Mission Connect Mild Traumatic Brain Injury (TBI) Integrated Clinical Protocol

Post-traumatic Stress Disorder Clinical Trial

Official title:

The Mission Connect Mild TBI Translational Research Consortium's Integrated Clinical Protocol

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01013870
• Other study ID #: W81XWH-08-2-0132
• Status: Active, not recruiting
• Phase: Phase 2
• First received: November 13, 2009
• Last updated: August 4, 2015
• Start date: February 2010
• Est. completion date: December 2015

Study information

• Verified date: August 2015
• Source: Baylor College of Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to improve the ability to diagnose problems after mild traumatic brain injury (MTBI) and to test a drug that may improve the outcome from these injuries. Of the more than 1.5 million people who experience a traumatic brain injury (TBI) each year in the United States, as many as 75% sustain a mild TBI which can cause long-term or permanent impairments/disabilities in a significant proportion of patients. In addition, traumatic brain injury has become a signature injury of the wars in Iraq and Afghanistan. For people with these injuries, it is difficult to determine whether symptoms are due to the head injury or another condition, such as Post-traumatic Stress Disorder. In this project, there are 3 observational studies that involve testing of mental functions and behavior, imaging of the brain with special x-ray procedures, and blood samples to look at glandular function, which may be affected by head injury. A fourth study is a test of a drug, atorvastatin, which may provide protection for injured brain cells and improve outcome. By collecting and analyzing the information from these tests, it will be possible to make the process of diagnosing mild TBI or post traumatic stress disorder (PTSD) more precise, and also to see if atorvastatin is a helpful drug for patients with MTBI.

Description:

Of the more than 1.5 million people who experience a traumatic brain injury (TBI) each year in the United States, as many as 75% sustain a mild TBI (MTBI) which can cause long-term or permanent impairments/disabilities in a significant proportion of patients. In addition, traumatic brain injury has become a signature injury of the wars in Iraq and Afghanistan.

One of the most difficult diagnostic problems is separating the effects of MTBI and post-traumatic stress disorder (PTSD), because signs and symptoms of these conditions often overlap. Early and accurate diagnosis of MTBI and its differentiation from both acute stress disorder (ASD) and PTSD are a major priority for military medicine due to overlap in symptoms (e.g., attention problems) and the frequent lack of external signs or even self-awareness of MTBI, especially in association with blast injury.

The major goals of this project are to improve the ability to diagnose mild traumatic brain injury (MTBI) and to test a drug, atorvastatin, which may improve outcome after MTBI. To accomplish these goals, 200 MTBI subjects and 100 orthopedic injury (OI) subjects, for comparison purposes, will be recruited for variety of clinical evaluations and a phase II drug trial. Only the MTBI subjects will participate in the phase II drug trial, and these subjects may choose to participate only in the observational studies, declining the drug trial.

Potential subjects will be identified in the Emergency Departments (EDs) of two level I trauma centers, located within a few blocks of each other in Houston, Texas. Once discharged from the ED, subjects will be enrolled and baseline procedures will be performed, including behavioral/cognitive testing, sample collection, and medication teaching, including the first dose of study drug. Subjects will be followed by phone at Day 3-4 during the 7-day dosing period of the drug trial, then with return visits for all subjects at one week, one month, three months, and six months after injury.

Investigation of acute civilian MTBI could potentially elucidate the diagnostic issues of distinguishing between MTBI, post-concussion syndrome (PCS), acute stress disorder (ASD), and post-traumatic stress disorder (PTSD) because, in the civilian setting, mild traumatic brain injuries can be characterized prospectively using advanced brain imaging, EEG, and neuropsychological assessment.

We hypothesize that in comparison with OI subjects, the MTBI group will exhibit slowing of EEG frequency, alteration of cerebral white matter microstructure on diffusion tensor imaging (DTI), and cognitive deficit within 24 hours after injury. We also hypothesize that MTBI subjects will show recovery in their EEG frequency and cognition over six months following injury despite residual white matter injury on DTI. We will also collect two plasma samples and a saliva sample, the first within 24 hr of injury (baseline) and the second at six months post-injury, for measurement of potential biomarkers and genetic studies.

Magnetoencephalography (MEG) will be used to detect and characterize focal abnormalities in neurophysiological function in subjects with MTBI diagnosed with PTSD for the purpose of distinguishing between the two. MEG is a completely non-invasive imaging modality which is able to provide information regarding focal abnormalities in the brain. MEG has been shown to be sensitive to cognitive complaints in patients with MTBI and to be more sensitive to these deficits than EEG. In addition, neurophysiological abnormalities found through testing can differentiate patients with MTBI and PTSD in some studies. Thus, we propose to explore the relationship between DTI and MEG findings which may lead to identification of more distinct, replicable patterns of brain abnormalities in subjects with PTSD and MTBI that may lead to better differentiation between these groups of patients and improve diagnostic precision, as well as from patients with a combination of both disorders.

A separate analysis is designed to examine the incidence and effects of hypopituitarism after MTBI. The incidence of hypopituitarism after MTBI is not known. However, in patients who have persistent symptoms at one year post-injury, 35% have been found to have deficiency one or more pituitary hormones. The clinical characteristics, MRI imaging results, EEG and MEG results of the patients who have pituitary deficiency will be compared to those of patients with normal pituitary function. The relationship between pituitary dysfunction and functional outcome, cognitive recovery, and resolution of PCS will be examined as well.

