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Appendix C
Recent and Ongoing Clinical
Trials: CRT for TBI
The following table includes recent and ongoing clinical trials related
to cognitive rehabilitation therapy and traumatic brain injury; these trials
may include criteria that go beyond the scope and methods used by the
IOM committee in its evaluation of the current evidence. The trials are
listed in alphabetical order, with start and end dates ranging from 1996 to
2013. The table was created based on information from ClinicalTrials.gov,
a service of the National Institutes of Health (NIH).
287
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288 COGNITIVE REHABILITATION THERAPY FOR TBI
Study Title,
Sponsor, and Principle
Investigator Study Purpose and Detailed Description
15 Year Longitudinal Phase 1: (Surveillance) DVBIC is collaborating with the Defense Man-
Study of TBI Incurred power Data Center (DMDC) to assess mortality surveillance of OIF/OEF
by Members of the veterans to determine whether an in-theatre history of TBI increases risk
Armed Forces in OIF/ of death among OIF/OEF veterans. DMDC obtains data from a variety
OEF of federal sources including information from the Social Security Admin-
istration’s Death Master File and deceased benefit information from Vet-
erans’ Affairs. To date, DMDC has identified approximately 1.5 million
Defense and Veterans
service members who have served in OIF/OEF of which over 15,000 are
Brain Injury Center
no longer alive as of March 2011.
PI: COL Michael Regarding those deaths, DVBIC is in the process of (a) determining cause
Lewis, M.D. of death; and (b) history of TBI. A series of statistical analyses will be
performed on the data to identify possible trends within the data in an
effort to determine factors that may have preventive benefit.
Phase 2: (Previous TBI Diagnosis) is submitting its protocol as an amend-
ment to the Natural History protocol (Phase 3). Phase 2 is designed to
collect neurobehavioral information on service members and veterans
who are 12 months or more post-TBI diagnosis (dating back to October
2001), as well as trauma controls and healthy controls. Phase 2 includes
a second protocol addressing health related quality of life in family care-
givers of service members and veterans with TBI. The caregiver protocol
will be submitted to OHSP for review last month.
Phase 3: (Incident TBI) has received approval for the Natural History
protocol from the WRAMC and USUHS IRBs. Recruitment began at
WRAMC in May 2011. The study is designed to collect comprehensive
pathophysiologic, neurobehavioral, and neuroimaging information on
service members newly diagnosed with TBI, trauma controls, and healthy
controls. Annual follow-up brief evaluations will be done and intermit-
tently will include a comprehensive examination similar to baseline.
Study Purpose: To learn more about behavior and everyday functioning
Acute Cognitive and
Neurobehavioral after brain injury, and to learn if behavior and functioning gets better
Intervention: Efficacy with more education about changes after brain injury.
Evaluation
Detailed Description: To evaluate the efficacy of the First Steps interven-
tion for improving neurobehavioral functioning, functional status, and life
Virginia
satisfaction, and for increasing knowledge about TBI and compensatory
Commonwealth
strategies. The First Steps program was developed to address the neurobe-
University; U.S.
havioral and emotional concerns of survivors of TBI during the course
Department of
of inpatient rehabilitation. Program format and content reflects clinical
Education
experience and extensive research review. Input from survivors, family
PI: Jeffrey S. Kreutzer, members, and rehabilitation staff trained in working with the TBI popula-
Ph.D. tion has also helped shape the implementation protocol. The foundation
of the protocol is a curriculum [Niemeier, J., Kreutzer, J., & Taylor, L.
(2005). Acute cognitive and neurobehavioral intervention for individuals
with acquired brain injury: Preliminary outcome data. Neuropsychological
Rehabilitation, 15(2), 129–146.] The First Steps curriculum consists of 10
lessons and was developed to address the common needs, issues, and con-
cerns of TBI survivors admitted acutely for inpatient rehabilitation.
