Prazosin and CSF Biomarkers in mTBI
Phase: PHASE4
Conditions: Dementia
Sponsor: VA Office of Research and Development

Human Subjects Protocol
VA Puget Sound IRB
Prazosin and CSF Biomarkers in mTBI
MIRB# 00914
VA Rehabilitalion Research and Development Service (RR&D)
Principal Investigator: Murray A. Raskind, MD
Version 4, Revised 11/02/2018
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Abstract
Background and Rationale: A majority of neurodegenerative dementing disorders, including
Alzheimer’s disease, (AD), dementia with Lewy bodies (DLB) and chronic traumatic
encephalopathy (CTE), now appear to be caused by the accumulation and aggregation of proteins
that cause progressive damage to the brain. Recent preclinical results suggest that clearance of
such neurotoxic proteins from the brain may be greatly increased during states where
noradrenergic (NA) tone is decreased or blocked, such as anesthesia and normal sleep, but
impaired in animal models of Traumatic Brain Injury (TBI). These results also suggest that
clearance through this mechanism, which has been termed the ‘glymphatic’ system, is likely to
be decreased in conditions where NA signaling is inappropriately maintained during sleep, such
as posttraumatic stress disorder (PTSD).
Importantly, the rate at which toxins are cleared through the glymphatic system has been found
to be under alpha-i adrenergic receptor (AR) control, and the application of noradrenergic
blockers such as the alpha-i AR antagonist drug, prazosin, has been shown to increase waking
clearance of these proteins to levels normally found during sleep or anesthesia. This suggests two
important possibilities: first, that conditions in which the brain NA signaling is increased and
sleep is impaired, such as posttraumatic stress disorder (PTSD) and TBI, may predispose people
to decreased clearance of neurotoxic proteins associated with the development and progression
of dementia; and second, that the use of prazosin may be able to prevent such effects.
Study Objectives, Specific Aims, and Hypotheses: We propose a two phase proof-of-concept
pilot study in Veterans with PTSD and/or a history of mild or moderate TBI; phase I will be open
label, and phase II will be randomized placebo controlled. It is hypothesized that prazosin (but
not placebo) will decrease cerebrospinal fluid (C SF) concentrations of three established
biomarkers of neurodegeneration: amyloid beta42 (Af342), total tau (tTau), and phosphorylated
taul8l (p-tauI8I). Such a finding would be consistent with prazosin resulting in increased
glymphatic clearance of neurotoxic molecules from the brain, and provide a rationale for larger
scale studies of clinical evaluation of prazosin. Further, we will also characterize predictors and
correlates of any observed effect, both in terms of the baseline characteristics of the participants
showing an effect, and any clinical changes which correlate with change in CSF biornarkers.
Study Design: Sixty Veterans with a history of PTSD and/or mild or moderate TBI will receive
either prazosin or placebo for a titration period plus 5 weeks. The first 22-37 of these participants
will comprise phase I, and will receive open-label prazosin; in phase II, participants will be
randomized to prazosin or placebo. CSF will be collected by lumbar puncture (LP) at
pretreatment baseline and again after completion of 5 weeks of steady-dose study drug treatment.
Unstable or serious medical conditions, conditions that are contraindications for LP, and
conditions that are relative contraindications for the use of prazosin (hypotension, orthostatic
hypotension, severe peripheral edema) will be exclusionary.
Relevance to VA Mission: If we find that prazosin increases clearance of potentially neurotoxic
proteins, we will move towards confirmation in a larger sample and with additional endpoints,
such as incidence of dementia. If confirmed, these results would provide the first rational
pharmacologic treatment strategy for prevention of neurodegeneration and dementia following
TBI and PTSD. They would also hold the potential of generalizing to the prevention of dementia
related to other risk factors.
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List of Abbreviations
ACT
Auditory Consent Trigrams
ACTH
Adrenocorticotropic hormone
AD
Alzheimer’s disease
ADRA1A
Alpha-la adrenergic receptor
ADRA2A
Alpha-2a adrenergic receptor
AEs
Adverse events
APOE
Apolipoprotcin E
AQP4
Aquaporin 4
AR
Adrenoreceptor
AUDIT-C
Alcohol Use Disorders Identification Test
- Consumption
Af3
Amyloid beta
AJ342
Amyloid beta42
BDNF
Brain-derived neurotrophic factor
BMI
Body mass index
BP
Blood pressure
BPH
Benign prostatic hypertrophy
CALHM I
Calcium homeostasis modulator I
CAPS
Clinician-Administered PTSD Scale for DSM-V
CBOC
Community-based outpatient clinics
CBTi
Cognitive Behavioral Therapy for Insomnia
CCK
Cholecystokinin
CNS
Central nervous system
CoC
Federal Certificate of Confidentiality
COMT
Catechol-O-methyltransferase
CPRS
Computerized Patient Record System
CPT
Cognitive Processing Therapy
CRF
Corticotropin-releasing factor
CRFs
Case report forms
CRHRI
Corticotropin Releasing Hormone Receptor type
1
CRP
C-reactive protein
CRU
Clinical research unit
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CSD-E
Consensus Sleep Diary-E
CSF
Cerebrospinal fluid
CTE
Chronic traumatic encephalopathy
CVLT
California Verbal Learning Test II
CYP19AI
Cytochrome P450, Family 19 Subfamily A polypeptide 1
DLB
Dementia with Lewy Bodies
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
DVBIC
Defense and Veterans Brain Injury Center
DVPRS
Defense and Veterans Pain Rating Scale
EKG
Electrocardiogram
EMDR
Eye Movement Desensitization and Reprogramming
FDA
Food and Drug Administration
FTLD
Frontotemporal Lobar Dementia
GAD-7
General Anxiety Disorders
— 7
GAO
Government Accountability Office
GRIN2B
Glutamate receptor, ionotropic, N-Methyl D-Aspartate 2B
HA
Headache
HAM-D
Hamilton Depression Rating Scale
HIPAA
Health Insurance Portability and Accountability Act of 1996
HR
Heart Rate
IFIS
Intraoperative floppy iris syndrome
IGF-l
Insulin-like growth factor-l
IRB
Institutional Review Board
LP
Lumbar puncture
LRP-l
Low density lipoprotein receptor-related protein 1
MAO
Monoamine oxidase
MAPT
Microtubule-associated protein tau
MHP
Mental Health Professional
MIRECC
Mental Illness Research, Education, and Clinical Center
MoCA
Montreal Cognitive Assessment
mTBI
Mild traumatic brain injury
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N3
NREM 3 sleep
NA
Noradrenaline
NCAM
Neural Cell Adhesion Molecule
NGF
Nerve growth factor
NMDA
N-Methyl D-Aspartate
NPY
Neuropeptide Y
NREM
Non-REM sleep
NSI
Neurobehavioral Symptom Inventory
OEF
Operation Enduring Freedom
OHRP
Office of Human Research Protections
OIF
Operation Iraqi Freedom
OIG
VA Office of the Inspector General
OND
Operation New Dawn
ORO
VA Office of Research Oversight
p-tau
Phosphorylated tau
p-tau
81
Phosphorylated tauisi
PCL
PTSD Checklist
PDR
Physicians’ Desk Reference
PE
Prolonged Exposure therapy
PHQ-9
Patient Health Questionnaire-9
PLPHA
Post-lumbar puncture headache
PSQI
Pittsburgh Sleep Quality Index
PTSD
Posttraumatic stress disorder
PVT
Psychomotor Vigilance Test
QCC
Quantification of Cannabis Consumption
R&DC
Research and Development Committee
RCT
Randomized clinical trial
REM
Rapid eye movement sleep
SAE
Serious adverse event
SCID
Structured Clinical Interview for DSM-5
SDMT
Symbol Digit Modalities
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SLC6A2
Solute carrier family 6 member 2 (gene name)
SMs
Servicemembers
SUCLG2
Succinyl-CoA ligase subunit beta
TLEQ
Traumatic Life Events Questionnaire
- Modified
TOMM4O
Translocase of outer mitochondrial membrane 40
tTau
Total Tau
VA
Department of Veterans Affairs
VR-12
Veterans RAND-12
WTAR
Wcchsler Test of Adult Reading
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Contents
1.0
Study Personnel
.9
2.0
Introduction
9
3.0
Objectives
10
4.0
Resources and Personnel
11
5.0
Study Procedures
11
5.1
Recruitment Methods
20
5.2
Informed Consent Procedures
22
5.3
Inclusion/Exclusion Criteria
23
5.4
Study Evaluations
25
5.5
Data Analysis
37
5.6
Withdrawal of Subjects
39
6.0
Reporting
40
7.0
Privacy and Confidentiality
41
8.0
Communication Plan
41
9.0
Information Security and Data Storage/Movement
41
10.0
References
42
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Protocol Title: Prazosin and CSF Biomarkers in mTBI
1.0 Study Personnel
Principal Investigator:
Murray Raskind, MD; Co-Director, VA NW Network Mental Illness Research,
Education, and Clinical Center (MIRECC) and Professor, Department of Psychiatry and
Behavioral Sciences, University of Washington School of Medicine.
Murray.Raskindva.gov; 206-277-3797
VA Puget Sound Co-Investigators:
Elaine Peskind, MD; Co-Director, VA NW Network MIRECC and Professor,
Department of Psychiatry and Behavioral Sciences, University of Washington School of
Medicine. Elaine.Peskind@va.gov; 206-277-3965
Rebecca Hendrickson, MD, PhD; MIRECC Fellow. Rebecca.Hendricksonva.gov; 206-
277-5054
Gail Li, MD, PhD; Staff Psychiatrist, VA Puget Sound and Associate Professor,
University of Washington School of Medicine. Ge.Liva.gov; 206-764-2485
Collaborators (at other institutions, not covered under the VA IRB approval): none
2.0 Introduction
Although the exact cause of neurodegenerative dementing disorders varies, a majority of them
—
including Alzheirner’s disease (AD), dementia with Lewy bodies (DLB), frontotemporal lobar
dementia (FTLD), and chronic traumatic encephalopathy (CTE)
— now appear to be caused by
the accumulation of abnormal aggregates of insoluble proteins that cause progressive damage to
the brain parenchyma’
2 Recent evidence has suggested that the clearance of many such proteins
from the brain may occur primarily during sleep35, and may in particular be dependent on the
dramatic decrease in noradrenergic (NA) tone known to occur during rapid eye movement
(REM) and non-REM slow wave sleep, particularly what is most commonly referred to as stage
III, or “N3”, sleep4.
These findings suggest that pathologic states that lead to inappropriately preserved NA tone
during sleep, such as PTSD67, may predispose to development of neurodegenerative dementing
disorders by impairing clearance of neurotoxic proteins8°
— but that reversal of the
inappropriately preserved NA tone may be protective against this increased risk. Furthermore,
these findings suggest that even in individuals without pathologically increased NA tone during
sleep, further lowering of NA tone during both wake and sleep may be able to increase protein
clearance above even baseline levels, and by doing so decrease the risk of AD or other fonns of
dementia in individuals with increased protein accumulation due to other predisposing factors,
such as due to increased aberrant tau accumulation in TBI.
Prazosin is a selective ui AR antagonist that has been used widely for many years to treat
hypertension and urinary outflow restriction secondary to benign prostatic hypertrophy (BPH),
and, more recently, as a treatment for trauma nightmares and other hyperarousal symptoms in
PTSD and for reducing alcohol consumption in alcohol use disorders1’3, as well as for
ameliorating post-concussive headaches14 h and managing disruptive agitation in dementia’6.
Prazosin has long been FDA approved, is widely available as inexpensive generic preparations,
and has a long track record of safety. Thus, prazosin is a rational choice for interrupting
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inappropriately high NA tone during sleep, and for seeking to convert low waking levels of
neurotoxic protein clearance to that seen during sleep, in humans with or without inappropriately
high NA tone during sleep. In addition, prazosin was in fact one of the alpha-blocking
medications used in the original research linking the blocking of NA signaling to increased CSF
flow through the brain5, and has since been shown to be the specific NA blocking mediator of
increasing CSF flow and neurotoxin clearance (Nedcrgaard, personal communication), further
validating its use in this context. However, there is nothing currently known in humans about the
potential of prazosin for increasing clearance of neurotoxic proteins and thus providing a
preventive strategy for neurodegenerative dementias.
Given the potential importance of this potential neuroprotective strategy and the safety and
likelihood of efficacy of this intervention, we are proposing an initial proof-of-concept clinical
trial of the feasibility and efficacy of prazosin as an intervention to ameliorate risk factors for
neurodegenerative dementia. We hypothesize that prazosin will antagonize NA activity during
sleep and waking to increase clearance of neurotoxic proteins. This is a biomarker-based proof-
of-concept study in which we will measure concentrations of widely-accepted CSF biomarkers
of neurodegeneration as our primary outcome measure. Our trial design will additionally allow
us to characterize baseline patient characteristics that are predictive of the presence or magnitude
of change in CSF biomarkers, as well as any clinical changes, such as changes in sleep or
behavioral, cognitive or somatic symptoms, that correlate with the presence or magnitude of
change in CSF biomarkers.
