Simvastatin for mTBI

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT01952288
• Collaborator: (none)
• Enrollment: 5
• Location: 1
• Arms: 2
• Actual Duration (Months): 45.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
TBI-Traumatic Brain Injury	Drug: simvastatin; Drug: Placebo Oral Tablet	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Simvastatin: Proof-of-Concept for Prevention of Neurodegeneration in Mild TBI
• Actual Study Start Date: Sep 16, 2013
• Actual Primary Completion Date: Jun 20, 2017
• Actual Study Completion Date: Jun 20, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: simvastatin simvastatin 40 mg/day	Drug: simvastatin; simvastatin 40 mg/day for 12 months; Other Names: Zocor
Placebo Comparator: placebo placebo	Drug: Placebo Oral Tablet; placebo comparator

Outcome Measures

Primary Outcome Measures

1. Cerebrospinal Fluid (CSF) T-tau Concentration [baseline, 12 months]

   Change in CSF total tau concentration from baseline to 12 months of study drug treatment

2. 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 Outcome Measures

1. CSF Abeta 1-40 Concentration [baseline, 12 months]

   change in CSF abeta 1-40 concentration from baseline to 12 months of study drug treatment

2. CSF Abeta 1-42 Concentration [baseline, 12 months]

   change in CSF abeta 1-42 concentration from baseline to 12 months of study drug treatment

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Puget Sound Health Care System Seattle Division, Seattle, WA	Seattle	Washington	United States	98108

Sponsors and Collaborators

• VA Office of Research and Development

Investigators

• Principal Investigator: Elaine R Peskind, MD, VA Puget Sound Health Care System Seattle Division, Seattle, WA

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 16, 2021

More Information

Publications

• 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.
• 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.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT01952288
• Other Study ID Numbers: B1195-I
• First Posted: Sep 27, 2013
• Last Update Posted: Dec 15, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Simvastatin

Study Results

Participant Flow

Arm/Group Title	Simvastatin	Placebo
Arm/Group Description	simvastatin 40 mg/day simvastatin: simvastatin 40 mg/day for 12 months	placebo Placebo Oral Tablet: placebo comparator
Period Title: Overall Study
STARTED	3	2
COMPLETED	3	2
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Simvastatin	Placebo	Total
Arm/Group Description	simvastatin 40 mg/day simvastatin: simvastatin 40 mg/day for 12 months	placebo Placebo Oral Tablet: placebo comparator	Total of all reporting groups
Overall Participants	3	2	5
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	3 100%	2 100%	5 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	3 100%	2 100%	5 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	3 100%	2 100%	5 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 50%	1 20%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 33.3%	0 0%	1 20%
White	2 66.7%	1 50%	3 60%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	3 100%	2 100%	5 100%

Outcome Measures

1. Primary Outcome

Title	Cerebrospinal Fluid (CSF) T-tau Concentration
Description	Change in CSF total tau concentration from baseline to 12 months of study drug treatment
Time Frame	baseline, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin	Placebo
Arm/Group Description	simvastatin 40 mg/day simvastatin: simvastatin 40 mg/day for 12 months	placebo Placebo Oral Tablet: placebo comparator
Measure Participants	3	2
Mean (Standard Error) [pg/ml]	24 (20)	33.5 (17)

2. Primary Outcome

Title	Cerebrospinal Fluid (CSF) P-tau 181 Concentration
Description	Change in CSF p-tau 181 concentration from baseline to 12 months of study drug treatment
Time Frame	baseline, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin	Placebo
Arm/Group Description	simvastatin 40 mg/day simvastatin: simvastatin 40 mg/day for 12 months	placebo Placebo Oral Tablet: placebo comparator
Measure Participants	3	2
Mean (Standard Error) [pg/ml]	3.1 (2)	1.6 (1.4)

3. Secondary Outcome

Title	CSF Abeta 1-40 Concentration
Description	change in CSF abeta 1-40 concentration from baseline to 12 months of study drug treatment
Time Frame	baseline, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin	Placebo
Arm/Group Description	simvastatin 40 mg/day simvastatin: simvastatin 40 mg/day for 12 months	placebo Placebo Oral Tablet: placebo comparator
Measure Participants	3	2
Mean (Standard Error) [pg/ml]	753 (363)	953 (710)

4. Secondary Outcome

Title	CSF Abeta 1-42 Concentration
Description	change in CSF abeta 1-42 concentration from baseline to 12 months of study drug treatment
Time Frame	baseline, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin	Placebo
Arm/Group Description	simvastatin 40 mg/day simvastatin: simvastatin 40 mg/day for 12 months	placebo Placebo Oral Tablet: placebo comparator
Measure Participants	3	2
Mean (Standard Error) [pg/ml]	43 (24.5)	82.5 (58.5)

Adverse Events

Time Frame	baseline through 12 months study participation
Arm/Group Title	Simvastatin		Placebo
Arm/Group Description	simvastatin 40 mg/day simvastatin: simvastatin 40 mg/day for 12 months		placebo Placebo Oral Tablet: placebo comparator
All Cause Mortality
	Simvastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/2 (0%)
Serious Adverse Events
	Simvastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Simvastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		2/2 (100%)
Gastrointestinal disorders
Diarrhea	2/3 (66.7%)	2	1/2 (50%)	2
General disorders
nasal congestion	1/3 (33.3%)	1	0/2 (0%)	0
night sweats	0/3 (0%)	0	1/2 (50%)	1
Infections and infestations
Upper Respiratory Infection	2/3 (66.7%)	2	0/2 (0%)	0
Tonsillitis	1/3 (33.3%)	1	0/2 (0%)	0
Musculoskeletal and connective tissue disorders
Sciatica	1/3 (33.3%)	1	0/2 (0%)	0
Back Pain	0/3 (0%)	0	1/2 (50%)	1
Shoulder pain	1/3 (33.3%)	1	0/2 (0%)	0
Nervous system disorders
Increased Confusion	1/3 (33.3%)	1	0/2 (0%)	0

Limitations/Caveats

Recruitment difficulties (persons with normal cholesterol levels were not interested in taking statins) led to not enrolling sufficient numbers of participants to achieve target power.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.