The final component of this protocol is a Phase II randomized clinical trial of the 200 MTBI subjects to evaluate atorvastatin (Lipitor®) as a neuroprotective agent for the treatment of MTBI. The primary endpoint for this trial is three months. This trial will examine the effects of atorvastatin, given orally in a dose of 1mg/kg (up to 80 mg) for seven days, on the development of post-concussive symptoms (PCS), PTSD symptoms, cognitive recovery, and functional outcome at 3 months post-injury, on recovery of EEG and MEG at 3 months post-injury, and on changes in DTI imaging, as well as any effects on liver function.

In conclusion, traumatic brain injury has become the signature injury of the Iraq and Afghanistan wars, and many veterans with mild TBI find their injuries overlooked and misunderstood. The goal of the Mission Connect Mild TBI Translational Research Consortium is to find answers to the challenging questions associated with the diagnosis and treatment of MTBI. The four studies in this Integrated Clinical Protocol begin that process.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 200
• Est. completion date: December 2015
• Est. primary completion date: August 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

• age 18-50 years

• MTBI subjects: evidence of closed head injury; Glasgow Coma Score 13-15; loss of consciousness < 30 minutes; post-traumatic amnesia < 24 hours; Abbreviated Injury Score </= 3 for any body region; absence of focal lesions on head CT scan

• Orthopedic Injury subjects: evidence of traumatic injury, other than head; Abbreviated Injury Score </= 3 for any body region

• does not require hospitalization for injuries

• visual acuity and hearing adequate to participate in testing

• fluent in either English or Spanish

Exclusion Criteria:

• Abbreviated Injury Score > 3 for any body region

• any type of penetrating injury

• history of significant pre-existing disease or systemic injuries

• history of schizophrenia or bipolar disorder

• blood alcohol > 200 mL/dL

• left-handed

• existing contraindications for MRI

• claustrophobia

• pregnancy

• exclusions related to atorvastatin, including currently taking any statin drug (atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, fluvastatin), no longer taking a statin drug but history of use within the last six months, previously taking any statin drug at any time but now discontinued due to side effects, taking any medication with known interactions with atorvastatin (cyclosporine, fibric acid derivative, erythromycin, clarithromycin, combination of ritonavir plus saquinavir or lopinavir, niacin in doses exceeding multivitamin dosage, or azole antifungals), active liver disease, history of unexplained persistent elevation of serum transaminases, and hypersensitivity to any component of atorvastatin.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain Concussion
• Brain Injuries
• Mild Traumatic Brain Injury
• Post-traumatic Stress Disorder
• Stress Disorders, Post-Traumatic
• Stress Disorders, Traumatic

Intervention

Drug:
• Atorvastatin
In this Phase II randomized clinical trial of 200 MTBI subjects to evaluate atorvastatin as a neuroprotective agent, subjects will receive either active drug or placebo (1:1 randomization) for 7 days, starting within 24 hours of the brain injury. The dosage for subjects in the treatment group will be weight-based at 1mg/kgm, up to 80 mg, which will be the maximal dose. Subjects will be monitored at 3-4 days after injury by phone, then with follow-up visits at 1 week, 1 month, 3 months.
• Placebo
In this Phase II randomized clinical trial of 200 MTBI subjects to evaluate atorvastatin as a neuroprotective agent, subjects will receive either active drug or placebo (1:1 randomization) for 7 days, starting within 24 hours of the brain injury. For the placebo group, subjects will take a daily dose of an inert preparation, visually indistinguishable from the active agent. They will take this preparation for seven days, started within 24 hours of MTBI, and their outcome will be compared with the group of subjects receiving active drug. Subjects will be monitored at 3-4 days after injury by phone, then with follow-up visits at 1 week, 1 month, 3 months.

Locations

Country	Name	City	State
United States	Baylor College of Medicine/Ben Taub General Hospital	Houston	Texas
United States	University of Texas Health Science Center at Houston/Memorial Hermann Hospital	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Baylor College of Medicine	The University of Texas Health Science Center, Houston

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Subjects with mild traumatic brain injury (MTBI) treated with atorvastatin for 7 days after MTBI will show a significant improvement in outcome, as measured by the Rivermead Post-Concussion Symptoms Questionnaire, administered at 3 months after injury.		3 months after injury	No
Secondary	MTBI subjects treated with atorvastatin for 7 days after mild TBI will show fewer symptoms of PCS and PTSD at 3 months post injury than those receiving placebo.		3 months	No
Secondary	MTBI subjects treated with atorvastatin for 7 days after mild TBI will show greater cognitive recovery and higher functional outcome than those receiving placebo.		3 months after injury	No
Secondary	MTBI subjects treated with atorvastatin for 7 days after mild TBI will show better preservation of whole brain volumes and reduced white matter abnormalities at 3 months post-injury than placebo treated subjects.		3 months after injury	No
Secondary	There will be no significant difference in liver function tests between the subjects treated with atorvastatin for 7 days and those receiving placebo.		1 week, 1 month, and 3 months after injury	Yes
Secondary	There will be no significant difference in clinical findings of liver dysfunction (jaundice, discolored urine, fatigue, or unexplained fever) or in other reported symptoms between subjects treated with atorvastatin for 7 days and those receiving placebo.		1 week, 1 month, 3 months after injury	Yes