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289
APPENDIX C
Sample
Description Study Type Study Design Time Frame
Phase I: Observational • Primary Purpose: 2007 Start
All OIF/OEF Veteran Observational
Service Members
since October 2001
Gender: Both
Group: Adult
Phase II:
TBI:
N = 1,600
Trauma Controls:
N = 800
Healthy Controls:
N = 800
Gender: Both
Group: Adult
Phase III:
Focus Groups:
N = 60
Cognitive Interviews:
N = 60
Longitudinal Online
Questionnaire:
N = 300
Gender: Both
Group: Adult
N = 103 Observational • Observational October 2002–
Model: Cohort October 2008
Gender: Both • Time Perspective:
Prospective
Group: Adult/Senior
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290 COGNITIVE REHABILITATION THERAPY FOR TBI
Study Title,
Sponsor, and Principle
Investigator Study Purpose and Detailed Description
Study Purpose: More than 1.4 million people a year in the United States
Acute Neurobehav-
ioral Program for begin confronting life with the medical, cognitive, and psychosocial chal-
Improving Functional lenges resulting from traumatic brain injury (TBI). A range of cognitive
Status After TBI impairments commonly observed following injury increase caregiver bur-
den as well as per-person lifetime costs for care and support of survivors
of TBI, estimated at $600,000 to $1,875,000. Our long-term goal is to
Virginia
lessen these burdens through improving the functional status of patients
Commonwealth
with TBI by providing an evidence-based, comprehensive, brief, acute-
University; Eunice
care intervention, First Steps Acute Neurobehavioral and Cognitive In-
Kennedy Shriver
tervention (FANCI). The 10-sesson, manualized FANCI Program will be
National Institute of
tested in a controlled, randomized study. Therapeutic components of the
Child Health and
FANCI include didactics, cognitive remediation, demonstration, guided
Human Development
self-reflection, rehearsal, and supported practice of skills and strategies.
(NICHD)
Specific hypotheses are that (1) FANCI will result in more improvement
PI: Janet P. Niemeier, in functional status compared to standard interdisciplinary rehabilitation
Ph.D. treatment and (2) FANCI will result in more improvement on measures of
neurobehavioral functioning compared to standard rehabilitation care for
patients with moderate to severe TBI. We base these hypotheses on the ob-
servations that (1) providing information about symptoms, treatment, and
coping results in reduced symptom intensity and duration for patients with
TBI, and (2) inpatient participants in recent FANCI pilot studies learned
> 80% of the FANCI Program curriculum, and (3) the most recent pilot
study participants had significantly better functional outcomes at discharge
than matched controls. The specific aims of the proposed study are to (1)
evaluate the efficacy of FANCI for improving functional status following
treatment using the FIM, (2) examine the impact of FANCI on broader
outcome measures of general emotional and behavioral functioning and
productive activity in the community as measured post-treatment and at
6-month follow-up, (3) examine contributions of participant injury sever-
ity and cognitive status at time of treatment to treatment outcome and
treatment response, (4) examine contributions of treatment variables of
session topic and mastery, caregiver presence, and concurrent therapies
on treatment outcome and treatment response for inpatients with TBI.
Primary outcome measure is the (FIM). We will secondarily compare
scores on the Disability Rating Scale (DRS), Glasgow Outcome Scale-
Extended (GOSE), Rehabilitation Intensity of Therapy Scale (RITS),
and Frontal Systems Behavior Scale (FRsBe). Our design is a parallel
groups, single-blind, randomized, controlled trial. We will enroll 150 (75
treatment, 75 control) participants. Inclusion Criteria: Mod. to Sev. TBI
based on time to commands, English speaker, Length of stay ≥ 5 days in
acute BI rehabilitation Unit, 18 years of age or older, ≥ 79 on GOAT.
Detailed Description: N/A
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291
APPENDIX C
Sample
Description Study Type Study Design Time Frame
N = 150 Interventional • Allocation: March 2008–
Randomized September 2013
Gender: Both • Control: Placebo
Control
Group: Adult/Senior • Endpoint
Classification:
Efficacy Study
• Intervention Model:
Parallel
Assignment
• Masking: Double
Blind (Investigator,
Outcomes
Assessor)
• Primary Purpose:
Treatment
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292 COGNITIVE REHABILITATION THERAPY FOR TBI
Study Title,
Sponsor, and Principle
Investigator Study Purpose and Detailed Description
Study Purpose: Patients with traumatic brain injury often experience
Amantadine for Treat-
ment of Symptoms of a period of acute confusion that may include agitation as they recover
the Post-Traumatic from their injuries. While this confusion generally resolves with time,
Confusional State patients may pose increased risk of injury to themselves or others during
this period. Their behavior may also increase stress for family members
and interfere with their ability to benefit from rehabilitation therapies.
Methodist
A number of different medications have been used to treat confusion to
Rehabilitation
decrease agitation, decrease risk of injury, and improve participation in
Center; U.S. Depart-
rehabilitation therapies. To this point, there has not been a research or
ment of Education
scientific basis for knowing which medication is the best for a specific
PI: Stuart A. Yablon, patient. The overall goal of this study is to conduct a scientific investiga-
M.D. tion to help determine which medication works best to treat confusion.
Detailed Description: Patients with TBI who require inpatient rehabilita-
tion are frequently confused at the time of admission for rehabilitation.