3.0 Objectives
We are proposing an initial, biomarker-based proof-of-concept pilot trial of prazosin as a
pharmacologic intervention to ameliorate PTSD and/or mild or moderate TBI as risk factors for
neurodegenerative dementia. In phase I, participant will receive open-label prazosin; in phase II,
participants will be randomized to double-blind prazosin or placebo. CSF Af342, total tau, and p
tauisi will be measured prior to study drug initiation and following a titration period plus 5
weeks of steady-dose treatment with study drug. Quantitative and qualitative biologic measures
likely to have predictive value for identifying individual variations in efficacy, including genetic
markers, known or suspected indicators of central NA tone, and data on sleep, will also be
collected.
Specific Aims and Hypotheses:
Aim 1: We will test for an effect of prazosin in decreasing CSF biomarkers of neurodegeneration
and dementia. Specifically, we will test the primary hypothesis that prazosin administration over
a titration period plus 5 weeks of steady-dose treatment will produce a consistent change across
all groups in CSF concentrations of A42, total tau and p-tauisi.
Aim 2: We will characterize predictors and clinical correlates of any observed effect of prazosin
on the CSF concentrations of Af342, total tau and p-tau 81. Specifically:
•
Aim 2a: We will test the primary hypothesis that the magnitude of any observed effect will
correlate across all groups with the degree of quantitative evidence of baseline sleep
disruption
— either short total sleep time or fragmented sleep
— as measured by actigraphy.
•
Aim 2b: We will carry out an exploratory analysis of the relationship of any observed effect
of prazosin on both CSF biomarkers of neurodegeneration and dementia and symptomatic
rating scales with genetic markers associated with increased risk and/or progression of
neurologic disorders and brain injury, as well as genetic markers associated with the uptake
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and biologic distribution of orally consumed drugs.
•
Aim 2c: We will carry out exploratory analyses of correlations between any observed
efficacy of prazosin and additional baseline and post-treatment clinical assessments,
including psychiatric symptom rating scales, pupillometry measurements, and baseline blood
pressure and heart rate.
4.0 Resources and Personnel
Research procedures will be conducted at VA Puget Sound, Seattle Division. Study personnel as
listed on the Institutional Review Board (TRB) and Research and Development Committee
(R&DC) applications will have access to protected health information, will be involved in
recruiting participants, will obtain consent, will conduct study interviews, and will administer
study instruments. Generally, the staff includes Clinicians, Raters, Psychometrists, Study
Coordinator(s), and Research Assistant(s) as described below.
Description of Study Personnel:
Study Clinicians: will perform safety assessments and examinations, make decisions regarding
the dose titration schedule for individual participants, and make any necessary unscheduled dose
changes. The Study Clinician will be a physician, physician assistant, or nurse practitioner with
experience conducting clinical research in Veterans with TBI and with PTSD.
Study Raters: will administer all interview-based assessments. Raters will be master’s level
social workers or other study professionals who have extensive experience in performing these
assessments in this study population.
Psychometrists(s) and/or Neuropsychologists: will administer all neuropsychological testing (as
described in the study procedures section below). Psychometrists will be experienced and will
have been trained by a neuropsychologist.
Study Coordinator(s) and Research Assistant(s): will be responsible for scheduling visits,
conducting the portions of study visits that do not require clinicians, maintaining case report
forms (CRFs), preparing reports for the IRB and subcommittees, and assisting the data manager.
Data Management: Database design, any required computer programming, and maintenance of
computer hardware and software will be performed by the Data Management team. Initial and
second data entry will be performed on a weekly basis by a study Research Assistant under the
supervision of the Database Manager. The Database Manager will generate weekly reports of
data discrepancies. The study Research Assistant under the supervision of the Study Coordinator
and Data Manager will be responsible for rectifying data entry errors on a weekly basis.
Database maintenance includes nightly backup of servers and storage of backups at a safe off-
site location. Only personnel having the correct user name, password, and signing on from a
computer with the appropriate IP address will have access.
5.0 Study Procedures
Overview: We are proposing an initial, biomarker-based proof-of-concept pilot randomized
clinical trial (RCT) of prazosin as a pharmacologic intervention to ameliorate PTSD and/or mild
to moderate TBI as a risk factor for neurodegenerative dementia in Veterans. There will be two
phases. In phase I, participants will all receive open-label prazosin. In phase II, participants will
be randomized to double-blind prazosin or placebo. In each case, the study drug will be
maintained for 5 weeks once full dose is reached. The first 5-8 weeks will be a titration period,
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where the dose of prazosin or placebo will be increased at regular intervals to a maximum dose
of 25 mg in divided doses (see section 5.5 below for detailed description of dose titration). All
procedures for this study are research procedures; none are standard of care.
Study Population: Participants will be Veterans from any conflict with a history of mild or
moderate TBI, plus Veterans from any conflict with a current diagnosis of PTSD. Persons of all
races, ethnicities, and genders are eligible to participate. Some participants may be VA
employees. However, we are not targeting employees as a study population. Any VA employee
will complete study visits on their off-duty time. Based on previous experience we expect a
screen-failure and dropout rate of 30% each, requiring for phase I 29 participants to be screened
in order to obtain an enrollment of 22, and requiring for phase 11120 participants to be screened
in order to obtain an enrollment of 90 participants with at least 60 completers.
Procedures: Participants will undergo a lumbar puncture (LP) and will have blood samples
collected prior to initiation of study drug and following 5 weeks at maximal dose of study drug.
Blood collection for DNA analysis will also be done at the time of the first LP. Symptom
assessments, neurocognitive testing, and quantitative and qualitative biologic measures likely to
have predictive value for identifying individual variations in efficacy, including data on
autonomic functioning and sleep, will also be collected both at baseline and at the time of
completion.
Samples will be used for measurement of CSF biomarkers (total tau, p-taul8l, A42, F2-
isoprostanes, brain-derived neurotrophic factor [BDNF], neuropeptide Y [NPY], corticotropin
releasing factor [CRF], hypocretin, nerve growth factor [NGF], Cholecystokinin [CCK],
dynorphin, a cytokine panel, catecholamines [norcpinephrine, epinephrine, and dopamine],
indoleamines [serotonin] and their precursors and metabolites), serum and plasma biomarkers
(fasting lipids, C-reactive protein [CRP], adrenocorticotropic hormone [ACTH], cortisol, total
testosterone, insulin-like growth factor-i (IGF-i), and catecholamines), RNA, microRNAs, and
proteornics.
Proteomics, similar to genomics, is an unbiased method that simultaneously assesses thousands
of proteins. There are several CSF biomarkers that reflect particular facets of neurodegeneration.
Conducting a large-scale survey of potential CSF biomarkers will allow us to define a panel of
biomarkers that may discriminate treatment effects and provide insight into as yet unknown
mechanisms of action.
We will be studying the following genes: APOE, MAPT, AQP4, LRP-1, SUCLG2, GRIN2B,
ADRAJA, NCAM, CYPI9A], TOMM4O, CALHMJ, MAO-A and COMT (see below for more
detailed discussion of each gene’s connection to the study); overall, each gene has been
implicated in the mechanism or regulation of glymphatic flow, the progression of AD, the
regulation of biomarkers of AD in CSF, and/or the metabolism of NA.
At the conclusion of the study, participants who have obtained relief of symptoms they may be
experiencing during the study and who are interested in continuing on the medication will be
provided with appropriate referrals to providers to prescribe prazosin for clinical care purposes,
and will be provided with a bridging supply of the medication at the dose on which they had
been stabilized.
Investigational Drug: This study will be conducted using the drug, prazosin, which has been
approved by the FDA for treatment of hypertension but is being used off-label for investigational
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purposes in this study. Prazosin and indistinguishable placebo will be obtained. All study
medications will be shipped to the investigational pharmacist at VA Puget Sound. Study drug
may be stored at room temperature. Unused drug will be disposed of by the investigational
pharmacist once notification has been made by the P1 that the study has been completed.
Pursuant to 21 CFR 312.2(b)(l), the clinical investigation of a marketed drug or biologic does
not require submission of an IND if all six of the following conditions are met:
(i)
it is not intended to be reported to FDA in support of a new indication for use or to
support any other significant change in the labeling for the drug;
(ii)
it is not intended to support a significant change in the advertising for the product;
(iii)
it does not involve a route of administration or dosage level, use in a subject
population, or other factor that significantly increases the risks (or decreases the
acceptability of the risks) associated with the use of the drug product;
(iv)
it is conducted in compliance with the requirements for IRE review and informed
consent [21 CFR parts 56 and 50, respectively];
(v)
it is conducted in compliance with the requirements concerning the promotion and
sale of drugs [21 CFR 312.7]’; and
(vi)
it does not intend to invoke 21 CFR 50.24 (Exception From Informed Consent
Requirements for Emergency Research).
We do not intend to use the results of this research in support of a new indication for prazosin,
nor do we intend to support significant change in advertising for prazosin. The route of
administration, dosage level, and subject population are all the same as in general clinical
practice, and do not increase the risks usually associated with prazosin. Thus, we have satisfied
requirements i., ii., and iii. Requirement iv. is satisfied through the approval of this study by the
appropriate Institutional Review Boards, and requirement v. is satisfied in that we are not
promising any benefit from the use of prazosin in this study.
Foreseeable Risks:
Venipuncture and i.v. placement: May cause transient pain and bruising at the site of the needle
stick. Infrequently, participants may experience fainting or dizziness and there is also a slight
risk of infection at the site of the needle stick.
Genetic Studies: We will be studying the following genes: APOE, MAPT, AQP4, LRP-],
SUCLG2, GRIN2B, ADRAJA, NCAM CYP]9A1, TOMM4O, CALHM], MAO-A,COMT, CRIJRJ,
SLC6A2, and ADRA2A. APOE and MAPT have been associated with increased risk and/or
progression of various neurological disorders as well as brain injury. The APOE-4 allele has
been implicated as a risk factor for development of AD in later life. However, APOE type should
not be considered a genetic test for AD since the results will not conclusively determine whether
a person or any of his/her relatives have or might develop AD. MAPT codes for the microtubule
associated protein tau, whose transcriptgives rise to a variety of splicing variants including the
Promotion ofun iniestigational new drug. A sponsor or investigator, or any person acting on behalf ofa sponsor or investigator, shall not
represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or
otherwise promote the drttg. This provision is not intended to restrict the full exchange of scientific information concerning the drug, including
dissemination of scientific findings in scientific or lay media. Rather, its intent is to restrict promotional claims of safety or effectiveness of the
drug for a use for which it is under investigation and to preclude comtisercialization of the drug before it is approved for commercial distribution.
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tau protein that accumulates in multiple neurodegenerative diseases. The rest of the genes we are
studying have even less clear clinical interpretation at present, and are considered entirely
experimental / investigational in their interpretation.
Participants are informed that currently, the results of these genetic tests do not have any clinical
relevance and will be used for research purposes only. Participants will not be informed of their
genotyping results. Participants will be told that if they wish to know their APOE genotype, that
they can have the testing done at a commercial lab at their own expense.
The Genetic Nondiscrimination Act of 2008 protects participants against risks to employability
and access to health insurance due to participation in genetic studies. However, it is theoretically
possible that participation in genetics studies may jeopardize access to life insurance, disability
insurance, or long-term care insurance if involvement and/or results of the study become part of
the medical record. Procedures to minimize such risk are described below.
Clinical Assessment and Neuropsychological Testing, including pupillometry: Risks due to
clinical assessment procedures are modest. Participants may experience stress similar to that of a
standard clinical evaluation for memory complaints or dementia. Participants may also receive
information that they are cognitively impaired. Such information may be distressing to a
participant. The neuropsychological assessment battery may cause fatigue and/or unpleasant
affective states due to the large number of individual tests. For the pupillometry portion of the
neurocognitive testing, participants will be expected to keep their head relatively still, with their
chin resting on a chin-rest platform, for approximately 15 minutes, which can be mildly
uncomfortable. Some of the clinician and self-administered assessment instruments may cause
participants to focus their attention on traumatic war-zone related experiences and as a result
may produce transient subjective distress. However, these war-zone experiences are routinely
assessed and discussed as part of standard clinical care.
Actigraphy, Ambulatory blood pressure (BP’) and heart rate (HR) measurement: Wearing an
Actiwatch for actigraphy measurements can be uncomfortable. Wearing the ambulatory BP
monitor can be uncomfortable, and the intermittent inflation of the cuff can be both
uncomfortable and can cause anxiety by occurring at unexpected times.
Wearing the ambulatory HR monitor can be uncomfortable as well. Some people find that the
leads irritate their skin over time. The leads can also cause discomfort at the time of removal if
they are placed over chest hair.
Confidentiality: We will take all due care so that responses to questionnaires are not commingled
with patient medical records. However, because we are administering medications which may
have interactions with other medications, it will be documented in the participant’s medical
record that they may be taking prazosin. We plan on obtaining a Federal Certificate of
Confidentiality (C0C) to protect information collected. The study team will have access to VA
Computerized Patient Record System (CPRS) records from initial consent until 30 days beyond
the end of study participation. Results of clinically indicated screening labs will be placed in the
participant’s CPRS record and will be available to any of the participant’s other VA health care
providers or any health care providers to whom a participant releases his/her medical records.
