | Potentially Associated Adverse Events: Sepsis | Subjects with events | 9 participants |
| Placebo | Potentially Associated Adverse Events: Sepsis | Subjects without events | 431 participants |
Secondary
Potentially Associated Adverse Events: Unexplained Increased Liver-enzyme Level
Unexplained increased liver enzymes (e.g. not due to liver injury ) - Events were defined based on aspartate transaminase (AST) and alanine transaminase (ALT) levels \> 500 U/L and/or total bilirubin levels \> 2.0 mg/dL.
Time frame: within 6 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Progesterone | Potentially Associated Adverse Events: Unexplained Increased Liver-enzyme Level | Subjects with events | 18 participants |
| Progesterone | Potentially Associated Adverse Events: Unexplained Increased Liver-enzyme Level | Subjects without events | 424 participants |
| Placebo | Potentially Associated Adverse Events: Unexplained Increased Liver-enzyme Level | Subjects with events | 14 participants |
| Placebo | Potentially Associated Adverse Events: Unexplained Increased Liver-enzyme Level | Subjects without events | 426 participants |