Our investigations of confusion conducted as part of the TBIMSM have
clarified the nature of confusion in early recovery after TBI. Early confu-
sion (PTCS) has been found to be a complex syndrome characterized by
disorientation, cognitive impairment, restlessness, decreased level of day-
time arousal, sleep disturbance, fluctuation of symptoms, and psychotic-
type symptoms. PTCS complicates early management of patients with
TBI, and may contribute to increased risk of injury to patients and hos-
pital staff, increased stress among family members and staff, decreased
participation in therapies, increased cost of care, and an increased likeli-
hood of being discharged to psychiatric or long-term care settings. These
facts indicate the need for effective management of PTCS. Consensus
regarding optimal treatment of the cognitive and behavioral symptoms
encountered among patients with PTCS does not exist currently. While
many agents have been tried to address such symptoms in TBI, few have
been investigated systematically. These circumstances indicate the need
for appropriate clinical trials to provide guidance to clinicians for medi-
cal treatment of PTCS. In response, the NIDRR-Traumatic Brain Injury
Model System of Mississippi proposed a randomized, double-blinded,
placebo-controlled, parallel group trial for the pharmacological treat-
ment of PTCS. The agent selected for this clinical trial is amantadine, an
NMDA and indirect dopamine agonist. This agent will be compared to
placebo on response measures of efficacy and safety. Study hypothesis:
Amantadine will reduce the severity and number of symptoms of PTCS.
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293
APPENDIX C
Sample
Description Study Type Study Design Time Frame
N = 79 Interventional • Allocation: April 2003–
Randomized June 2008
Gender: Both • Control: Placebo
Control
Group: Child/Adult/ • Endpoint
Senior Classification:
Efficacy Study
• Intervention Model:
Parallel
Assignment
• Masking: Double
Blind (Subject,
Caregiver,
Investigator, Outcomes
Assessor)
• Primary Purpose:
Treatment
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294 COGNITIVE REHABILITATION THERAPY FOR TBI
Study Title,
Sponsor, and Principle
Investigator Study Purpose and Detailed Description
Study Purpose: This study investigates how well a new therapy program
An Intervention
Program to Reduce prevents persistent symptoms (e.g., headaches, fatigue, irritability, etc.)
to the Risk of after concussion. The program involves examining beliefs about concus-
Persistent Symptoms sion and learning healthy coping strategies, and is completed with the
After Concussion first three months post-injury.
Detailed Description: Although the majority of patients with mild trau-
University of British
matic brain injury (MTBI) experience complete recovery within three
Columbia
months, a sizeable group continues to report frequent and severe symp-
PI: Noah Silverberg, toms such as headaches, fatigue, difficulty concentrating, forgetfulness,
Ph.D. and irritability, in what is labeled persistent post-concussion syndrome
(PCS). Persistent PCS is associated with vocational, recreational, and
social disability. Early education and reassurance (treatment as usual) is
effective in general, but appears insufficient for this subgroup. Recent re-
search has identified risk factors for persistent PCS, including inaccurate
illness beliefs, maladaptive coping behavior, and emotional distress. The
present study will evaluate the additive efficacy of a cognitive-behavioral
therapy protocol designed to modify these risk factors, over and above
treatment as usual. Participants with MTBI will be recruited within 6
weeks of injury. Those identified as being at-risk for persistent PCS based
on evidence-based criteria will receive treatment as usual and then be
randomly assigned to receive either no further intervention or cognitive-
behavioral therapy. We hypothesize that the group receiving cognitive-
behavioral therapy will have fewer PCS symptoms and be less disabled
at follow-up. We also hypothesize that compensation-seeking status will
mitigate this improvement and that illness beliefs, coping behavior, and
emotional distress will mediate this improvement. A blinded rater will
conduct the baseline and outcome assessments.
Study Purpose: Memory deficits are common after traumatic brain inju-
Behavioral and
Neuroimaging ries (TBIs) and are characteristic of various forms of dementia, such as
Changes After Alzheimer’s disease and its common precursor mild cognitive impairment
Cognitive Rehab in (MCI). This project intends to assess the efficacy of cognitive rehabilita-
Traumatic Brain tion in these patient populations. We will also use neuroimaging (func-
Injuries (TBI) and Mild tional magnetic resonance imaging [fMRI]) to assess changes in brain
Cognitive Impairment activity that occurs following cognitive rehabilitation.
(MCI)
Detailed Description: N/A
Department of
Veterans Affairs;
Emory University
PI: Benjamin M.
Hampstead, Ph.D.