Prazosin: There are no known absolute contraindications to prazosin. In clinical trials of
prazosin, the most frequent adverse reactions were: dizziness (10%), drowsiness (8%), headache
(8%), lack of energy (7%), weakness (7%), palpitations (7%), and, nausea (5%). Less frequent
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adverse reactions (1-4%) reported in clinical trials were: vomiting, diarrhea, constipation, edema,
orthostatic hypotension, dyspnea, syncope, vertigo, depression, nervousness, rash, urinary
frequency, blurred vision, reddened sciera, epistaxis, dry mouth, and nasal congestion. Fewer
than 1% of patients have reported the following (causal relations sometimes not established):
abdominal discomfort or pain, liver function abnormalities, pancreatitis, tachycardia,
paresthesias, hallucinations, pruritus, alopecia, lichen planus, incontinence, impotence, priapism,
tinnitus, diaphoresis, fever, positive ANA titer, and arthralgia.
Prazosin may cause syncope. In most cases this is believed to be due to excessive postural
hypotension although occasionally the syncopal episode has been preceded by severe tachycardia
with heart rates of 120-180 beats per minute. Syncopal episodes have usually occurred within
30-90 minutes of the initial dose. The incidence of the syncopal episodes is 1% if the initial dose
is 2 mg or more. Clinical trials suggest that syncopal episodes can be minimized by starting with
a dose of 1 mg and slowly titrating up to the final dose, as we are doing in this study.
Headache (HA) is listed in the Physician Desk Reference (PDR)17 as a potential adverse reaction
to prazosin, reported in as many of 8% in early clinical trials. However, in our experience, the
incidence of this is lower. In a placebo-controlled pilot study evaluating use of prazosin for
treatment of PTSD in Iraq and Afghanistan active-duty servicemembers (SMs) in which HA was
monitored as a potential side effect of prazosin, 22 of 26 participants had HA at baseline. Among
those randomized to prazosin,
1 of these 22 had worsening of their HAs, and 1 of 4 participants
with no prior HAs developed HAs. In contrast, 11 of the 22 with baseline HAs had improvement
or complete resolution of their HAs while on prazosin.
Regarding mood alterations, although depression is listed in the PDR as occurring in 1-4% of
patients, we have found little evidence for prazosin precipitating or worsening symptoms of
depression. In 33 participants administered the Hamilton Depression Rating Scale (Ham-D) in
our recently completed placebo-controlled study of prazosin for PTSD. Ham-D scores actually
improved more in the prazosin vs. placebo group (5.3 vs. 0.7, t=1.9 [2-tailed], p0.07)’8.
However, for safety reasons, participants will be carefully monitored for signs and symptoms of
depression and other mood disorders.
Prazosin should not be taken concurrently with trazodone. Potential participants who are taking
trazodone for sleep and who are willing to discontinue will be washed out before starting this
study. Care should be taken when alpha-i blockers are combined with erectile dysfunction
medications. We will be following VA pharmacy prescribing guidelines regarding these
medications. They will not be allowed during the Titration Period. Once participants have
reached their stable dose, erectile dysfunction medications will be allowed at 1/2 the usual
clinical dose.
In our current study of prazosin in active duty service members at Madigan, we have noticed an
increased use of dietary supplements containing nitrates. In one case, a participant experienced
three episodes of priapism while taking one of these supplements with prazosin. Therefore, use
of these supplements and supplements containing stimulants (such as ephedra) will be
exclusionary for the duration of the study.
In post-marketing experience, intraoperative floppy iris syndrome (IFIS) has been observed
during cataract surgery in some patients who are taking or have taken alpha-i blockers. The
patient’s ophthalmologist should be prepared for possible modifications to the surgical technique
to reduce the surgical risk of IFIS. If a patient needs to have cataract surgery, he/she should tell
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his/her eye surgeon that he/she may have taken prazosin in a research study.
Lumbar Puncture: The risk of serious effects from LP (infection, nerve root damage) is
extremely low. Rarely, patients may experience transient local pain either at the site of the
puncture or in the distribution of the sciatic nerve if the nerve roots of the cauda equina are
stimulated. Because the LP is performed well below the termination of the spinal cord and
because the nerve roots readily move aside from the spinal needle, the possibility of permanent
damage to a nerve root is very remote. Participants with blood clotting abnormalities, on
anticoagulant medications, or with inadequate platelet function will be excluded. A previously
common (approximately 20% in young persons) adverse effect was post-LP headache. The
incidence of headache is a function of the diameter and type of spinal needle used and
the
amount of fluid removed.
We have instituted use of the 24g Sprotte atraumatic bullet tip spinal needle. Use of the Sprotte
needle has been recommended in the American Academy of Neurology practice parameter on
post-lumbar puncture headache’9. Both the literature and our experience in performing over 1000
LPs with the Sprotte 24g needle indicate that we may anticipate a low risk of post-LP headache
of less than 1% 2023 Among the approximately 1000 LPs with the Sprotte 24g needle, we have
had only 2 severe post-LP headaches that required intervention with epidural blood patch.
In addition, it should be noted that removal of up to 30 cc of CSF does not increase the incidence
of headache since CSF is rapidly produced. Since CSF is produced normally at the rate of
0.35cc/5 minutes, it is estimated that the amount of CSF withdrawn will be replaced in about 6-7
hours. Post-LP headache is thought to occur due to a persistent leak of CSF from the hole left in
the dura by the larger bore (18-20g) Quincke cutting spinal needle used in commercial LP kits,
rather than the amount of CSF removed acutely. This leads to a depletion of the normal CSF
hydraulic “cushion” and leads to a headache the day after the procedure. Use of the noncutting
24g Sprotte atraumatic spinal needle greatly reduces post-LP headache risk. We further reduce
the risk of CSF leak by having participants remain in a recumbent position for one hour after the
procedure, having them increase their fluid intake, and by instructing them to not engage in any
exertion for the 48 hours following the procedure. All investigators performing LPs are very
experienced in performing this procedure in these subject populations.
Headaches following LP, if they occur, are usually mild to moderate and may last for 24-48
hours; such headaches are successfully managed with acetaminophen and caffeine. In unusual
cases, typical post-LP headache, which is posturally sensitive, may occur; these may be fairly
severe and can last as long as a week with conservative management. Our approach to treatment
of severe typical post LP headache is the epidural blood patch, performed on the first morning of
severe post-LP headache (usually the day following LP). Epidural blood patch consists of the
injection of 30 ccs of the participant’s own blood into the epidural space over the lumbar
puncture site. This procedure is done by an anesthesiologist and usually provides immediate
relief of post-LP headache. The Anesthesiology Service at VA Puget Sound Health Care System
has agreed to perform these procedures if necessary and has quite graciously and successfully
performed them in the past.
There is also a small risk of infection at the site of the LP, although sterile technique will be
used. Participants will be given the option to have lidocaine used in placement of the IV catheter
used before LP, and lidocaine will be used to provide local anesthesia at the LP site.
Occasionally, an allergic reaction to the lidocaine such as transient stinging (less than 1 minute)
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at site of injection and rare dermatitis can occur. Participants will be asked if they have a history
of lidocaine allergy.
We analyzed data from 428 research LPs performed on 342 subjects (67 with AD or MCI, and
275 cognitively normal adults). The frequency of any adverse event (11.7%), clinically
significant adverse events (3.97%), and typical post-lumbar puncture headache (PLPHA)
(0.93%) was low. Risk of PLPHA was unrelated to age, gender, position during LP, mis CSF
collected, or minutes of recumbent rest following LP22.
Risk Management and Emergency Response: Evaluation for adverse effects and review of
concurrent medications will be completed at all study visits. Participants are asked about suicidal
ideation at each in-person visit (see below). A study clinician will be on call at all times to
receive calls from participants regarding any adverse events; participants will be provided with
24-hour emergency contact numbers.
Risk management for prazosin: vital signs, including orthostatic BP and HR will be performed at
all study visits. Systolic and diastolic BP and HR will be obtained following 10 minutes of
supine posture, and repeated following 2 minutes of standing. Occurrences of lightheadedness,
dizziness on standing, palpitations, drowsiness, nausea, nasal congestion, peripheral edema,
headache, and other adverse effects will be rated by the clinician. For vital signs parameters,
unacceptable side effects will include supine hypotension (systolic BP<100 mm Hg) and
clinically meaningful hypotension (20 mm Hg or more drop in systolic BP accompanied by
dizziness, lightheadedness, or syncope).
For participants taking other antihypertensive medications, their primary care provider will be
informed of clinically significant BP reductions at any time during the study, to allow adjustment
of the participant’s antihypertensive regimen. As a further precaution, male participants will be
advised to sit on the toilet for urination the first two nights to avoid orthostatic hypotension
secondary to micturition syncope.
Safety monitoring is based on long-term clinical experience with prazosin. Prazosin was first
introduced in 1976 under the trade name Minipress (Pfizer) for clinical management of
hypertension, and later became widely prescribed for urinary outflow obstruction secondary to
benign prostatic hypertrophy (BPH). It has been safely prescribed to large numbers of middle-
aged and older people over the past 35 years. The following information regarding the side effect
profile and safety record or prazosin is a synopsis from the Minipress package insert: “The most
important adverse effect to be considered when prescribing prazosin is a “first dose effect”
manifested by syncope with sudden loss of consciousness believed to be due to postural
hypotension in approximately 1% of patients given an initial dose of 2 mg or greater. This rare
adverse effect is self-limiting and in most cases does not recur after the initial period of therapy
or during subsequent dose titration. However, patients should always be started on
1 mg of
prazosin. In clinical trials of prazosin, most frequent adverse reactions were dizziness (10%),
HAs (8%), drowsiness (8%), lack of energy (7%), weakness (7%), palpitations (5%), and nausea
(5%). Less frequent adverse reactions (1-4%) were: vomiting, diarrhea, constipation, edema,
orthostatic hypotension, dyspnea, syncopc, vertigo, depression, nervousness, rash, urinary
frequency, and nasal congestion. Fewer than 1% of patients have reported the following (causal
reactions sometimes not established): abdominal discomfort or pain, tachycardia, paresthesias,
hallucinations, pruritus, incontinence, impotence, and priapism.
.
Through extensive experience of our group, including open-label clinical studies, placebo-
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controlled trials, and clinical application. prazosin has demonstrated a favorable safety profile. It
has been estimated that over 70,000 Veterans nationwide are being treated with prazosin for
PTSD. Approximately 5% of those treated with prazosin have discontinued it secondary to
subjectively unpleasant side effects, most commonly transient orthostatic dizziness, nasal
congestion, or exercise-induced tachycardia.
Female participants of childbearing potential will have a urine pregnancy test at screen. Urine
pregnancy test must be negative within one week of taking the first dose of study medication. If
more than one week has elapsed since the screening visit, urine pregnancy test will be repeated.
Women of childbearing potential with either positive pregnancy test at screen or refusal to avoid
activities that may result in pregnancy or take precautions to avoid the possibility of becoming
pregnant while participating in this study will be excluded. Contraception is not required after
completion of study. Contraception is not required for male participants.
Risk management for LP: Women of childbearing potential will have a negative urine pregnancy
test before undergoing any LP procedures. Pain at the needle insertion site will be minimized by
adequate local anesthesia with subcutaneous injection of 1% lidocaine. We will use an
atraumatic 24g Sprotte spinal needle which is associated with a reduced risk of adverse events,
including post-LP headache. The Sprotte needle has been recommended in published guidelines
for reducing risk of post-LP headache. We have performed over 1000 LPs since we began using
the Sprotte spinal needle and in our hands, risk of post-LP headache is 0.5%.
We reduce the risk of CSF leak by having the participant lie in bed for one hour after the
procedure, having them increase their fluid intake, and by instructing participants not to engage
in any strenuous activity for the 48 hours following the procedure. All investigators performing
LPs are very experienced in performing this procedure in these subject populations.
We provide a snack of chips and a mountain dew (or other caffeine-containing beverage) to
participants after the LP. We have found in the past that giving participants something salty and
something with caffeine lowers the risk of mild-moderate headaches. Participants will also be
given the choice of lunch or a voucher to use in the VA cafeteria after the LP if they wish.
Lastly, if the participant wishes, the participant’s spouse, other family member, or friend may be
present in the room during the LP, and is able to help keep the participant relaxed and
comfortable.
Risk Management for venipuncture and iv. placement: All such procedures will be performed by
experienced study staff using sterile technique.
