Conditions: PTSD
Keywords: PTSD TBI Riluzole Rilutek augmentation supplement double blinded clinical trial placebo RCT Randomized Control Trial
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 75
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether Riluzole is effective in the augmentation treatment of post-traumatic stress disorder (PTSD) that is experienced by Active Duty military service members and Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) veterans who have not had symptom reduction after one or more kinds of medications or therapies.

Detailed description:
Riluzole is a glutamatergic modulator that inhibits glutamate release and enhances AMPA trafficking and clearance of excessive synaptic glutamate resulting in neuroprotective properties. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis (ALS) and has been found to have antidepressant and anxiolytic properties in animals and in humans (Zarate et al., 2004). Posttraumatic stress disorder (PTSD) is a chronic and seriously debilitating anxiety disorder that develops following exposure to severe trauma, such as combat exposure. Structural magnetic resonance imaging has been used to measure the volume of crucial structures implicated in the pathophysiology of PTSD, with several morphometric studies confirming smaller hippocampal volume in PTSD patients. Current pharmacological treatment for PTSD, and particularly combat-related PTSD, is suboptimal. Drugs that alter neuronal survival pathways through reduction of glutamate activity may play a role in reversing the loss of neuronal integrity and possible focal atrophy in regions of the brain implicated in the pathophysiology of PTSD, potentially improving the symptoms of PTSD, as well as TBI. This study will evaluate the efficacy of acute riluzole treatment in active duty and Operation Iraqi Freedom (OIF), Operation Enduring Freedom (OEF), and Operation New Dawn (OND) veterans with PTSD, with or without mild TBI (mTBI), who are sub-optimally responsive to other medication treatments. A total of 158 active duty and OIF, OEF and OND veterans, aged 18 to 65 will be enrolled from WRNMMC and the Syracuse VA Medical Center to participate in this 8-week randomized, double- blind, placebo-controlled, parallel study. Patients who are suboptimal responders to their current psychotropic drugs will continue these at stable dosage for at least 2 weeks prior to randomization during the screening period. We hypothesize that those subjects with PTSD, with or without mTBI, who are only partially responsive to initial therapy and are subsequently randomized to augmentation therapy with Riluzole (100-200mg/day) will have a superior response rate compared to those subjects randomized to placebo.

Arms:
arm 1: Weeks 1 and 2: Riluzole 50 mg tablet by mouth every 12 hours (100 mg/day) for 2-weeks

Weeks 3 to 8 (optional dose increase): 2 Riluzole 50 mg tablets by mouth every 12 hours (200 mg/day) for 6-weeks arm 2: Weeks 1 and 2: Placebo 50 mg tablet by mouth every 12 hours (100 mg/day) for 2-weeks

Weeks 3 to 8 (optional dose increase): 2 Placebo 50 mg tablets by mouth every 12 hours (200 mg/day) for 6-weeks

Interventions: intervention 1: Riluzole intervention 2: Placebo (for Riluzole)
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
Study: 
Riluzole for PTSD: Efficacy of a Glutamatergic 
Modulator as Augmentation Treatment for
Posttraumatic Stress Disorder
NCT02155829
Date: 
04/30/2019


EIRB Protocol Template (Version 1.13)
1.0
General Information
*Please enter the full title of your study:
Riluzole for PTSD: Efficacy of a Glutamatergic Modulator as Augmentation Treatment for 
Posttraumatic Stress Disorder
*Please enter the Protocol Number you would like to use to reference the protocol:
380797
* This field allows you to enter an abbreviated version of the Protocol Title to quickly identify
this protocol.
Is this a multi-site study (i.e. Each site has their own Principal Investigator)?
No
Does this protocol involve the use of animals?
Yes
No
2.0
Add Site(s)
2.1 List sites associated with this study:
Primary 
Dept?
Department Name
P and R - Walter Reed National Military Medical Center (WRNMMC)
3.0
Assign project personnel access to the project
3.1 *Please add a Principal Investigator for the study:
Benedek, David Manfred MD, MD
Select if applicable
Student
Site Chair
Resident
Fellow
3.2 If applicable, please select the Research Staff personnel:
A) Additional Investigators
Dempsey, Catherine L, PhD 
Associate Investigator
Paxton, Megan Marie 


 Associate Investigator
Spangler, Patricia Tschirhart, PhD 
 Associate Investigator
Strother, Natara 
 Associate Investigator
WEST, JAMES C, M.D. CAPT 
 Associate Investigator
B) Research Support Staff
Aliaga, Pablo Alfredo 
 Statistician
Asabre, Eva Y, MPH 
 Research Coordinator
Morganstein, Joshua CHAIM 
 Monitor
ROY, MICHAEL JOSEPH 
 Monitor
Schuler, Keke, PHD 
 Statistician
3.3 *Please add a Protocol Contact:
 
