Simvastatin for mTBI

Many Iraq and Afghanistan Veterans have experienced repetitive blast exposure mild traumatic
brain injury (mTBI) with persistent cognitive, emotional, and neurological postconcussive
symptoms. There is an urgent need to develop effective treatments to reduce both the
intensity of these Veterans' current symptoms as well as their potential long-term risks for
developing neurodegenerative dementing disorders related to repetitive mTBI: chronic
traumatic encephalopathy (CTE) and Alzheimer's disease (AD). Converging evidence suggests
that statins may possess neuroprotective effects against pathologic processes related to tau
protein metabolism that appear to be a common feature of CTE, AD, and other neurodegenerative
sequelae of repetitive mTBI.

The investigators propose a 12-month, double-blind, randomized, active-drug-controlled trial
to establish proof-of-concept for use of simvastatin (40 mg/d) for decreasing CSF biomarkers
of neurodegeneration and increasing CSF neurotrophins in 120 Iraq and Afghanistan Veterans
with repetitive blast trauma mTBI.

Inclusion Criteria:

- Males and females ages 21-50 years.

- Documented hazardous duty in Iraq and or Afghanistan with the U.S. Armed Forces.

- Exposure to one or more blast trauma events resulting in mTBI according to American
Congress of Rehabilitation Medicine (ACRM) criteria.

- More than 6 months since last blast trauma exposure

- Ability to complete psychometric and other clinical assessments in English (i.e.,
adequate English language skills, vision and hearing).

- elevated cholesterol levels, i.e. total cholesterol >200 and/or LDL >130. This would
generally prompt the initiation of a lipid-lowering agent as standard care in the
general medical community.

- No use of statins during the previous year and no recent (past 4 weeks) use of other
lipid-lowering drugs (e.g., fibrates, niacin > 500mg/d, or high dose omega-3 fatty
acids) preceding randomization.

- No clinically significant laboratory abnormalities (electrolytes, glucose, carbon
dioxide, blood urea nitrogen (BUN), creatinine, vitamin B12, folate, albumin, thyroid
stimulating hormone).

- Platelet count > 100,000/mm2.

- Body Mass Index (BMI) between 18 and 36 inclusive

Exclusion Criteria:

- History of head trauma with loss of consciousness (LOC)>30 minutes, or with a
penetrating head wound, or with moderate to severe memory or other cognitive
impairment.

- Neurological disorders: multiple sclerosis, epilepsy, stroke, Parkinson's disease
(PD), other degenerative Central Nervous System (CNS) disorders, or neuropathy with
radicular involvement.

- Acute or chronic major psychiatric disorders: schizophrenia, bipolar disorder or
severe major depressive disorder, or severe anxiety disorder except PTSD and panic
disorder (PTSD and depressive symptoms are common co-morbid conditions for combat mTBI
and a subset of these patients have symptoms consistent with panic disorder as well).

- Use of illegal drugs; alcohol abuse within the past 6 months.

- Poorly controlled hypertension, heart failure, coronary heart disease, peripheral
artery disease, carotid artery disease, diabetes mellitus, pulmonary disease with
hypoxia or hypercapnia, significant hepatic disease or hepatitis C seropositivity,
renal failure, treatment for cancer, HIV positive, active infectious disease or
presence of abdominal aortic aneurysm.

- Contraindications to lumbar puncture (LP) (e.g., spinal cord injury; deformity, severe
disease or infection in the region of the lumbosacral spine; bleeding tendency, use of
anticoagulant medications, or platelet count <100,000/mm2).

- Receiving medication in an investigational drug study.

- Exclusionary medications (used in the 4 weeks prior to screening):

- Fibrates and niacin due to increased risk for myopathy in combination with statins;

- Potential drug-drug interactions with statins via effects on CYP3A4: itraconazole,
ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone,
amiodarone, cyclosporine, isoniazid, quinidine, or large quantities of grapefruit
juice (>1 quart daily);

- Selected CNS-acting medications: antipsychotics, anti-Parkinson's disease medications
and CNS stimulants

- Other medications affecting coagulation and/or inflammation: coumadin, potent
anti-inflammatory medications (hydrocortisone, methotrexate or other potent
immune-modulating medications), and anti-HIV medications.

- All female subjects of childbearing potential will undergo a urine pregnancy test at
every subject visit; subjects with positive pregnancy test results will be excluded.
In addition, all female subjects of childbearing potential will be required to use a
reliable method of contraception throughout the duration of the study.