Risk management for Actigraphy and ambulatory BP and HR measurement Some people find
that wearing a sweatband under the wrist strap of the Actiwatch helps. Participants will be
instructed to remove the Actiwatch if it interferes with sleep. The overall comfort of wearing the
BP cuff for an extended period of time is maximized by providing disposable covers designed to
reduce irritation and rubbing of the cuff against the skin. The anxiety and discomfort of the
periods of inflation are minimized through the use of a “comfort setting” on the Actiwave
monitor, which shapes the waveform of the initial pressure inflation to minimize both sudden
increases in and peak pressures. The intermittent inflation of the cuff can also disrupt sleep
briefly around each assessment, the impact of which is minimized by taking only the minimum
nt.imber of measurements to provide a representative assessment of blood pressure during sleep,
and by minimizing the total number of nights of recording.
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Discomfort from the HR measurement equipment can be addressed by minimizing the total
amount of recording time as well as allowing participants to move the leads to alternate locations
on the chest if necessary. For some participants, we may recommend that participants remove
chest hair at the specific recording locations.
When these devices are returned to study staff, the information will be downloaded immediately.
If any abnormal readings are discovered, they will be reviewed by a study physician. If the
physician, based on their review and possibly additional information gathered from the subject,
believes the results to be clinically significant, the participant will be notified of the finding, and
referred for follow up with their primary care provider.
The Actiwatch and HR monitors can be worn in the shower, but should not be submerged in
water for long periods of time. The ambulatory blood pressure monitor should not get wet, as it
would ruin the equipment. All devices can be safely and easily removed by participants at any
point if they find them too uncomfortable or wish to do so for any other reason.
Risk Management for questionnaires and assessments: To prevent the development of fatigue
and/or unpleasant affective states due to the subject matter and the large number of individual
tests, participants will be able to take breaks between individual tests. Snacks and water will also
be available to participants during the longer study visits. Participants are free to refuse to answer
any question.
Risk Management for loss of confidentiality: We plan on obtaining a Federal Certificate of
Confidentiality to protect against compelled disclosure of answers to the questionnaires. We will
keep study records and data in a secure location, either in locked filing cabinets in locked rooms
or on restricted-access, password-protected computers which meet all VA-mandated data
security standards. Identifying information will not be stored with study data.
Safety procedures specific to the war zone population: include exclusion of participants with
severe psychiatric instability or severe situational life crises, including evidence of being actively
suicidal or homicidal, or any behavior that poses an immediate danger to patient or others. For
participants enrolled in the study, requiring psychiatric interventions to manage deterioration of
clinical status will result in early study termination, and appropriate crisis management by a
study clinician, in conjunction with the participant’s primary mental health care provider and
referral to outpatient or inpatient psychiatric care at each study site.
In addition, due to the increased scrutiny surrounding studies of persons with comorbid
depression, we will specifically ask about suicidal ideation at each study visit. Participants who
endorse suicidal ideation will be assessed as to their level of risk and the level of care required to
keep themselves or others from harm. If a patient requires inpatient treatment in order to prevent
harm but is unwilling to accept that care, referral will be made to the county-designated Mental
Health Professional (MHP) and the patient will be supervised in a safe setting in the VA Puget
Sound emergency department until evaluated by the MHP and appropriate disposition made. In a
similar fashion, patients that are found to have symptoms of disorganized thought processes
secondary to psychosis would be accompanied by study personnel for emergency psychiatric
evaluation at VA Puget Sound.
Safety Monitoring: We do not intend to establish a data safety monitoring board for this study.
However, all adverse events (AEs) and serious AEs (SAEs) will be recorded and communicated
to the study P1 or other study clinician as soon as they are discovered. If AEs occur at a greater
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rate or with greater severity than previously encountered in our other prazosin studies, the study
will be suspended and the IRB notified. We will then work with the IRE to determine if and
when the study should be re-started.
Unanticipated AEs (physical complaints that are not present at baseline and which may be
related to study procedures) and AEs which are more serious than anticipated, but are not SAEs
will be reported to the IRE at the time of the annual report. SAEs (defined as any untoward
medical occurrence which may be related to study participation at any time during the study that
results in participant death, is life threatening, requires hospitalization, or results in persistent or
significant disability/incapacity) will be reported to the IRB within 5 business days of being
reported to the P1.
Adverse Events: all treatment for adverse events related to the study will be provided free of
charge. The Department of Veterans Affairs (VA) authorizes treatment for any study approved
by a VA R&DC. Participants who seek treatment for study-related adverse events in a non-VA
facility will be reimbursed for treatment costs. We have adequate personnel and equipment to
respond to expected and unexpected adverse events.
Specimen Banking: Participants may be asked to sign a separate consent form to allow us to
bank any samples leftover after study analyses for future research. This consent form will be
approved under a different IRB application. Information about potential specimen banking is
included in the consent form for this study. Participants may decline specimen banking and still
participate in this study.
Consideration of Potential Risks vs. Potential Benefits: All components of this study (use of
the medication prazosin, LPs, IV line placement, clinical assessments, cognitive assessments,
and actigraphy) are procedures routinely used in a wide variety of clinical settings in diverse
populations. There is currently no established or suspected intervention available to increase
clearance of neurotoxic protein biomarkers of neurodegeneration and dementia. This is an
adjunct study, so no usual care or alternative intervention will be avoided or delayed through
participation in this study.
Participants will not benefit from study procedures. Through participation in this research, all
participants will receive thorough medical and psychiatric assessments, which may benefit them
by providing them information about these assessments. Society at large will benefit if
treatments to increase clearance of neurotoxic proteins are discovered through this research.
If we can demonstrate that prazosin increases clearance of potentially neurotoxic proteins, this
will provide perhaps the first rational pharmacologic treatment strategy for prevention of post
repetitive mTBI CTE, and a novel approach for reducing the long-term increased risk of
Alzheimer’s disease following both TBI and PTSD.
5.1
Recruitment Methods
Description of the Recruitment Process: Participants will be recruited via referrals from VA
outpatient clinics, including MIRECC mTBI/Behavioral Specialty, Neurology, Primary Care,
Mental Health, Neuropsychology, Rehabilitation Medicine, Polytraurna, and others; VA
community-based outpatient clinics (CBOCs); local area Veterans centers; National Guard and
Reserve units; hospital health fair and hallway information tables; advertisement on VA
electronic reader-boards; public outreach presentations; posted IRB-approved advertising in
highly trafficked areas and clinic waiting rooms; advertisements in newsletters, local
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newspapers, radio, and the Internet; presentations to appropriate clinical services (such as grand
rounds presentations or service staff meetings); and word-of-mouth. All recruitment materials
will be submitted to and approved by the IRB before use.
Interested potential participants will contact the study team for more information. In addition, if a
clinical provider documents in their clinical note that a Veteran has expressed interest in
receiving information about the study, and the provider notifies us of this, we will contact that
Veteran directly; the request for contact (documentation in a CPRS note and co-sign to study
team) and the outcome will be documented in the pre-screen log. Please note that the note will
only say that the provider spoke to the patient about research, and that the patient has given
permission for the team to contact himlher, but will not include details about the type of research.
We may also contact a Veteran directly if they are in the BNG registry and have indicated that
they would like to hear about future research opportunities, or we have sent them the mailing
with opt-out information, but have not received an opt-out request. When we make contact with
a Veteran who has expressed interest, the study will be described privately either over the phone
or in person; eligibility requirements will be explained, preliminary eligibility will be
determined, and any questions will be addressed. Those meeting initial eligibility criteria will be
scheduled for an initial screening visit. The study consent form will be sent to potential
participants for their review prior to that visit.
Compensation: Participants will be compensated per the table below:
Type of Visit
Amount of
Total
reimbursement per visit
Reimbursement
Screen
$100
$100
Behavioral/Cognitive testing and
$50 (2 visits)
$100
questionnaires
Sample Collection (LP, blood)
$200 (2 visits)
$400
Titration and safety visits
$25 (up to 7 visits)
up to $175
Potential extra titration visits
$25 (0-3 total visits)
up to $75
Total for completed study without extra titration visits:
$775
Total for completed study with extra titration visits:
up to $850
Payments will be pro-rated, based on the number of completed study visits and weeks of
actigraphy. In addition, Participants will be compensated an additional $25 per visit if they must
travel between 50-100 miles round trip and $50 per visit if they must travel over 100 miles round
trip to attend study visits, to defray travel costs. This rate of compensation complies with the VA
Puget Sound IRB guidelines for prevention of research study participant financial coercion.
Small snacks (such as trail mix or granola bars) and water will be available for participants
during and/or following visits involving sample collection and neurocognitive testing.
Participants will be given lunch or a voucher to use in the VA cafeteria after LPs.
Payments for the screen and baseline 1 and 2 visits will be contingent on the return of all
equipment loaned to the participant for home use prior to these visits. Payments for the two parts
of the End of Study visits will be similarly contingent on the return of all loaned equipment prior
to the end of the study.
At the end of the study, participants will be given a certificate of appreciation and a tote bag to
thank them for study participation.
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5.2
Informed Consent Procedures
We will be performing a Medical Records Review before obtaining written study consent as
follows: potential participants will contact the study team as described above, or may be referred
to the study by their health care provider (the provider would either obtain permission from
his/her patient to release the potential participant’s name and contact information to the study
team, or the provider will give the study team’s contact information to the potential participant).
After the potential participant has spoken to a member of the study team and given verbal
permission to have medical records reviewed, a trained study team member will review the
records to screen for exclusionary medical conditions and medications. We will first obtain a
waiver of the requirement to obtain Health Insurance Portability and Accountability Act of 1996
(HIPAA) authorization and consent in order to pre-screen medical records from CPRS. If we
require non-VA medical records, a written Release of Information will be obtained.
Personnel who will be obtaining Informed Consent: Before co-Investigators and study staff
are considered qualified to obtain consent, they must first undergo all VA mandated trainings
and will also undergo internal training. They must become familiarized with MIRECC
procedures regarding obtaining consent, must be familiar with the study protocol, and must be
familiar with the risks and benefits of study participation. Once the P1 is satisfied that a co
Investigator or study staff member is competent to obtain consent, he will formally delegate
authority to obtain consent to that person. Because this is a clinical trial, a clinician (physician,
PA, or nurse practitioner) will be available either in person or by telephone to answer any of the
potential participant’s questions regarding the study drug.
Description of the Informed Consent Process: The P1 or another qualified study staff member
will explain the consent form at the Screening visit before study procedures are performed. If an
investigator is also the potential participant’s primary health provider, an alternate will conduct
the consent process. The consent discussion will be conducted in a private location. If the
potential participant wishes to have a relative or friend present during the consent process, we
will accommodate the potential participant. The person obtaining consent will give the potential
participant time to read the consent form and ask questions. The following elements will be
discussed with the potential participant:
•
The purpose and objectives of the study
•
The length of the study
•
Any potential risks, discomfort and inconvenience
•
The importance of following study procedures
•
The importance of compliance with all assessments and study visits
•
The possibility of the need for unscheduled visits
•
Randomization
— there is a 60%/30% chance of being randomized to either treatment
(active medication or placebo)
•
Participation is entirely voluntary and that the participant may withdraw from the study at
any time without loss of benefits to which he/she may otherwise be entitled
•
Alternative treatments
•
Compensation schedule for visits
•
The participant’s social security number (SSN) is required in order to maintain a medical
record and to reimburse participants. Participants will be informed that if they do not
wish to give us their SSN, they cannot participate in the study.
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•
Provisions for keeping study data confidential and exceptions to confidentiality
•
That adverse events are treated at no cost to the participant
The participant must sign an informed consent and HIPAA authorization as approved by the IRB
before any study procedures are performed. A progress note will be written in the participant’s
study chart to document the consent discussion was conducted and all questions were answered
to the participant’s satisfaction. A note will also be placed in CPRS records per current VA Puget
Sound guidelines.
A copy of the informed consent form can be given or mailed to interested potential participants
to review and discuss with family members or their primary physician without any time limit.
All participants will be able to provide consent on their own behalf. Because all
assessments are conducted in English, all participants will be sufficiently fluent in
English to read and understand the consent form. We do not anticipate enrolling any
illiterate volunteers.
5.3
Inclusion/Exclusion Criteria
Inclusion criteria:
•
Age? 21 years
•
Veteran of the U.S. Armed Forces
•
Ability to complete psychometric and other clinical assessments in English
•
No clinically significant laboratory abnormalities at screen
•
Platelet count >l00,000Irnm2 within two weeks of lumbar puncture (LP)
•
Body mass index (BMI) between 1 8 and 36 inclusive (BMIs outside this range may make
LPs for CSF collection difficult to perform). If a potential participant has a BMI over 36
but still in the 30s, they may be included if the clinician determines an LP would not be
difficult to perform.
•
Women of childbearing potential must agree to abstain from sexual relations that could
result in pregnancy or use an effective method of birth control acceptable to both
participant and the study clinician during the study. Men arc not required to use
contraception during the study
•
Meeting criteria for at least one of the following:
1.
History of mild or moderate TBI:
o
Exposure to at least one blast or experiencing at least one collision of the head
associated with acute symptoms that meet VA/DoD criteria for mild or
moderate TBI (loss of consciousness, if present, <24 hours; posttraumatic
amnesia, if present, <1 week; Glasgow Coma Scale (if available) 9-15)
o
>6 months since last TBI.
