- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01952288
Simvastatin for mTBI
Simvastatin: Proof-of-Concept for Prevention of Neurodegeneration in Mild TBI
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
Washington
-
Seattle, Washington, United States, 98108
- VA Puget Sound Health Care System Seattle Division, Seattle, WA
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: placebo
|
placebo comparator
|
Experimental: simvastatin
simvastatin 40 mg/day
|
simvastatin 40 mg/day for 12 months
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Cerebrospinal Fluid (CSF) T-tau Concentration
Time Frame: baseline, 12 months
|
Change in CSF total tau concentration from baseline to 12 months of study drug treatment
|
baseline, 12 months
|
Cerebrospinal Fluid (CSF) P-tau 181 Concentration
Time Frame: baseline, 12 months
|
Change in CSF p-tau 181 concentration from baseline to 12 months of study drug treatment
|
baseline, 12 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
CSF Abeta 1-40 Concentration
Time Frame: baseline, 12 months
|
change in CSF abeta 1-40 concentration from baseline to 12 months of study drug treatment
|
baseline, 12 months
|
CSF Abeta 1-42 Concentration
Time Frame: baseline, 12 months
|
change in CSF abeta 1-42 concentration from baseline to 12 months of study drug treatment
|
baseline, 12 months
|
Collaborators and Investigators
Investigators
- Principal Investigator: Elaine R Peskind, MD, VA Puget Sound Health Care System Seattle Division, Seattle, WA
Publications and helpful links
General Publications
- Riekse RG, Li G, Petrie EC, Leverenz JB, Vavrek D, Vuletic S, Albers JJ, Montine TJ, Lee VM, Lee M, Seubert P, Galasko D, Schellenberg GD, Hazzard WR, Peskind ER. Effect of statins on Alzheimer's disease biomarkers in cerebrospinal fluid. J Alzheimers Dis. 2006 Dec;10(4):399-406. doi: 10.3233/jad-2006-10408.
- Li G, Mayer CL, Morelli D, Millard SP, Raskind WH, Petrie EC, Cherrier M, Fagan AM, Raskind MA, Peskind ER. Effect of simvastatin on CSF Alzheimer disease biomarkers in cognitively normal adults. Neurology. 2017 Sep 19;89(12):1251-1255. doi: 10.1212/WNL.0000000000004392. Epub 2017 Aug 18.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Wounds and Injuries
- Craniocerebral Trauma
- Trauma, Nervous System
- Brain Injuries
- Brain Injuries, Traumatic
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antimetabolites
- Anticholesteremic Agents
- Hypolipidemic Agents
- Lipid Regulating Agents
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Simvastatin
Other Study ID Numbers
- B1195-I
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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