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295
APPENDIX C
Sample
Description Study Type Study Design Time Frame
N = 65 Interventional • Allocation: June 2009–April
Randomized 2011
Gender: Both • Control: Active
Control
Group: Adult • Endpoint
Classification:
Efficacy Study
• Intervention Model:
Parallel
Assignment
• Masking: Single
Blind (Subject)
• Primary Purpose:
Prevention
N = 60 Interventional • Allocation: Randomized July 2008–June
• Control: Active 2013
Gender: Both Control
• Endpoint
Group: Adult/Senior Classification: Efficacy
Study
• Intervention Model:
Parallel Assignment
• Masking: Single Blind
(Subject)
• Primary Purpose:
Treatment
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296 COGNITIVE REHABILITATION THERAPY FOR TBI
Study Title,
Sponsor, and Principle
Investigator Study Purpose and Detailed Description
Study Purpose: The purpose of this study is to determine whether an inves-
CDP-Choline and
Working Memory tigational drug, called “CDP-Choline,” improves memory in people with
After TBI: A Neuroim- traumatic brain injury (TBI). To do this, we are asking for people with
aging Study traumatic brain injury and people without traumatic brain injury to be a
part of this study. We will compare results between each group to see if this
investigational drug makes a difference with memory. We will also compare
University of Pitts-
brain imaging results and information collected before and after the taking
burgh; National Insti-
of the study medication to see if there are any differences. We hypothesize
tutes of Health (NIH);
that there will be differences in brain activation patterns between individu-
Eunice Kennedy
als with TBI and healthy controls, as well as differences in performance on
Shriver National In-
memory testing at baseline. We further hypothesize that, after treatment
stitute of Child Health
with CDP-Choline, the patterns in neuroimaging findings and cognitive test-
and Human Develop-
ing results for individuals with TBI will more closely resemble results ob-
ment (NICHD)
served for healthy individuals. We hope that what we learn from this study
PI: Patricia M. Arenth, will be helpful in the future treatment of individuals with head injury.
Ph.D.
Detailed Description: Despite the prevalence of working memory deficits
following traumatic brain injury (TBI), the scientific data regarding phar-
macological treatment of this problem is limited. As deficits in working
memory are known to have a significant impact on functional outcomes
for individuals with TBI, further research in this area is essential in or-
der for physicians to be able to treat this problem more effectively. The
primary goal of the proposed project is to examine the efficacy of a par-
ticular pharmacological agent, CDP-Choline, in the treatment of working
memory deficits following traumatic brain injury (TBI). The study sample
will consist of 48 subjects: A group of 24 individuals who have sustained
moderate to severe TBI, and a group of 24 healthy controls. Each group
will be divided into a placebo and treatment group. The project will utilize
functional Magnetic Resonance Imaging (fMRI) to investigate the cerebral
neurophysiological effects of treatment with CDP-Choline. A working
memory task (N-Back) will be employed during fMRI sessions. In addi-
tion, the effects of treatment with CDP-Choline on neuropsychological
testing performance will also be evaluated, and the correlations between
behavioral performance and neuroimaging results will be observed. We
will achieve these goals by comparing baseline neuropsychological testing
results as well as fMRI results, with a second set of testing and neuroim-
aging results obtained following 1 month of pharmacological treatment
with CDP Choline or placebo. Based on our preliminary studies and the
available literature, we expect to see the following: Baseline fMRI results
are expected to show that individuals with TBI display altered patterns of
cerebral activation during a working memory task, as compared to healthy
controls. With CDP-Choline treatment, we expect TBI subjects to display
fMRI laterality and dispersion patterns that more closely resemble patterns
of healthy controls. In addition, we anticipate improvements in behavioral
performance on both the specific working memory task (N-Back), and on
traditional neuropsychological tests to be associated with CDP-Choline
treatment, with greater magnitude of change on testing results for the
TBI group as compared to any changes noted for the control or placebo
groups. Finally, we anticipate that specific significant correlations will be
observed between neuropsychological testing results and neuroimaging
findings, and that the strength of these relationships will be greater for
the TBI treatment group, as compared to the placebo or healthy control
groups. By conducting the proposed study in this manner, we hope to pro-
vide scientific data that will allow for improved treatment, and ultimately
improved functional outcomes for individuals who have sustained TBI.
