TBI-Traumatic Brain Injury
Conditions
Brief summary
Study of simvastatin in Iraq/Afghanistan Veterans with multiple blast exposure and mTBI. The study will measure substances in cerebrospinal fluid (CSF) that are related to dementing disorders.
Detailed description
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.
Interventions
DRUGsimvastatin
simvastatin 40 mg/day for 12 months
DRUGPlacebo Oral Tablet
placebo comparator
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cerebrospinal Fluid (CSF) T-tau Concentration | baseline, 12 months | Change in CSF total tau concentration from baseline to 12 months of study drug treatment |
| Cerebrospinal Fluid (CSF) P-tau 181 Concentration | baseline, 12 months | Change in CSF p-tau 181 concentration from baseline to 12 months of study drug treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CSF Abeta 1-40 Concentration | baseline, 12 months | change in CSF abeta 1-40 concentration from baseline to 12 months of study drug treatment |
| CSF Abeta 1-42 Concentration | baseline, 12 months | change in CSF abeta 1-42 concentration from baseline to 12 months of study drug treatment |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Simvastatin simvastatin 40 mg/day
simvastatin: simvastatin 40 mg/day for 12 months | 3 |
| Placebo placebo
Placebo Oral Tablet: placebo comparator | 2 |
| Total | 5 |
Baseline characteristics
| Characteristic | Simvastatin | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 2 Participants | 5 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 | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 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 | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment United States | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 2 |
| other Total, other adverse events | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 0 / 3 | 0 / 2 |
Outcome results
Primary
Cerebrospinal Fluid (CSF) P-tau 181 Concentration
Change in CSF p-tau 181 concentration from baseline to 12 months of study drug treatment
Time frame: baseline, 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin | Cerebrospinal Fluid (CSF) P-tau 181 Concentration | 3.1 pg/ml | Standard Error 2 |
| Placebo | Cerebrospinal Fluid (CSF) P-tau 181 Concentration | 1.6 pg/ml | Standard Error 1.4 |
Primary
Cerebrospinal Fluid (CSF) T-tau Concentration
Change in CSF total tau concentration from baseline to 12 months of study drug treatment
Time frame: baseline, 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin | Cerebrospinal Fluid (CSF) T-tau Concentration | 24 pg/ml | Standard Error 20 |
| Placebo | Cerebrospinal Fluid (CSF) T-tau Concentration | 33.5 pg/ml | Standard Error 17 |
Secondary
CSF Abeta 1-40 Concentration
change in CSF abeta 1-40 concentration from baseline to 12 months of study drug treatment
Time frame: baseline, 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin | CSF Abeta 1-40 Concentration | 753 pg/ml | Standard Error 363 |
| Placebo | CSF Abeta 1-40 Concentration | 953 pg/ml | Standard Error 710 |
Secondary
CSF Abeta 1-42 Concentration
change in CSF abeta 1-42 concentration from baseline to 12 months of study drug treatment
Time frame: baseline, 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin | CSF Abeta 1-42 Concentration | 43 pg/ml | Standard Error 24.5 |
| Placebo | CSF Abeta 1-42 Concentration | 82.5 pg/ml | Standard Error 58.5 |