Asabre, Eva Y, MPH 
Benedek, David Manfred MD, MD 
The Protocol Contact(s) will receive all important system notifications along with the Principal 
Investigator. (i.e. The protocol contact(s) are typically either the Protocol Coordinator or the 
Principal Investigator themselves).
3.4 If applicable, please select the Designated Site Approval(s):
 
Waits, Wendi Michelle, MD COL 
Department Chair
Add the name of the individual authorized to approve and sign off on this protocol from your Site 
(e.g. the Site Chair).
4.0
 
Project Information
4.1  Is this a research study?
 Yes   
 No
4.2  What type of research is this?
Biomedical Research
Clinical trial (FDA regulated)
Behavioral Research
Educational Research
Psychosocial Research
Oral History


Other
4.4  Is this human subjects research (Activities that include both a systematic investigation designed to 
develop or contribute to generalizable knowledge AND involve a living individual about whom an 
investigator conducting research obtains data through intervention or interaction with the individual 
or identifiable private information.  Activities covered by 32 CFR 219.101(a) (including exempt 
research involving human subjects) and DoDI 3216.02)?
 Yes   
 No
4.5  Do you believe this human subjects research is exempt from IRB review?
  Yes   
  No
5.0
 
Personnel Details
5.1  
Will you have a Research Monitor for this study?
Yes 
No 
N/A 
Research Monitor Role:
Research Monitor will be responsible to promptly report any observations and findings to the
Institutional Review Board (IRB), the Human Protections Administrator (HPA), or the Institutional 
Official.  The research monitor will review the study monitoring plans, review Adverse Events and 
determine their relatedness to the protocol, review Unanticipated Problems Involving Risks to Subjects of 
Others, make recommendations on changes to the informed consent process based on the review of 
study events, and review and sign the continuing review report.  The monitor will notify the IRB or HPA if 
you will not be able to fulfill your duties due to reassignment, retirement, deployment, or change of 
responsibilities. A replacement Research Monitor will need to be assigned and approved.
If applicable, you may nominate an individual to serve as the Research Monitor:
Selected Users
Joshua CHAIM Morganstein
MICHAEL JOSEPH ROY
6.0
 
Data/Specimens
6.1  Does the study involve the use of existing data or specimens only (no interaction with human 
subjects)?
  Yes   
  No
7.0
 
Funding and Disclosures


7.1  Source of Funding:
Funding Source
Funding Type
Amount
:
Congressionally Directed 
Medical Research Program 
(CDMRP)
DOD - MRMC
:
Research Development 
Testing and Evaluation 
(RDT&E) funds
1948488
Total amount of funding:
1948488
7.2  Do you or any other Investigator(s) have a disclosure of a personal interest or financial nature 
significant with sponsor(s), product(s), instrument(s) and/or company(ies) involved in this study?
  Yes   
  No
8.0
 
Study Locations
8.1  List any Research Team members without EIRB access that are not previously entered in the 
protocol:
Name:
(Last, First, M.I.)
Lin, Alexander
Role on Protocol:
Collaborator
Phone Number:
 
617-525-5081
Email Address:
 
APLIN@bwh.harvard.
edu
Associated Institution:
 
Brigham and 
Women's Hospital / 
Harvard Medical 
School
Name:
(Last, First, M.I.)
Irvine, John
Role on Protocol:
Collaborator
Phone Number:
 
Email Address:
 
jirvine@draper.com
Associated Institution:
 
Charles Stark Draper 
Laboratory, Inc.
8.2  Has another IRB reviewed this study?
 Yes   
 No
IRB Name
Review Date
Determination
.
: USUHS IRB 
#1
If other, please define:
04/22/2016
Approved via expedited 
procedures
Other Determination:
Secondary Concurrence of CR


8.3  Is this a collaborative or multi-site study? (e.g., are there any other institutions involved?)
 Yes   
 No
8.4  Study Facilities and Locations:
Institution
Site Name
Site Role
FWA or DoD 
Assurance 
Number
Assurance 
Expiration 
Date
Is there an 
agreement?
IRB 
Reviewing 
for Site
Other:
Other 
Institution 
Site
Site Role
FWA or DoD 
Assurance 
Number
FWA or DoD 
Expiration 
Date
Is there an 
agreement?
IRB Reviewing 
for Site
Central New 
York 
Research 
Corporation
Performance 
site
: MOU
: Other
8.5  Are there international sites?
Attach international approval documents, if applicable, when prompted. Note: Ensure local research 
context has been considered
  Yes   
  No
8.6  Is this an OCONUS (Outside Continental United States) study?
  Yes   
  No
Select  the area of responsibility:
Have you obtained permission from that area of responsibility? (This is a requirement prior to study 
approval)
  Yes   
  No
9.0
 