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297
APPENDIX C
Sample
Description Study Type Study Design Time Frame
N = 48 Interventional • Allocation: March 2009–
Randomized August 2012
Gender: Both • Control: Placebo
Control
Group: Adult • Endpoint
Classification: Efficacy
Study
• Intervention Model:
Parallel
Assignment
• Masking: Double
Blind (Subject,
Caregiver,
Investigator, Outcomes
Assessor)
• Primary Purpose:
Treatment
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314 COGNITIVE REHABILITATION THERAPY FOR TBI
Study Title,
Sponsor, and Principle
Investigator Study Purpose and Detailed Description
Study Purpose: The purpose of this study is to determine whether mind-
Mindfulness-Based
Cognitive Therapy fulness-based cognitive therapy is effective in reducing depression symp-
Intervention to Treat toms in individuals who have experienced a traumatic brain injury. The
Depression in investigators hypothesize that participants who are given the 10-week
Individuals with a intervention will have fewer depression symptoms than the participants
Traumatic Brain Injury in the control group, and this improvement will be maintained at the
3-month follow-up assessment.
Lakehead University;
Detailed Description: Major depression is a significant chronic problem
Ontario Neurotrauma
for people with traumatic brain injury (TBI), and its treatment is dif-
Foundation
ficult. A promising approach to treat depression is mindfulness-based
PI: Michel Bédard, cognitive therapy (MBCT), a relatively new therapeutic approach rooted
Ph.D. in mindfulness-based stress-reduction (MBSR) and cognitive behavioral
therapy (CBT). This multi-site, randomized, controlled trial of a MBCT
intervention will examine the value of this intervention in improving
quality of life and decreasing depression in people with TBI. MBCT may
represent a time-limited, cost-effective group intervention through which
clinicians would have an opportunity to address some of the most debili-
tating aspects of TBI.
Study Purpose: The investigators will evaluate whether it is possible to
PC-Based Cognitive
Rehabilitation for improve memory and attention in patients who have suffered traumatic
Traumatic Brain Injury brain injury through the use of at-home computer training. Patients will
(TBI) be issued a computer and will train for three months on tasks that become
more challenging as the subjects performance improves. The investigators
will evaluate whether the training strengthened mental abilities in general,
Department of
but evaluating mental abilities in the laboratory before and after testing.
Veterans Affairs
Detailed Description: Here we propose two randomized clinical trials to
PI: David L. Woods,
Ph.D. determine if at-home PC-based adaptive training can improve cognitive
function in chronic TBI patients. Both trials will use protocols designed
to drive beneficial neuroplastic changes using paradigms similar to those
that have shown promising results in smaller scale studies. The first experi-
ment will investigate the effects of training of short-term verbal and spatial
memory. Thirty-six patients with chronic mild, moderate and severe TBI
will be evaluated with an extensive battery of neuropsychological tests
(NPTs) and subjective rating scale measures at study entry. NPT and rating
scale data will be compared to those obtained from 100 matched control
subjects to characterize the cognitive deficits following mild, moderate and
severe TBI. Patients will then be randomly assigned to immediate training
(IT) or delayed training (DT) groups in a longitudinal crossover design. IT
patients will begin training for 20 min/day on each of three different mem-
ory tasks for a period of three months. Training data will be automatically
uploaded to monitor daily compliance and learning rate. NPT and rating
scale assessments will be obtained midway through the study. Compari-
sons of changes in trained (IT) and untrained (DT) groups will be used to
evaluate training efficacy. Then, during the second phase of the study, the
DT group will undergo identical training. Repeat testing at the end of the
study will quantify the effects of training on the DT group, and evaluate
retention of training benefit in the IT group. The second experiment will
evaluate the effects of training on attention and executive function using a
similar randomized trial with a separate group of 36 chronic TBI patents.
A comparison of the magnitude of training-related improvements in the
two experiments will be used to evaluate specific and non-specific factors
that contribute to training benefit and identify the patient characteristics
that are most critical for successful cognitive rehabilitation.
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315
APPENDIX C
Sample
Description Study Type Study Design Time Frame
N = 120 Interventional • Allocation: March 2009–
Randomized April 2010
Gender: Both • Endpoint
Classification:
Group: Adult/Senior Efficacy Study
• Intervention Model:
Crossover
Assignment
• Masking: Open
Label
• Primary Purpose:
Treatment
N = 100 Interventional • Allocation: July 2009–
Randomized December 2012
Gender: Both • Endpoint
Classification:
Group: Adult Efficacy Study
• Intervention Model:
Crossover
Assignment
• Masking: Open
Label
• Primary Purpose:
Treatment
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316 COGNITIVE REHABILITATION THERAPY FOR TBI
Study Title,
Sponsor, and Principle
Investigator Study Purpose and Detailed Description
Study Purpose: Growth Hormone (GH) deficiency, defined by insufficient
Recombinant Human
Growth Hormone GH response to a variety of stimulating compounds, is found in 20-35%
During Rehabilitation of adults who suffer traumatic brain injuries (TBIs) requiring inpatient re-
From Traumatic Brain habilitation1. However, there is no accepted gold standard for diagnosing
Injury GH deficiency in this population. Further, the major effector molecule of
the somatotropic axis, Insulin-Like Growth Factor-1 (IGF-1) has recently
been recognized as an important neurotrophic agent. Since most repair
University of Texas
and regeneration after TBI occurs within the first few months after injury,
Southwestern Medical
absolute or relative deficiencies of GH and IGF-1 in the subacute period
Center; Baylor
after TBI are potentially important factors why some patients fail to make
University
a good functional recovery. The proposed study is a randomized, double-
PI: Ramon R. Diaz- blind, placebo-controlled trial of recombinant human Growth Hormone
Arrastia, M.D., Ph.D. (rhGH), starting at 1 month post TBI, continuing for 6 months. This study
has one primary hypothesis, that treatment with rhGH in the subacute
period after TBI results in improved functional outcome 6 months after
injury. As secondary hypotheses, we will investigate what is the optimal
method to diagnose GH deficiency in TBI survivors and study the relation-
ship between GH deficiency and insufficiency and functional recovery.
