1. Progesterone and Traumatic Brain Injury

2. from: http://www.drugs.com/progesterone.html Progesterone is a female hormone important for the regulation of ovulation and menstruation. http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/Progesterone.gif

3. Traumatic brain injury (TBI), a form of acquired brain injury, occurs when a sudden trauma causes damage to the brain. TBI can result when the head suddenly and violently hits an object, or when an object pierces the skull and enters brain tissue. Symptoms of a TBI can be mild, moderate, or severe, depending on the extent of the damage to the brain. from: http://www.ninds.nih.gov/disorders/tbi/tbi.htm from: http://www.strongarm.org.uk/style/injury3.jpg

4. http://brainandspine.titololawoffice.com/Anatomy%20of%20Impairment0001.jpg

5. http://www.ebmedicine.net/media_library/aboutUs/The%20Glasgow%20Coma%20Scale%20And%20The%20Glasgow%20Outcome%20Scale%20Emergency%20Medicine%20Practice_2.JPG

7. Acute neurodegenerative conditions such as cerebral ischaemia (e.g. stroke) and traumatic brain injury are characterized by rapid and (usually) severe insults to the brain that lead to substantial loss of nerve cells with associated functional deficits. The former is associated with abrupt cessation of blood supply to the brain... Several processes have been implicated in the ensuing damage, including increased glutamate release (excitotoxicity), oxidative stress and disturbances in ionic homeostasis. There are also substantial data demonstrating the active involvement of inflammatory processes in these diseases. … Although not as comprehensive, there are many published studies to indicate that inhibition of other inflammatory mediators can ameliorate brain injury after acute insults. from: http://rstb.royalsocietypublishing.org/content/358/1438/1669.full.pdf

8. Progesterone for the Treatment of Traumatic Brain Injury (ProTECT III) 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. Inclusion Criteria Moderate to severe brain injury (GCS 12-4) Age 18 years or older Blunt, closed head injury Arrival within four hours of injury

9. Exclusion Criteria Non-Survivable injury Bilateral dilated unresponsive pupils Severe intoxication (ETOH > 250 mg %) Spinal cord injury with neurological deficits Cardiopulmonary arrest Status epilepticus on arrival 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 eggs Known history of clotting disorder

10. Recruitment and Informed Consent The standard for recruitment is that study subjects volunteer for study participation with full knowledge of the requirements, risks and potential benefits of the study treatments. In acute care settings, however, it is difficult to obtain direct subject consent – in this case, modified consent protocols may be employed, where a proxy gives informed consent in place of the subject.

11. Enrollment and Assignment to Treatment Once eligible (under inclusion and exclusion) subjects have given informed consent (or proxy consent under certain circumstances, they are enrolled in the study. Study subjects are then randomly assigned to treatment. Double blinding is employed, so that neither the subjects nor the study personnel are aware of individual treatment assignments.

12. Treatments Progesterone or Placebo Progesterone 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 progesterone ) will be administered as a continuous intravenous infusion at 0.5 mg/kg for 72 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/placebo will be combined with a 20% Intralipid mixture for infusion.

13. Primary Outcome Measures Progesterone will significantly increase the proportion of patients with a favorable outcome as determined by the Glasgow Outcome Scale-Extended (GOSE) score at 6 months post injury when compared to placebo. Secondary Outcome Measures Examine the efficacy of IV progesterone vs. placebo for treating patients with moderate to severe TBI on additional 6 month outcomes: Mortality, DRS(?), cognitive, neurological and functional outcomes, and rates of Adverse Events and Serious Adverse Events. Follow-up Once assigned to treatment, enrolled subjects are followed for primary and secondary outcomes and for drug-related safety and toxicity.