Progesterone for the Treatment of Traumatic Brain Injury III

Study Overview
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Brief Summary
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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.

Official Title
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Phase 3 Clinical Trial to Determine if Progesterone Along With Standard Medical Care for Brain Injury is More Effective at Limiting the Amount of Damage Cause by a Traumatic Brain Injury Than Standard Medical Care Alone.

Conditions
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Traumatic Brain Injury

Intervention / Treatment
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* Drug: Progesterone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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: Progesterone<br>Following a one hour loading dose of 0.714 mg/kg per infusion pump through a dedicated IV line, the study drug (progesterone) 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 72 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 will be combined with a 20% Intralipid mixture for infusion. | Drug: Progesterone<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Placebo stock solution was the ethanol diluent required for dissolving progesterone. The volume of placebo to be mixed with intralipid was based on the same mg/kg/hr volume that would be required if PROG had been in the vial. Using an infusion pump through a dedicated IV line - a one hour loading dose of placebo plus intralipid was administered as a continuous intravenous infusion for 71 hours, then tapered over an additional 24 hours. To simplify the infusion protocol, a weight based dosing table was used by the on-sight pharmacy to mix the correct dose for a 10 cc/hour continuous infusion over the 72 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 placebo will be combined with a 20% Intralipid mixture for infusion. | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 6 months post randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality |  | 6 months | 
| Disability Rating Scale | A measure of functional impairment, with complete recovery scored a 0 and vegetative state scored a 29. | 6 months | 
| Potentially Associated Adverse Events: Phlebitis/Thrombophlebitis | Phlebitis/Thrombophlebitis (not due to infiltration or misplacement of the IV) | within 6 months | 
| 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). | within 6 months | 
| 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) | within 6 months | 
| Potentially Associated Adverse Events: Deep Venous Thrombosis (DVT) | DVT - Events were defined based on a positive Doppler ultrasound exam | within 6 months | 
| 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. | within 6 months | 
| 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. | within 6 months | 
| 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. | within 6 months | 
| 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. | within 6 months | 
| 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.) | within 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trauma, Brain Injury