Detailed Description: N/A
Study Purpose: Context: Traumatic brain injury (TBI) is a common
Rehabilitation of Trau-
matic Brain Injury in condition associated with significant long-term cognitive, behavioral,
Active Duty Military and functional morbidities. There are minimal controlled efficacy data
Personnel and Veterans of various acute rehabilitation intervention approaches. Objective: To
determine the relative efficacy of two different acute TBI rehabilitation
approaches—cognitive-didactic versus functional-experiential. Second-
The Defense and
arily to determine relative efficacy for different patient subpopulations
Veterans Brain Injury
based on baseline cognitive functioning.
Center; James
A. Haley Veterans
Detailed Description: A randomly assigned, intent-to-treat model of two
Administration
different comprehensive treatment programs conducted between July 19
Hospital; Hunter
1996 and May 16, 2003 in 360 adult participants with moderate to severe
Holmes McGuire
TBI treated in four participating Veterans Administration TBI rehabilitation
Veteran Affairs
centers. All patients admitted to the Commission for Accreditation of Re-
Medical Center;
habilitation Facilities (CARF) accredited acute inpatient rehabilitation brain
Minneapolis
injury programs at four participating Veterans Administration Medical
Veterans Affairs
Centers (VAMCs) (Minneapolis, Palo Alto, Richmond, and Tampa) during
Medical Center;
the study enrollment period were screened for eligibility. The design was a
VA Palo Alto
randomized-controlled trial with two treatment arms (cognitive-didactic
Health Care System;
and functional-experiential), both embedded within an interdisciplinary
Department of
TBI rehabilitation program. All treatment was hospital based. The interac-
Veterans Affairs
tive nature of the experimental conditions precluded subject blinding. Since
PIs: Deborah L. each participating site serves a wide geographic area, the protocol permitted
Warden, M.D., Elaine post-hospital outcome assessments by structured telephonic interview, to
Date, M.D., Steven minimize drop out. Participants completed baseline assessment then received
Scott, D.O., Barbara by random assignment one of the two standardized protocol rehabilitation
Sigford, M.D., Ph.D., programs (summarized below and described in detail elsewhere). Partici-
William Walker, M.D. pants received 1.5 to 2.5 hours daily of protocol-specific therapy plus an-
other 2 to 2.5 hours daily of occupational and physical therapy. Independent
teams of therapists functioned at each site to deliver the separate treatments
and by necessity were not blinded to treatment. Protocol monitoring site
visits, biweekly conference calls, and biannual investigator meetings were
conducted to ensure uniformity of protocol treatment over time.
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317
APPENDIX C
Sample
Description Study Type Study Design Time Frame
N = 164 Interventional • Allocation: September 2008–
Randomized September 2012
Gender: Both • Control: Placebo
Control
Group: Adult • Endpoint
Classification:
Safety/Efficacy
Study
• Intervention Model:
Parallel
Assignment
• Masking: Double
• Blind (Subject,
Caregiver, Investigator,
Outcomes
Assessor)
• Primary Purpose:
Treatment
N = 360 Interventional • Allocation: July 1996–May
Randomized 2003
Gender: Both • Intervention Model:
Parallel
Group: Adult/Senior Assignment
• Masking: Single
Blind (Outcomes
Assessor)
• Primary Purpose:
Supportive Care
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318 COGNITIVE REHABILITATION THERAPY FOR TBI
Study Title,
Sponsor, and Principle
Investigator Study Purpose and Detailed Description
Study Purpose: Each year in the United States alone, a third of a mil-
Resuscitative
Endocrinology: Single- lion persons are hospitalized for traumatic brain injury (TBI), of whom
Dose Clinical Uses for approximately one-quarter die. Most are less than 30 years of age.