2.
Documented diagnosis of PTSD related to combat trauma (from any conflict)
Exclusion criteria:
•
Medical
—
History of severe TBI (Glasgow Coma Scale (if available) <9, loss of consciousness >24
hours, posttraumatic amnesia >1 week)
—
Acute or unstable chronic medical illness, including unstable angina, recent myocardial
infarction (within 6 months), congestive heart failure, preexisting hypotension (systolic
<110) or orthostatic hypotension (systolic drop > 2OmmHg after two minutes standing or
any drop accompanied by dizziness), autoimmune disorders; insulin-dependent diabetes;
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HIV.
—
Chronic renal or hepatic failure, acute pancreatitis, Meniere’s disease, benign positional
vertigo, narcolepsy, or diagnosed untreated sleep apnea (sleep apnea currently being
treated is not exclusionary).
—
Contraindications to LP (e.g., spinal cord injury; deformity, severe disease or infection in
the region of the lumbosacral spine; bleeding tendency, clotting abnormalities, use of
anticoagulant medications, or platelet count <iOO,000/mm2); trauma or infection in the 4
weeks before LP
—
Current pregnancy or lactation. Women of childbearing potential must agree to abstain
from sexual relations that could result in pregnancy or use an effective method of birth
control acceptable to both participant and the study clinician during the study. Men are
not required to use contraception during the study.
Note: Wounds requiring surgery, embedded shrapnel, and recent surgical amputation do not
comprise an exclusion if the individual is otherwise medically eligible.
Psychiatric/Behavioral
—
Meets DSM(IV or 5, depending on what evaluative method was used in this subject)
criteria for current schizophrenia, schizoaffective disorder, other specified or unspecified
psychotic disorder, delirium, or any DSM cognitive disorder
—
Current substance use disorder (except caffeine-related disorders, tobacco-related
disorders, or cannabis intoxication) other than in remission for at least 3 months. The use
of cannabis other than that meeting criteria for cannabis use disorder is not exclusionary.
Use of cannabis will be documented.
—
Current use of any stimulant, including prescribed stimulant medications
—
Current use (within the past 1 month, ongoing, or expected during the study period) of
any drugs that are illegal under Washington state law.
—
Severe psychiatric instability or severe situational life crises, including evidence of being
actively suicidal or homicidal, or any behavior which poses an immediate danger to
participant or others.
Note.’ Nonsuicidal depression comorbid with PTSD will not be exclusionary. Participants
may continue in any stable concurrent psychotherapy in which they are participating with the
exception of the evidence based trauma- and sleep-focused psychotherapies listed below.
Participants with active suicidal ideation or with depression severe enough to require
psychiatric hospitalization will be excluded.
Medications/Therapies
—
Current use of prazosin or other alpha-i antagonist or trazadone, or use of such agent
within the 3 month period prior to when the baseline 2 visit would be scheduled (a 3-
month washout is required due to the potential effects it may have on the biomarker
measurements).
Allergy or previous adverse reaction to prazosin or other alpha-i antagonist
—
Use of exclusionary medications in the 4 weeks prior to screening: selected CNS-acting
medications; antipsychotics, anti-Parkinson’s disease medications and CNS stimulants;
Coumadin or other medications affecting coagulation and/or inflammation (low-dose
aspirin and use of NSAIDs for pain will not be exclusionary); potent immune-modulating
medications, such as hydrocortisone or methotrexate.
—
Use of avanafil (Stendra), sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra)
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will be not be permitted during the study dose titration period because of increased risk of
hypotension in combination with alpha-i blockers, but will be allowed at 1/2 the usual
starting dose following dose titration
—
Current use of stimulants or nitrates, or of alternative medications or supplements with
stimulant properties (e.g., ephedra) or vasodilatory properties (e.g., nitrate containing
supplements)
—
Recent evidence based trauma- or sleep-focused psychotherapy, such as Prolonged
Exposure therapy (PE), Cognitive Processing Therapy (CPT), Eye Movement
Desensitization and Reprogramming (EMDR), Cognitive Behavioral Therapy for
Insomnia (CBTi) or Image Rehearsal and Rescripting therapy for nightmares. These
therapies must have been completed > 4 weeks before first baseline assessment visit
(study visit 2).
Note: Other psychotropic medications and/or maintenance psychotherapy at a stable dose for
at least 5 weeks prior to the Baseline-i visit and ambulatory monitoring will not be
exclusionary.
•
Other
—
Allergy or previous adverse reaction to prazosin or other alpha- 1 antagonist
—
Receiving another medication in another interventional study (except as described in
section 5.5 below).
5.4
Study Evaluations
Study Visits and Procedures: This is a two phase study. In phase I, all subjects will receive
open-label prazosin; in phase II, it will be an RCT where participants will be randomized 2:1 to
take prazosin or placebo, have samples collected for biomarker, and genetics, undergo sleep and
activity monitoring, and have cognitive and behavioral testing. The schedule of study visits table
at the end of this section provides a summary of study visits, procedures that will be performed at
each visit, and the estimated time required per visit. A detailed description of study instruments
follows the description of study visits.
Written informed consent will be obtained from potential participants prior to any study
procedures. The P1 or another qualified study staff member will explain the study procedures and
will review the consent form with the potential participant in a private setting. The potential
participant will be given time to read the consent form and ask questions. If an Investigator is
also the potential participant’s primary health provider, an alternate study staff member will
conduct the consent process.
Screening Procedures: At the screening visit, we will review the potential participant’s list of
medications; medical, psychiatric, military, and head trauma histories; including mechanisms
and circumstances of trauma (using the Traumatic Life Events Questionnaire [TLEQ] and
Combat Exposure Scale [CES]). Potential participants will be interviewed using the Structured
Clinical Interview for DSM-5 (SCID-5), SCID-IV, or MINI to rule out disqualifying major
psychiatric disorders and the Clinician-Administered PTSD Scale (CAPS) to diagnose and assess
severity of PTSD.) A short measure of cognitive function will be administered (Montreal
Cognitive Assessment [M0CA]):
Screening medical and neurologic exams will be performed. The physical exam will include
orthostatic BP and HR. A 12-lead electrocardiogram (EKG) will be obtained, if clinically
indicated. Laboratory studies, including but not limited to complete blood count, chemistry
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panel, vitamin B12, thyroid function, and coagulation (PT and PTT/INR) tests and a routine
urinalysis will be performed. Female participants of childbearing potential will have a urine
pregnancy test, which must be negative in order to continue study participation. If it is found that
a potential participant does not meet the inclusion criteria, follow-up care will be coordinated.
Participants who remain eligible after screening will be asked to undergo the following study
procedures:
At-home BP monitoring and monitoring of sleep activity (description of equipment and sleep
logs below after the description of study visits): At the end of the screen visit, we will place the
at-home BP monitoring equipment on the study participant. The participant will remove the BP
monitoring equipment after 24 hours and will bring it back at Baseline visit 1. We will also give
the study participant an Actiwatch to wear until Baseline visit 2 (typically 9-14 days total,
although possible alterations in this timing are discussed under “Potential exceptions to visit
schedule” below). Instructions for wearing the Actiwatch and filling out a sleep diary during this
time will also be given to participants.
Baseline visit 1—Clinical and Cognitive Assessments, pupillometry, placement of HR monitor:
Health history and list of medications will be updated as needed. Vital signs will be taken.
Behavioral, functional, and cognitive instruments/questionnaires will be administered as outlined
in the schedule of study visits. If it has been longer than 2 weeks since screen (or if BL visit 2 is
expected to be longer than two weeks from screen), about 5-10 ml of blood will be collected for
blood count and coagulation tests.
Participants will return the BP monitoring equipment and will have an ambulatory HR monitor
placed. When possible, the HR monitor will be placed at a point in the visit prior to the
completion of the neurocognitive testing, in order to allow the degree of correlation between the
results of the heart rate variability analysis and the pupillometry analysis to be assessed; this will
then count as the beginning of 24 hours of use, after which the participant may remove the HR
monitor. Participants will continue wearing the Actiwatch and filling out sleep diaries until the
baseline 2 visit.
Baseline Visit 2—Collection of samples for DNA and biomarker measurements (LP, and blood
collection): This visit will take place in the Clinical Research Unit (CRU) at the VA in Seattle.
Participants will be asked to arrive at the CRU at 8 am. They will have been fasting (nothing to
eat or drink except water) from midnight the night before the study. If participants take
medications in the morning, they will be asked to bring the medications with them to take after
the LP is done (usually by 11 am). This study visit will take approximately 3-3.5 hours.
Participants will be given lunch (or a voucher to use in the VA cafeteria) and instructions for
what to do for 24 hours post-LP before they leave. The day after the LP, our research nurse or
clinician will call the participant to make sure there are no adverse events.
Participants will return the HR monitor, Actiwatch, and sleep diaries. We will ask about the
participant’s health and current medications to make sure the participant has not had an acute
illness within the past two weeks. A urine sample will be collected from women of childbearing
potential. If the pregnancy test is positive, the participant will be withdrawn from the study.
Next, participants will lie in bed, at which point an indwelling i.v. catheter will be placed in an
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antecubital vein and kept patent with a slow (50 ml/hr) infusion of normal saline. A small
amount of blood will be collected right away to test platelet levels. The i.v. allows us to infuse
fluids if needed and to collect 150 ml of blood for DNA and measurement of plasma and serum
biomarkers and proteomics.
Following blood collection, CSF will be obtained by LP. All LPs will be performed by a
physician credentialed to perform LPs and trained in our specific research procedures. The
participant will be placed in the lateral decubitus position (asked to lie on his or her side with
knees curled up toward the chest). The L3-4 or L4-5 interspace will be infiltrated with 1%
lidocaine to provide local anesthesia. The LP will be performed atraumatically with a 24g bullet-
tip Sprotte spinal needle and 28cc of cerebrospinal fluid will be withdrawn with sterile syringes.
Use of the 24g Sprotte atraumatic spinal needle is recommended by published guidelines on
prevention of post-lumbar puncture headache and greatly reduces frequency of post-lumbar
puncture headache (<1%). We have been using this technique for 8 years with very low
incidence of adverse events. After the LP, the i.v. catheter will be removed. The participant will
remain in bed for one hour following the LP to reduce the chance of post-LP headache.
Randomization and Study Drug Titration: Following collection of the samples, participants will
receive the first week’s supply of study drug and will be instructed in dosing procedures and
safety precautions to prevent potential adverse effects. They will be instructed to start taking the
study drug the third night following LP. The starting dose for all participants will be 1 mg taken
at bedtime (qhs) for the first 2 nights. The dose will be increased to 2 mg qhs on days 3-7.
Titration Schedule
AM dose (morning)
PM dose (afternoon)
QHS dose (bedtime)
Days 1-2
1 mg
Days 3-7
2 mg
Week2
1mg
1mg
4mg
Week3
1mg
1mg
6mg
Week4
2mg
2mg
10mg
Week5
2mg
2mg
15mg
Weeks 6-10
5 mg
5 mg
15 mg
For the first week, the study drug will be taken while the participant is in bed for the night, to
avoid orthostatic syncope, an uncommon but recognized “first-dose” effect of prazosin. The first-
dose effect is avoidable by starting treatment with a low dose, then titrating upward gradually,
per the table above.
Participants will be seen at each dose increase after completion of the first week to evaluate for
adverse effects, record any new medications and interval medical problems, monitor supine and
standing BP and HR, to assess drug compliance, determine whether proceeding to the next step
of the dose titration is appropriate, and to provide additional study drug for the scheduled dose
increase, decrease, or dose maintenance.
Occurrence of lightheadedness, dizziness on standing, palpitations, drowsiness, headache,
nausea, nasal congestion, peripheral edema, and other adverse effects will be rated by a clinician
as absent, present, ongoing, worsening or unacceptable. The clinician will also assess if these
side effects are due to factors that may be unrelated to the medication (i.e., if the participant has
been ill or is dehydrated) For vital signs parameters, unacceptable side effects will include supine
hypotension (supine systolic BP<100) and clinically meaningful orthostatic hypotension (> 20
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mrnHg drop in systolic BP accompanied by dizziness, lightheadedness or syncope).
For participants maintained on other antihypertensive medications, their primary care provider
will be informed of clinically significant blood pressure reductions at any time during the study
to allow adjustment of the participant’s antihypertensive regimen. As a further precaution, male
participants will be advised to sit on the toilet for urination during the first night of medication
use. Participants will be asked to call a study clinician the day after the first dose to make sure
there was no occurrence of postural dizziness.
If a participant has unacceptable side effects, the dose will be reduced to the previous titration
step. Participants who cannot tolerate the dose of 1mg morning,
1 mg afternoon and 4 mg
bedtime will be reduced to the dose of 1 mg morning,
1 mg afternoon and 2 mg bedtime. If the
participant is unable to tolerate a minimum dose of 1 mg morning, 1 mg afternoon, and 2 mg
bedtime, he/she will be terminated from the study.
