Mission Connect Mild Traumatic Brain Injury (TBI) Integrated Clinical Protocol
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Hospital, Neurology, Psychiatric |
| Therapuetic Areas: | Neurology, Psychiatry / Psychology, Other |
| Healthy: | No |
| Age Range: | 18 - 50 |
| Updated: | 4/21/2016 |
| Start Date: | February 2010 |
| End Date: | December 2015 |
The Mission Connect Mild TBI Translational Research Consortium's Integrated Clinical Protocol
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.
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.
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.
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.
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
- Orthopedic Injury subjects: evidence of traumatic injury, other than head;
Abbreviated Injury Score
- 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.
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