Estrogen-Traumatic Not only are the health care costs staggering for both initial care and
Brain Injury rehabilitation, but the societal loss in terms of economic impact reaches
into the billions of dollars annually in the United States alone. Despite
advances in neurosurgical interventions and intensive care management,
University of Texas
many survivors do not fully recover. A significant cause of this mortality
Southwestern Medical
and morbidity is thought due to potentially preventable secondary injury,
Center
namely oxidant injury, inflammation, and apoptosis in the penumbra
PI: Jane G. Wigginton, (the area of brain surrounding the primary lesion, which is at-risk, but
M.D. potentially salvageable), beginning in the first few hours after the severe
traumatic event. Despite the current bleak outlook for many of these
patients, a series of animal investigations have uncovered a promising
solution to the problem of the secondary injury seen in severe TBI and
other similar processes, namely the early administration of estrogen, a
strong anti-oxidant, anti-inflammatory and anti-apoptotic compound.
Based on these encouraging results from animal studies, the investigators
hypothesize that early administration of IV Premarin® in patients with
severe TBI will safely reduce secondary brain injury, improve neurologi-
cal outcomes, and improve survival.
Detailed Description: N/A
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319
APPENDIX C
Sample
Description Study Type Study Design Time Frame
N = 50 Interventional • Allocation: July 2009–
Randomized Unknown
Gender: Male • Control: Placebo
Control
Group: Adult • Endpoint
Classification:
Safety/Efficacy Study
• Intervention Model:
Parallel Assignment
• Masking: Double
Blind (Subject,
Caregiver, Investigator,
Outcomes Assessor)
• Primary Purpose:
Treatment
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320 COGNITIVE REHABILITATION THERAPY FOR TBI
Study Title,
Sponsor, and Principle
Investigator Study Purpose and Detailed Description
Study Purpose: The scientific objective of this program is to meet the
Telerehabilitation for
Operation Iraqi rehabilitation needs of combat wounded veterans with mild to moderate
Freedom/ Traumatic Brain Injury (TBI) via telerehabilitation and determine the
Operation Enduring effect of this modality of care on patients’ physical health and outcomes
Freedom (OIF/OEF) including function and community participation. We will also evaluate
Returnees with the benefits and limitations of rehabilitation using telehealth from the
Combat-Related veteran and caregiver perspectives and evaluate the impact of rehabilita-
Telerehab for Trau- tion via telehealth on Veterans Administration (VA) healthcare facility
matic Brain Injury use.
Detailed Description: Rational: TBI can cause life-long impairments in
Department of
physical, cognitive, behavioral and social function that are usually more
Veterans Affairs
disabling than the residual physical deficits. Recovery can continue many
PI: Kris Siddharthan, years after initial trauma. Little is known about optimal methodologies
Ph.D. to treat the vast and complicated secondary manifestations of combat-
related TBI. Applicability: The goal of this rehabilitation program is
eventually to optimally define telerehabilitation services for all veterans
with polytrauma, including accurate and efficient screening instruments,
educational material for patients and families, family support, and fam-
ily counseling to enhance care coordination and to maximize functional
outcomes and quality of life. Patient population: The program will help
wounded veterans with a diagnosis of TBI from combat operations in
Iraq and Afghanistan. Many veterans reside in rural and underserved
areas. Although access to health care for rural patients remains a critical
challenge, telerehabilitation may represent a viable means for the deliv-
ery of therapeutic services to such patients, particularly those served by
the VA. The program has implications for civilian populations as well
including those injured in automobile or industrial accidents and similar
in illness to the cohort of veterans we intend to follow. Clinical applica-
tions, benefits and risks: The goals of the rehabilitation project will be
to enhance the wounded veteran’s capacity to process and interpret in-
formation and to improve his ability to function in all aspects of family
and community life. It will involve a combination of restorative training
which focuses on improving a specific cognitive function and compensa-
tory training which educates veterans on adapting to the presence of a
cognitive deficit that may or may not be curable using singular one to
one interventions as well as integrated interdisciplinary approaches to
target multiple conditions. We see no risks involved in this clinical inter-
vention. Projected time to achieve a consumer-related outcome: The re-
sults of the telerehabilitation project should immediately be available for
dissemination throughout the VA. The VA has already committed itself
to a nationwide rollout of similar telerehabilitation projects for wounded
veterans. Hence, the findings should have immediate application in VA
care for returnees from combat.