If a participant is unable to make it to a titration visit (due to illness, scheduling, etc.), the
participant will be offered the option of completing the visit via the telephone; this visit will
include all of the elements of a regular titration visit except for those that must be done in person,
such as vital sign assessment. Alternatively, if the participant is not able to complete the study
visit at all, the study clock will be “stopped” temporarily and his/her dose will be maintained at
the current level until he/she is able to come for another titration visit. The titration period can be
extended up to an additional three weeks in that maimer.
Study Treatment Period: Once the participant has reached his/her highest tolerated dose, he/she
will enter the Study Treatment Period. The participant will maintain this dose for a minimum of
5 weeks. A clinic visit will take place at one and four weeks after stable dose is achieved to
assess for adverse events. Concomitant medications and health status will be updated. Study drug
adherence will be tracked by pill counts.
At the 4 week stable dose visit, we will place the ambulatory blood pressure monitoring
equipment, and the participant will be sent home with the Actiwatch and sleep diaries and told to
wear them as before.
After 5 weeks at stable dose, participants will undergo cognitive/behavioral testing and sample
collection visits just as in baseline visits 1 and 2 (with the exception that blood will not be
collected). Ambulatory heart rate measurements will be collected during and following the end
of study 1 visit, again as during the baseline period.
Potential exceptions to visit schedule:
If the content of either the screening or a baseline part 1 assessment visit cannot be completed in
the expected time, or the participant wishes, the visits can be divided into separate visits.
If CSF cannot be collected at an LP visit, and the participant is willing, an additional LP visit
will be scheduled. Participants will be compensated for the time and effort involved for any extra
LP visit. Additional safety visits may be required if participants have laboratory abnormalities or
adverse events (AEs) that require continued follow-up (we will follow until abnormality/AE is
resolved).
If the participant is unable for some reason to wear the ambulatory monitoring equipment during
the usual periods of time, their use may be delayed for up to two weeks. To accommodate this,
the participant may take the equipment home early and be trained in placing the equipment on
themselves; alternatively, if the participant or clinician are for any reason concerned about the
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participant’s ability to place the monitoring devices on themselves, or simply for participant
preference, the participant may visit the clinic for an extra 1-2 brief visits for the devices to be
placed on the participant.
If upon return of ambulatory monitoring equipment it is discovered that user or technical error
prevented sufficiently high quality data from being collected, the ambulatory monitoring attempt
may be repeated if the participant is willing and the involved clinicians believe there is a
reasonable chance of success with a second attempt. In such cases, the ambulatory monitoring
periods may also extend for up to two weeks beyond their usual time windows.
At times, for any of these reasons or to accommodate the participant’s scheduling constraints for
the baseline visits, the period of actigraphic monitoring may be extended to up to 30 days in
order to encompass both the periods of ambulatory blood pressure and heart rate monitoring and
the week prior to the two baseline visits.
However, ambulatory monitoring will not be done any more than two weeks past baseline LP nor
once prazosin has been started, and end of study measures will not be completed any more than
two weeks past baseline LP nor once prazosin has been stopped. If necessary, an additional
period of up to two weeks delay after the baseline LP but prior to the initiation of prazosin may
be added to accommodate this or other scheduling difficulties in obtaining baseline ambulatory
monitoring data, and an additional period of up to two weeks of taking the achieved stable
prazosin dose may be added to the end of the study in order to accommodate this or other
scheduling difficulties in obtaining end of study ambulatory monitoring data. Overnight blood
pressure monitoring will not be performed within the 7 day period immediately prior to an LP, to
ensure that this procedure does not change the results of the laboratory results via an impact on
sleep.
Although all efforts will be made to complete study visits in person, it may be necessary to
obtain assessments by telephone. The following actions will be attempted (as appropriate per
visit schedule): 1) adverse events will be assessed, 2) assessments shall be completed by
telephone interview with the raters, 3) self-rated measures will be provided to participants, then
returned by mail using prepaid envelopes, and 4) dispensing of study drug shall be done by
trackable shipment. No-show, missed visits and actions taken will be documented in the study
record.
In general, we expect that ambulatory monitoring equipment will be returned by participants in
person at subsequent visits. If, however, a schedule change, early termination or other unplanned
alteration (e.g., a participant forgets to bring it to a visit as planned), there will be two alternative
methods for collecting the equipment: first, a member of the study team may go to the
participant’s location in the community to receive the item from them, or, second, the item can
be mailed back using postage-paid, self-addressed packing.
Potential exceptions to study procedures:
Participants already randomized to prazosin versus placebo prior to approval of the protocol
modification instituting an initial, phase I open-label phase will continue to receive prazosin
versus placebo in a double-blind fashion without alteration. Similarly, an individual who is
participating in the study only via dual-enrollment (where the prazosin versus placebo is being
administered as part of another study, and it is only assessments being conducted as a part of this
study), will continue to be directly enrolled in the phase II version of the trial. All changes in
study procedures will only apply to subjects who have not yet been randomized.
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Phase I is designed to run until at least 22 participants have completed the full protocol, and their
data has been analyzed. As discussed below in the data analysis section, if at the end of phase I
the results are potentially consistent with a clinically significant effect, but do not yet meet
statistical significance, we will continue the open label portion until we have 37 subjects who
have completed the study (15 subjects beyond the initial 22), which is expected to involve 26
additional subjects screened when allowing for expected screen failure and dropout rates.
Some participants may also be (or have been in) in another study longitudinal study of mTBI that
is being conducted by the MIRECC research group. If these participants have also agreed to have
samples and data stored in the Behavioral Neurosciences Group (BNG) research repository
(MIRE #00891, Elaine Peskind PT), many screening/study assessments and the baseline sample
collection may not need to be repeated (as described below).
The MIRECC research group is also conducting a study of the potential efficacy of prazosin in
relieving post-traumatic headaches in Veterans with mTBI. Some of these participants will also
be eligible for participation in this study. We wish to allow these participants to be in both
studies simultaneously in order to maximize scientific learning and medical advances while
minimizing participant burden. It also limits potential bias in the results of this study that might
come if participants that qualified for competing local studies were enrolled at lower rates than
their prevalence in the local community.
In this case, once the potential participant is recruited and enrolled into the related headache
study and the BNG repository, and if the potential participant and both study PIs agree, we will
alter the schedule of this study as described below and will place information gathered in each
study in the BNG repository in real time so that it will be possible to share information between
studies so that participants may be able to be in both studies at the same time without having to
repeat study evaluations and other procedures.
1.
Screen: All items except study consent and vital signs that are scheduled for the screening
visit may be taken instead from the same item previously carried out within the prior year
with the following exceptions:
a.
a previously completed TLEQ will only be used if it contains the modifications that
include collection of information on the timing of events;
b.
updates will be obtained for medical and psychiatric history and current medications;
c.
physical and neurological exams will be repeated if they were last done more than 3
months ago, or 4 weeks ago if there are any elements in the medical or psychiatric
history, vital sign data, or on previous physical/neurologic exam that suggest the Veteran
may have increased risk for adverse outcomes with prazosin;
d.
a general screening question will be asked to ascertain whether there may have been any
potentially traumatic experiences since the SCID, CAPS, and TLEQ were last completed,
and if so, they will be redone as indicated.
2.
Baseline 1:
a.
Any previously completed WTAR may be substituted for the WTAR for the baseline 1
visit of this study.
b.
Any other component of the baseline 1 visit may be taken instead from an equivalent
item previously carried out as long as it is completed within one month of the baseline
LP. Although we will try to carry out these assessments in an order and configuration that
is consistent across participants, this will not be an absolute requirement; for example, if
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a participant has completed the WTAR two years ago and the ACT and SDMT one week
ago, we will only include the CVLT, dot counting test, emotional Stroop test, and PVT
for the baseline 1 neurocognitive testing, as the repeated-measure effects from repeating
the ACT and SDMT so close together would be more of a concern than the variability in
administration context.
3.
Baseline 2: Any LP completed in the two weeks prior to scheduled randomization date and
with sufficient CSF sample collected for our primary outcome measures will be allowed to
substitute for the baseline LP. Any previous genetic testing from the prior 10 years may be
substituted for equivalent genetic testing in this study.
4.
Prazosin or placebo titration and maintenance: If a participant is concurrently enrolled in
MIRECC prazosin vs. placebo study with overlapping inclusionlexclusion criteria the dosing
schedule and data collected from stable dose study treatment period of the other study will
be used (instead of the schedule for this study), if the following conditions are met:
a.
The target dose per day of study drug is within 25% of the target dose per day in our
study
b.
The procedures performed at end of study visits 1 and 2, including the associated
ambulatory monitoring, will be completed after the participant completes the study
treatment period of the concurrent study. We will attempt to coordinate study schedules
so there is a mid-point visit that matches when our Stable Dose week 4 visit would be
scheduled.
5.
End of study assessments: substitutions will be allowed as with the baseline assessments,
described above.
Any non LP visit-related adverse events will be reported to the IRB for both studies, and it will
be noted that the participant is in both studies simultaneously.
Schedule of Study Visitsa:
2
2.
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4-8
9
10
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Study Week
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0
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1-5
6
9
9-10
10
10
Obtain Consent
X
Medical and Psychiatric 1-listory
X
Physical exam, Neurological exam
X
Urine pregnancy test (women of
X
X
x
childbearing potential)
Screening labs
xb
EKG (if clinically indicated)
X
Demographic Information, Military
X
History, Combat Experiences Scale
SCID/MINI
x
Quantification of Blast Exposure
X
CAPS
X
X
X
TLEQ
X
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.
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STOP-BANG Sleep Apnea Screening
X
MoCA
X
X
X
WTAR
X
ACT
X
X
SDMT
X
X
CVLT
X
X
Dot Counting Test
X
X
Emotional Stroop Test
X
PVT
X
X
PHQ-9
X
X
X
GAD-7
X
X
X
PSQI
X
x
X
X
X
VR-12
X
X
X
DVPRS
X
X
X
AUDIT-C
X
X
X
QCC
x
CSN
X
X
X
PCL
X
X
X
NSI
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
Review Concurrent Medications
X
X
X
X
X
X
X
X
Review Adverse Events
X
X
X
X
X
X
X
X
Dispense/collect study drug
X
X
X
X
X
Wear Actiwatch, Complete Sleep Diary
X
X
Wear blood pressure/heart rate monitor
X
X
Lumbar Puncture
XC
X
Blood collection for biomarkers/DNA
XC
Estimated Time of Visit (hrs.)
4.5-
2.5
3
.5
.5
1.5
.5
.5
3
3
6.5
This schedule may be revised if procedures have been done for a different study within a certain period of time or if
participating in two studies simultaneously. Participants will be informed if their existing data can be reused.
blf more than two weeks will have passed between screen LP visit, then platelet count and clotting time labs will be drawn
at these visits.
C If DNA is already available in a research repository, it will not be collected. If an LP has been performed within two
weeks of randomization, and sample is available in the repository, LP will not be done at baseline visit 2.
dFor second and third QCC, an abbreviated follow up version will be used
There may be up to three additional titration visits, which would add three weeks to the total length of the study.
Blood and saliva for DNA will only be collected at first biomarker collection visit.
routine titration / follow up visits, an abbreviated, 1 page version of the PSQI will be used.
Detailed Descriptions of Study Assessments:
•
Structured Clinical Interviewfor DSM-5 Axis I Disorders (SC’1D5,)24: A widely used
structured interview that assesses Axis I psychiatric history. The SCID has very good
reliability and validity. The SCID will be used at the screen visit to rule out exclusionary
diagnoses and to describe the subject sample.
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•
Structured Clinical lntervieivfor DSM-lVAxis 1 Disorders (SC’ID-IV,): Previously version of the same
widely used structured interview that assesses Axis I psychiatric history. The SCID has very good
reliability and validity. The SCID will be used at the screen visit to rule out exclusionary diagnoses
and to describe the subject sample. If clinically or logistically more accessible, due to previous
assessments undergone by this particular subject or new information on the relative utility of the
different instruments, we may carry out and/or accept the SCID for DSM-IV or the MINI in place of
the SCID5. The SCID for DSM-IV has been a widely used structured interview that assesses Axis I
psychiatric history according to the DSM-IV criteria, and is still administered in many of the ongoing
research studies here at the MIRECC. The Mini International Neuropsychiatric Interview
(MINI)(Sheehan et al., 1998) is a widely used alternative that is also designed to take into account the
International Classification of Disease (lCD) 10 criteria, and is widely used internationally.
•
Clinician-Administered PTSD Scalefor DSM-5 (‘APS,25: A structured clinical interview
designed to assess the symptoms of PTSD outlined in the DSM-5. The CAPS allows the
interviewer to make current (past month) and lifetime diagnoses of PTSD. The frequency and
intensity of each symptom on the CAPS is rated on separate 0-4 scales. The CAPS has
become the standard for psychopharmacologic outcome trials in PTSD.
•
Combat Experiences Scale (‘CES,)26: Will be used to describe the degree of combat trauma
exposure in the study sample. Scores range from 1-18. The CES has been utilized in many
studies evaluating combat Veteran samples and is relevant to any war zone setting from
WWII to OEF/OIF/OND.