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321
APPENDIX C
Sample
Description Study Type Study Design Time Frame
N = 85 Interventional • Control: July 2008–May
Uncontrolled 2012
Gender: Both • Endpoint
Classification:
Group: Adult Efficacy Study
• Intervention Model:
Single Group
Assignment
• Masking: Open
Label
• Primary Purpose:
Treatment
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322 COGNITIVE REHABILITATION THERAPY FOR TBI
Study Title,
Sponsor, and Principle
Investigator Study Purpose and Detailed Description
Study Purpose: The objective of this trial is to evaluate the effectiveness of
The Study of Cogni-
tive Rehabilitation cognitive rehabilitation in OIF/OEF service members with a history of mild
Effectiveness for Mild traumatic brain injury and persistent (3–24 months post-injury) cognitive
Traumatic Brain Injury complaints. This is a prospective, randomized, control treatment trial of
(SCORE) cognitive rehabilitation for OEF/OIF Service Members with a history of
mild traumatic brain injury and persistent (3–24 months post-injury) cogni-
tive complaints. Subjects will be recruited from consecutive patient referrals
Brooke Army Medical
to the TBI Service at SAMMC-North. Patients who meet eligibility criteria
Center; The Defense
and consent to participate in the treatment trial will be randomly assigned
and Veterans Brain In-
to one of four, 6-week treatment arms of the study. Subjects will be evalu-
jury Center; Henry M.
ated prior to the start of treatment and 3, 6, 12, and 18 weeks following
Jackson Foundation
the initiation of the study. The total number of patients to be studied is 160
for the Advancement
(maximum), which is approximately 20 patients per month.
of Military Medicine
Detailed Description:
PI: Douglas B. Cooper,
Ph.D. This is a prospective, randomized, control treatment trial of cognitive reha-
bilitation for OEF/OIF Service Members with a history of mild traumatic
brain injury (mTBI) and persistent (3–24 months post-injury) cognitive
complaints. Subjects will be recruited from consecutive patient referrals to
the TBI Service at SAMMC-North. Patients who meet eligibility criteria
and consent to participate in the treatment trial will be randomly assigned
to one of four, 6-week treatment arms of the study: 1. Psychoeducational
control group; 2. Non-therapist directed, computerized cognitive reha-
bilitation; 3. Therapist-directed individualized cognitive rehabilitation;
and 4. Integrated interdisciplinary cognitive rehabilitation combined with
cognitive-behavioral psychotherapy. (Components of the treatment arms
are described in detail in section 4.6; Research Design and Methods.) All
subjects enrolled in the study will receive the standard of care in manage-
ment of chronic post-concussive symptoms, consistent with the VA/DoD
Clinical Practice Guidelines for the Management of Concussion/mild TBI
(Barth et al., 2009), regardless of treatment assignment. The standard of
care includes provision of patient education materials (adapted from exist-
ing studies to address more persistent rather than acute symptom manage-
ment), regular scheduled follow-up with a medical provider every 3 weeks,
and symptom-based treatment of post-concussive complaints (e.g., medica-
tion trials for headache and co-occurring psychiatric disorders, physical
therapy for vestibular complaints, case management, and supportive coun-
seling with social work for soldiers assigned to the Warriors-in-Transition
Battalion). Study participants who are assigned to treatment arms 2, 3, or
4 will additionally receive manualized cognitive rehabilitation therapies
during the 6-week treatment phase of the study. Cognitive rehabilitation
treatment intensity (i.e., number of hours of treatment per week) will be
matched for individuals assigned to treatment arms 2, 3, or 4. Participants
assigned to the control treatment group (treatment arm 1) will be offered
individualized cognitive rehabilitation therapy if their cognitive complaints
do not abate following the completion of the 6-week treatment trial.
Study participants will be evaluated prior to the initiation of treatment, as well
as at 3-weeks, 6-weeks, 12-weeks, and 18-weeks following the start of treat-
ment. Study evaluators will be blind to treatment assignment. Pre-treatment
baseline assessments and peri-/post-treatment outcome assessments will
include demographic information, injury-related variables, self-report inven-
tories, performance on neuropsychological testing, and functional status (e.g.,
work status; healthcare utilization). Detailed descriptions of the data to be
collected including primary and secondary outcome measures, as well as co-
variate measures can be found in section 4.8: Instrumentation.
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323
APPENDIX C
Sample
Description Study Type Study Design Time Frame
N = 160 Interventional • Allocation: Randomized June 2011–
• Endpoint Classification: August 2014
Gender: Both Efficacy Study
• Intervention Model:
Group: Adult Factorial Assignment
• Masking: Double Blind
(Subject, Outcomes
Assessor)
• Primary Purpose:
Treatment
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