•
Traumatic Lfe Events Questionnaire (TLEQ)
— modifIed27: A 23-item self-report measure of
22 types of potentially traumatic events including natural disasters, exposure to warfare,
childhood abuse, and community violence, developed and validated by VA researchers.
Traditionally this scale was designed around the DSM-IV, and for each event, respondents
are asked to provide the number of times it occurred and whether fear, helplessness or horror
was present. However, with the criterion for the experience of fear, helplessness or horror
having been removed from the definition of PTSD in DSM-5, and with our interest in
potential physiologic impacts of traumatic exposures, which may vary based on the age at
which an event was experienced and the time since the event, we have modified the TLEQ to
replace the questions about the experience of fear/helplessness/horror with the question “At
approximately what age(s) did this happen?”
•
STOP-Bang Sleep Apnea Screening28: A widely used screening tool that uses 8
yes/no questions to screen for individuals having an elevated risk of obstructive sleep
apnea (OSA) sufficient to warrant further evaluation. The STOP-Bang will be used to
assess for indications of OSA to be used as covariates in later analysis. In addition,
those who screen positive for an elevated risk of OSA and who have not been
evaluated for OSA will be provided with appropriate referral options for further
evaluation, either by referral to the VA sleep medicine service (for Veterans) or by
referral to community providers (non-Veterans and requesting Veterans).
•
Montreal Cognitive Assessment (MoC’A)29: A clinician-administered instrument designed to
detect mild cognitive impairment, providing a brief assessment of short-term memory recall,
executive function, sustained attention, calculation, language, and orientation. Scores range
from 0-30, with lower scores indicating greater cognitive impairment. Test-retest reliability is
high, with less than one point variation. Internal consistency is good (Cronbach alpha=0.83).
To correct for education, I point is added for those with less than 12 years of education.
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Patient Health Questionnaire-9 (PHQ-9)30: The 9-item depression module of the Patient
Health Questionnaire, a self-report version of the PRIME-MD used to diagnose major mental
disorders. The PHQ-9 items correspond with DSM-IV criteria for depression, with each item
scored from “not at all” to “nearly every day.” Items of the PHQ-9 are internally consistent
(alpha = 0.86-0.89) and the questionnaire exhibits high test-retest reliability coefficients.
Agreement between the PHQ-9 and clinician-based interview diagnosis of major depression
is high, with a sensitivity of 88% and a specificity of 88% using a PHQ-9 score? 10.
•
General Anxiety Disorders-7 (GAD-7,)31: A 7-item self-report questionnaire assessing
generalized anxiety symptoms that has been broadly assessed for reliability and validity as a
measure of anxiety across the general population. Each item assesses the participant’s
frequency of experiencing a different common anxiety symptom over the past two weeks on
a scale of “not at all” I “several days” / “over half the days” and / “nearly every day”. Each
response can be assigned a number from 0-3, and the responses can be summed to provide a
simple quantification of overall anxiety.
•
Pittsburgh Sleep Quality hidex (PSQI)32: A self-report questionnaire assessing sleep quality
and disturbances over a 1-month time interval. Nineteen individual items generate seven
subscale scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep
efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. A global
score may be obtained by summing the seven component subscales (total score range: 0-2 1).
•
Veterans’ RAND-]2 (VR-]2,)33: A shorter version of the Veterans SF-36, which was based on
the administration of the Medical Outcomes Study SF-36 to a large sample of Veterans. The
Veterans SF-36 differs only slightly from the standard SF-36, in that the physical and social
role scales are converted from dichotomized choices to 5-point ordinal response options to
reduce floor and ceiling effects. The SF-I 2V assesses the same 8 heath concepts (physical
functioning, role limitations due to physical problems, bodily pain, general health, vitality,
social functioning, role limitations due to emotional problems, and mental health) as the SF
36V but uses fewer items for 7 of the 8 scales. Results are expressed as physical and mental
component summaries. Scores on the SF-12V have been shown to correlate strongly with the
Veterans SF-36. The SF-12V is the “gold standard” for measuring health related quality of
life, owing to its established reliability, validity, and widespread adoption in clinical
treatment trials.
•
Defrnse and Veterans Pain Rating Scale (DVPRS)34: A visual pain rating scale assessing the
severity of pain in various areas of the body and how much pain affects the participant’s
daily activities, sleep, mood, and stress.
•
PTSD Checklistfor DSM-5 (PC’L,) without Criterion A35: A well validated 20-item self-report
measure assessing severity of PTSD symptoms consistent with DSM-5 criteria, with scores
ranging from 0 to 80.
•
Alcohol Use Disorders Identification Test-Consumption (AUDIT-c’,)36: A 3-item modification
of the AUDIT questionnaire that enquires about frequency and quantity of typical alcohol
consumption, and the frequency with which the respondents report an episode of heavy
drinking in the past year. The AUDIT-C demonstrates excellent sensitivity and specificity for
detection of heavy drinking and is used as a standard screening tool for alcohol problems in
VA primary care settings.
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Quantification of Cannabis Consumption (QCC): A brief questionnaire developed by our
research group in consultation with local cannabis researchers that enquires about frequency,
quantity and methods of typical cannabis consumption. The questionnaire has been designed
around local consumption patterns since the state-level legalization of cannabis use in
Washington state, assessing the use of edible and concentrated forms of cannabis as well as
smoked forms. The questionnaire also includes questions about subjects’ experiences with
the effects of cannabis on their mental health and daily functioning.
•
Caffeine, Sugar and Nicotine (CSN) assessment: A 1 page questionnaire developed by our
research group that draws two items from the Fagerstrom test for nicotine dependence and
adds a general frequency of use assessment of different sources of nicotine, caffeine and
sugar and some of the primary motivations for this use. This assessment is designed to
rapidly accomplish two things: first, to assess for levels of caffeine and nicotine use that are
likely to be directly affecting sleep structure or quality, and second, to detect any large
changes in patterns of use over the course of the study.
•
Neurobehavioral Symptom Inventory (NSI,)37: A 22-item questionnaire designed to assess the
presence and severity of common cognitive, emotional, sensory, and somatic symptoms that
can occur after traumatic brain injury. Patients rate on a 5-point scale the extent to which
each symptom has affected them (rated from “absent” to “very severe”). Anchor descriptions
are provided for level of severity. This scale is widely used in VAs across the country as part
of the standardized TBI Comprehensive Evaluation.
•
Wechsler Test ofAdult Reading (WTAR)38: Will be used to assess premorbid intellectual
ability. This measure has excellent internal consistency (0.90 to 0.97), high test-retest
reliability (>0.90), and it correlates highly with WAIS-Ill Verbal IQ (r=.75) and Full Scale
IQ (r=0.73). This test typically takes 5 minutes or less to complete.
•
Auditomy Consonant Trigranis Test (AC])39: A measure of short term working memory in
which individuals will be asked to recall a series of items after a delay. During the delay,
they are asked to complete an interference task (like mental arithmetic). This test takes
approximately 5 minutes to complete.
•
Symbol Digit Modalities Test (‘SDM])40.’ Will be used to measure processing speed and
divided attention. The participant is provided with a coding key that contains 9 abstract
i..
symbols, each paired with a number. Then the participant is asked to fill in empty boxes with
the correct number, using the key described above. In part 1 of the task, the participant writes
down the answers. In part 2 of the task, they say the answers out loud. This test takes
approximately 5 minutes to complete.
•
California Verbal Learning Test-If (‘CVL])41: A measure of verbal learning and memory. It
has also been shown to be a reliable measure of learning and memory (with internal
consistency values ranging from .78 to .94). This measure takes 15-20 minutes to complete.
•
Dot Counting Test: Developed in the 1940s as a test of effort and used with minimal
modification since this time, this test consists of 12 cards with differently grouped patterns of
dots, which subjects are asked to count as quickly as possible. The test has been assessed for
validity in a wide variety of populations including those with MCI or mild AD, depression,
brain injuries, stroke, and populations with learning disabilities. This measure typically takes
less than 5 minutes to complete.
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•
Emotional Stroop Test42: This test is a widely used measure of the extent to which affective
arousal interferes with cognitive processing. It can be tuned to different categories of
emotionally arousing stimuli, including combat-related terms, and has been found to be
particularly sensitive to the presence of PTSD in combat Veterans, including OEF/OIF
Veterans. It is a computerized test where an individual is shown one word at a time and asked
to identify the color of the word being shown, and the reaction time as a function of whether
the word presented is one with a positive affective tone, a negative affective tone, is neutral,
or is combat related, is assessed. It is compatible with simultaneous recording of pupil
diameter (pupillometry) to correlate results with an independent physiologic measure of
affective arousal, vigilance, and locus ceruleus activity in particular. It takes 15-20 minutes to
complete this task.
•
Psychomotor Vigilance Test (P VT)43: This test is a widely used measure of behavioral
alertness, with high sensitivity to both acute and chronic sleep deprivation, as well as
sensitivity to restoration of healthy sleep. It is a computerized test that is given in 5-minute or
10-minute versions, where subjects are asked to press a button each time a visual stimulus
appears on the computer screen. The stimulus appears at random inter-stimulus intervals, and
both response time and false starts are recorded. The 10-minute PVT has been shown to be
highly reliable across a wide variety of populations, and has no measurable learning effects
with repeat administration. It is compatible with simultaneous recording of pupil diameter
(pupillometry) to correlate results with an independent physiologic measure of affective
arousal, vigilance, and locus ceruleus activity in particular.
•
Pupillometrv: Pupil diameter provides a noninvasive real-time physiologic measure of
affective arousal, vigilance and locus ceruleus activity. Pupil diameter will be recorded using
an eyetracking-based pupillometry system both at rest and during the performance of the
computer-based neurocognitive tests (the PVT and the Emotional Stroop). This equipment
monitors pupil diameter using a camera placed at a distance from the participant’s eye and
carries no additional risk to the participant.
•
Actigrapliv: The Actiwatch Spectrum Plus (Philips Respironics, Bend, OR) is a wristwatch-
like device that measures gross motor activity, integrates the degree and intensity of motion,
and records an activity count per a specified epoch length. Recorded activity may vary from
zero (no activity) to hundreds per epoch (high activity). An activity count for each epoch is
downloaded from the device to a computer program (Actiware, Philips Respironics, Bend,
OR), and analyzed using standard statistical software. Sleep variables calculated include total
sleep time, total time spent in bed, sleep onset latency, number of awakenings, sleep
efficiency, and wake time after sleep onset.
•
Blood Pressure (BP,) monitoring: The SpaceLabs OnTrak ambulatory blood pressure
monitoring system consists of a blood pressure cuff connected to a small computerized
device that is programmed to inflate the cuff and take and record a BP measurement at
preprogrammed intervals. The previous version of this same device has been used by
researchers to demonstrate a connection between PTSD and/or trauma exposure, and a failure
to display the normal nighttime drop in BP that occurs during sleep44.
•
Heart Rate (HR) Monitoring. The CamNTech Actiwave cardio ambulatory single channel
ECG waveform recorder consists of two electrodes connected by a short lead, which clip
onto two standard ECG pads worn on the chest; the entire unit weighs only I 0.3g, and can
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record up to 31 hours of data at 128Hz resolution. A tn-axial accelerometer is built into the
unit as well, to facilitate correlation of the recorded data with sleep and activity states. The
recorded data can be used to assess baseline HR during wake and sleep states, as well as HR
variability, a measurement frequently used to provide an indication of both sympathetic and
parasympathetic activity during both wake and sleep.
Consensus Sleep Diaiy-E (C’SD-)45: A pre-printed form in calendar format used for self-
report of quantitative and subjective measures of sleep quality, completed on a daily basis
during the same periods that the participant is wearing an actigraph. The CSD-E includes two
sections, one to be completed in the morning upon awakening and the other to be completed
before bed. This sleep diary is based on consensus recommendations of sleep experts.
5.5
Data Analysis
Power calculations were carried out for the primary endpoint of CSF A342. For both phases, an
estimated mean baseline value of 294 ng/L with a baseline standard deviation of 54 ng/L, based
on previous findings from a group of boxers with repetitive mTBI46, and the previously reported
Pearson’s coefficient of.98 for the stability of CSF A42 measurements within a single
individual but based on CSF samples collected six months apart47 were used. With these
numbers, we can estimate an expected standard deviation of the change from baseline of 10.8
ng/L.
For phase I, our goal is to rapidly test whether there is a reasonably high likelihood of efficacy
based on the first, smaller series of subjects. To achieve this, we will formally examine the data
at the point where we have an 80% power to detect a decrease in the prazosin group as compared
to the placebo group of approximately 5%, which is the minimum we expect to have the
potential to be clinically significant. Using a one-sample t-test with a 5% Type I error rate, this
means we will require 22 patients to complete the study. Based on previous experience, we
expect a screen-failure rate and dropout rate of 30% each, suggesting that we will need 38
participants to be screened in order to obtain an enrollment of 39 participants with at least 22
completers.
If the results of the initial phase I portion are positive, we will continue on to phase IT. Here, our
goal is to provide a stronger, randomized controlled test of the effect of prazosin on biomarkers
of neurodegeneration and dementia. Setting our Type II error rate now at 10%, using a two-
sample, two-sided t-test using a 5% Type I error rate, this means we will require 60 total patients,
with 40 receiving prazosin and 20 receiving placebo, in order to have a 90% power to detect a
decrease in the prazosin group as compared to the placebo group of approximately 5%, which is
the minimum we expect to have the potential to be clinically significant. Based on previous
experience we expect a screen-failure and dropout rate of 30% each, which suggests that we will
need 120 participants to be screened in order to obtain an enrollment of 90 participants with at
least 60 completers.
If at the end of phase I the results are potentially consistent with a clinically significant effect,
but do not yet meet statistical significance, we will continue the open label portion until we have
enough subjects who have completed the study to increase the power from 80% to 95%. Again
using a one-sample t-test with a 5% Type I error rate, this would require 15 additional
completers above the 22 initially planned, or 26 subjects screened when allowing for the same
expected screen failure and dropout rates.
Particinant Randomization: Participants in phase II will be randomly assigned 2:1 to prazosin or
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placebo, stratified by gender and group (TBI only, PTSD only, or both). Permuted block
randomization codes within each stratum will be generated by a MIRECC staff member
uninvolved with this study using statistical software. This person will create one card per subject
number specifying treatment assignment and will prepare double envelopes labeled with the
subject number and containing the treatment group assignment card. These envelopes will be
used for purposes of breaking the blind when necessitated by medical emergency when a
computer and the Internet may not be available, and following study termination assessments
(see section 5.7 below). In addition, the investigational pharmacist will have access to the
randomization codes. No other study personnel will have access to the randomization codes.
Descriptive statistics of baseline characteristics will be calculated: demographic variables, vital
signs, number and cause of TBI, mental health and substance use assessment scales, cognitive
testing scores, total sleep time by participant report and by actigraphy, and sleep fragmentation
index as measured by actigraphy.
Primary outcome measures will be CSF total-tau, p-taulsl, and A42. For each outcome, we will
use a linear regression model to compare, between treatment groups, the within-subject changes
in biomarkers from baseline. The model will include concentration at study completion as the
response (dependent) variable, and the concentration at baseline and treatment group as the
predictor (independent) variables, along with the covariates age, gender, APOE*4 status, and
blast exposure quantification. To account for dropouts and subjects who have their final
biomarker assessment prior to 10 weeks, we will also use a linear mixed-effects regression
model48 with biomarker concentration as the response variable, and the predictor variables time,
treatment group, and a time by treatment group interaction term, along with the same covariates
as for the linear regression model. Exploratory analyses will be conducted of the interaction
among biomarkers; sleep and ambulatory monitoring variables; participant-reported symptoms
of PTSD, depression, and postconcussive symptoms; and cognition.
Data will be analyzed by co-investigator Rebecca Hendrickson, with consultation as necessary
with the MIRECC biostatistician, Steven Millard, PhD, regarding the analysis plan and
interpretation.
Data Management: All study information will be recorded on standardized CRFs. Forms will
be labeled with study code numbers only. Code numbers will be assigned sequentially, and will
not include participant initials or any other personally identifiable information. Source
documents, which may include identifying information, will be maintained in locked files within
a locked office. The study coordinators at VA Puget Sound and Madigan will keep the key
between the identity of participants and study code number. The key will not be shared with to
anyone other than members of the research team.
The VISN-20 Northwest Network MIRECC (Dr. Raskind, Director; Dr. Peskind Co-Director)
will supervise database design, double data entry, and any required computer programming. The
MIRECC will provide maintenance of computer hardware and software at VA Puget Sound.
Initial and second data entry will be performed on a weekly basis at VA Puget Sound by the
study Research Assistant under the supervision of the MIRECC Database Manager. The
Database Manager will generate weekly reports of data discrepancies. The study Research
Assistant under the supervision of the Study Coordinator and Data Manager will be responsible
for rectifying data entry errors on a weekly basis. Database maintenance includes nightly backup
of hard drives and storage of backups at a safe off-site location. Only personnel having the
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correct user name, password, and signing on from a computer with the appropriate IP address
will have access.
Disposition of Data: CRFs will be kept at VA Puget Sound. Data will be retained for six years
after study closure, at which point it will be destroyed per guidelines in place at the time of
destruction. Exceptions are if a participant agrees to specimen/data banking, data will be retained
indefinitely. The link between study code and participant identity will be retained for the
duration of data retention.
5.6
Withdrawal of Subjects
There are three conditions under which participants will be withdrawn from the research
independent of participant request:
1.
If the participant is not able to tolerate a minimum dose of 1 mg morning, 1 mg afternoon,
and 2 mg bedtime of prazosin, he or she will undergo early termination. Such participants
will be referred back to their primary or referring providers for further management; if they
do not have such providers, Veterans will be offered a referral to an appropriate VA provider,
and non-Veterans and requesting Veterans will be provided with appropriate community
referrals. Reasons for early discontinuation or withdrawal will be recorded.
2.
Participants may be discontinued prematurely from study treatment to manage deterioration
of clinical status. Any participant who: (1) reports active suicidal ideation with intent and/or
with plan, (2) displays a marked deterioration of clinical and/or functional status, or (3) is
otherwise judged by the study clinician to be not stable enough to continue participation,
including due to any other indication of severe participant distress or presentation of
immediate danger to self or others, will be discontinued from the study for management of
acute or unstable symptoms. For participants whose status necessitates emergent care, study
termination will be followed by a warm hand-off to appropriate VA Emergency Department
personnel for emergent care. For participants who are discharged from the study due to acute
symptoms or clinical deterioration that does not require emergent care, referral to appropriate
VA personnel for Veteran participants or referral for appropriate community care for non-
Veteran or requesting Veteran participants will be provided.
3.
Participants who are unable to come to regularly scheduled visits or who are noncompliant
with study procedures or taking medication will also be withdrawn from the study. Reasons
for early discontinuation or withdrawal will be recorded.
Participants may remain in the study despite declining ambulatory heart rate or blood pressure
monitoring, genetic testing, and/or quantification of cannabis consumption, as long as the study
staff working with the participant continue to feel he or she is able to continue in good faith and
it remains clinically appropriate. However, a participant cannot decline any screening
procedures, the PCL, the PVT and emotional Stroop, the PSQI, the LP, or the prazosin titration
and remain in the study (except in the circumstance that the participant is already participating in
an allowed substituting prazosin titration as described above). In these cases, any participant will
be considered withdrawn from the study.
Participants who withdraw early from the study due to their own decision will be thanked for
participation. They will be asked to undergo the two final study visits (for ITT analysis purposes)
but will not be required to have these visit (prazosin may be discontinued abruptly without
adverse consequences). They will be asked why they decided to withdraw early so we can record
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the reason. The participant will be notified that any data and/or samples collected will be
continued to be used in the analyses unless the participant specifically requests that samples and
data not be used. If the participant requests, samples (including DNA) will be destroyed.
Participants who withdraw from the study or are withdrawn by the P1 will be reimbursed on a
pro-rated basis for the visits they have completed, as long as all ambulatory monitoring
equipment has been returned; if this equipment is not returned, all payments outstanding will be
placed on hold until it is returned.
For participants completing the entire trial, the blind will be broken by a Study Clinician at the
end of the study (except if they are participating in a simultaneous prazosin study: in those cases,
the blind will be broken when the longer study period ends). Maintaining the blind until all
participants have completed the protocol and the database has been locked would be ideal;
however, previous studies have shown that optimal safety and follow-up patient care argues in
favor of breaking the blind for each person when they complete the trial. All participants will be
given the option of treatment with open-label prazosin after study completion (an important
condition for recruitment, given that prazosin is clinically available). The appropriate and safe
method for initiating open-label prazosin differs depending on whether the participant had been
randomized to prazosin or placebo. For those randomized to prazosin and wishing to continue,
subsequent open-label prazosin should be kept at the maximum achieved dose, and may be
titrated further upward, if additional clinical benefit might be obtained. On the other hand,
participants randomized to placebo will require titration to effect, as per the study titration
schedule, initiated at a low dose (1 mg) to avoid the risk of first-dose hypotension.
Once the blind has been broken for a participant, they will be provided a written report
describing the information from their ambulatory blood pressure and actigraphic monitoring
data. These will be provided as a standardized report, generated by the analysis software for
these systems. The participant will be informed that these are not being conducted as medical
tests but rather as experimental data collection, and the data is being provided for their interest,
rather than as the result of a medical test. We will be able to discuss the reports with the
participants and refer them to their primary care provider if follow-up is warranted.
6.0 Reporting
Collection of adverse event information will begin at the screening visit.
Serious adverse events (SAEs): SAEs (defined as any untoward medical occurrence which may
be related to study participation at any time during the study that results in participant death, is
life threatening, requires hospitalization, or results in persistent or significant
disability/incapacity), will be reported to the P1, or if not available, another clinician investigator
immediately upon discovery. SAEs will be reported to the VA Puget Sound IRB per VA
guidelines.
Adverse Events (AEs): Unexpected, but not serious, AEs, which the PT determines are related or
possibly related to research participation, will be reported to the IRB per local guidelines.
Expected adverse events, which are not serious and possibly related to research participation,
will be reported on the annual report.
Unanticipated problems: Involving breach of confidentiality or HIPAA violation or any other
risk to the health or welfare of participants that the P1 determines are related or possibly related
will be reported to the IRB per local guidelines.
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Adverse events or problems that the P1 determines are unrelated to research participation will not
be reported.
A summary of all above reports will be sent to with the annual report. Departures from the
protocol which do not involve risks to volunteers or affect the scientific integrity of the study
will be reported annually. Deviations which involve unanticipated problems involving risks to
volunteers or others will be reported promptly, using the procedures described in reporting of
adverse events above.
7.0 Privacy and Confidentiality
The study will both use and disclose PHI. Information to be used are participant name,
phone number, address, medical record number, SSN (for creating or updating a medical
record at VA Puget Sound and for purposes of remuneration, and all elements of dates
(i.e. birthdate, dates of admission, discharge, and diagnosis.
All data are coded. Participants are given a 3 digit screening code, and if randomized a 1
letter + 3 digit randomization code (those in phase I will still receive a 3 digit code prior
to the initiation of study drug). The crosswalk between participant identities and code
number are kept electronically on the VA research drive. The list is only accessible to the
personnel listed on the R&DC application.
Data which are recorded on paper case report forms are kept a restricted access area (VA Puget
Sound, Seattle Division, Building 1, rooms B22 and B25). Coded data (with no identifiers save
study visit date) will be kept on shelves in areas that arc locked at all times. Source documents
(which contain identifiers) will be kept in file cabinets in these locked areas. File cabinets are
also locked when the rooms are unoccupied. Electronic data will be kept on the VA research
server. Access to the Electronic data will be restricted to persons listed on the R&DC
application.
Risks to Confidentiality: There is a risk of loss of confidentiality. We will be
creating/updating VA medical records. All clinical labs will be ordered through CPRS
and results will be placed automatically in CPRS. We are not ordering any clinical labs
which would contain sensitive information (i.e., are not performing drug, HIV, or
hepatitis testing). The study team will have access to CPRS records from initial consent
until 30 days beyond the end of participant study participation to monitor for adverse
events
Reduction of risk due to loss of confidentiality: We plan on obtaining a Federal Certificate of
Confidentiality to protect against compelled disclosure of answers to the questionnaires.
8.0 Communication Plan
N/A—this is not a multi-site study.
9.0 Information Security and Data Storage/Movement
All data collection, management and analysis procedures will take place at VA Puget Sound.
Study personnel will have access to protected health information. All data are coded. Participants
are given a sequential code number. The crosswalk between participant identities and code
number are kept electronically on the VA research drive. The list is only accessible to the
personnel listed on the R&DC application.
VA Committees that oversee research (VA IRB, R&DC) as well as the following regulatory
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bodies may have access to PHI, but will not be able to remove PHI from any facility: other
Federal agencies including, but not limited to, the Food and Drug Administration (FDA), the
Office for Human Research Protection (OHRP), the VA Office of Research Oversight (ORO),
the VA Office of the Inspector General (OIG), and the Government Accountability Office
(GAO).
The VA Puget Sound Fiscal Department and U.S. Department of the Treasury will be provided
with the full name, address, phone number, and social security number of participants in order to
authorize payment for participation in the study
Physical transportation of Identifying or Sensitive Data: There will be no physical
transportation of identifying or sensitive data.
Electronic Transmission of Data: There will be no electronic transmission of data outside the
VA servers.
Final Disposition of Data: Data will be retained for six years after study closure, at which point
it will be destroyed per guidelines in place at the time of destruction. Exceptions are if a
participant agrees to specimen/data banking, data will be retained indefinitely. The link between
study code and participant identity will be retained for the duration of data retention.
10.0 References
1.
Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nat Med.
2004;10 Suppl:S10-7. doi: 10.1038/nm1066. PubMed PMID: 15272267.
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