Study Details
9.1  Abstract/ Summary:
Summarize the proposed study in 500 words or less, to include the purpose, the subject population, the 
study’s design type, and procedures
 
Riluzole is a glutamatergic modulator that inhibits glutamate release and enhances AMPA 
trafficking and clearance of excessive synaptic glutamate resulting in neuroprotective properties. Riluzole 
is FDA-approved for the treatment of amyotrophic lateral sclerosis (ALS) and has been found to have 
antidepressant and anxiolytic properties in animals and in humans (Zarate et al., 2004). Posttraumatic 
stress disorder (PTSD) is a chronic and seriously debilitating anxiety disorder that develops following 
exposure to severe trauma, such as combat exposure.  Structural magnetic resonance imaging has been 
used to measure the volume of crucial structures implicated in the pathophysiology of PTSD, with several 
morphometric studies confirming smaller hippocampal volume in PTSD patients.  Current 


pharmacological treatment for PTSD, and particularly combat-related PTSD, is suboptimal.  Drugs that 
alter neuronal survival pathways through reduction of glutamate activity may play a role in reversing the 
loss of neuronal integrity and possible focal atrophy in regions of the brain implicated in the 
pathophysiology of PTSD, potentially improving the symptoms of PTSD, as well as TBI. 
This study will evaluate the efficacy of acute riluzole treatment in active duty and Operation Iraqi 
Freedom (OIF), Operation Enduring Freedom (OEF), and Operation New Dawn (OND) veterans with 
PTSD, with or without mild TBI (mTBI), who are sub-optimally responsive to other medication 
treatments.  A total of 158 active duty and OIF, OEF and OND veterans, aged 18 to 65 will be enrolled 
from WRNMMC and the Syracuse VA Medical Center to participate in this 8-week randomized, double-
blind, placebo-controlled, parallel study.  Patients who are suboptimal responders to their current 
psychotropic drugs will continue these at stable dosage for at least 2 weeks prior to randomization during 
the screening period.  We hypothesize that those subjects with PTSD, with or without mTBI, who are only 
partially responsive to initial therapy and are subsequently randomized to augmentation therapy with 
Riluzole (100-200mg/day) will have a superior response rate compared to those subjects randomized to 
placebo.
 
9.2  Key Words:
Provide up to 5 key words that identify the broad topic(s) of your study
9.3  Background and Significance:
Include a literature review that describes in detail the rationale for conducting the study. Include 
descriptions of any preliminary studies and findings that led to the development of the protocol.  The 
background section should clearly support the choice of study variables and explain the basis for the 
research questions and/or study hypotheses.  This section establishes the relevance of the study and 
explains the applicability of its findings
An over-simplification of the Research Proposal:
 
A service member experiences a physical and or emotional stressor during combat. The release of 
glutamate (from stress or brain injury) along with higher levels of glucocorticoids (endogenous cortisol) 
is toxic to the hippocampus causing a constellation of symptoms defined as PTSD.  The neurotoxic effects 
on the hippocampus are part of the picture; the effects of glutamate on the ability to extinguish fear 
memory is really what we are concerned about as failure to extinguish fear memory (that is failure to 
learn to forget) seems to be the process responsible for the intrusive recollections and excessive over-
generalized response to new stimuli we observe in PTSD.  The challenge is that increased concentrations 
of glutamate in the brain have been linked to a variety of cognitive effects included over-excitation, 
neurodegeneration and impaired neuronal plasticity, and many of the associated symptoms such as 
impaired memory, depression and chronic stress are also correlated with PTSD.  Whether PTSD is solely 
a direct result of changes in glutamate concentration is an open question.
 
Posttraumatic stress disorder (PTSD)
 
PTSD is a chronic anxiety disorder that develops in approximately one fifth of individuals exposed to 
severe trauma (Kessler et al., 1995; Breslau et al., 1998).  Rates of PTSD in returning OIF and OEF 
active duty soldiers are between 6 and 19% (Hoge et al., 2004; Hoge et al., 2007; Friedman, 2007; 
Erbes et al., 2007).  Over 20% of those injured in Iraq have suffered head/brain injuries that require 
lifetime continual care and rates of TBI have been estimated as high as 30%.  The presence of PTSD in 
patients with TBI can be difficult to identify and treat.  Although TBI and PTSD are among the most 
common disorders as a result of the OIF and OEF missions, currently available treatments are not 
targeted towards this group.  A recent Institute of Medicine (IOM) review found insufficient evidence to 
support the efficacy of any single pharmacologic agent for PTSD (IOM, 2007).  While the American 
Psychiatric Association’s 2009 Practice Guideline Watch and the most recent DoD-VA practice guideline 
suggestthat there is growing evidence for the efficacy of certain pharmacologic treatments, studies 
suggest these treatments may not be effective for combat-related PTSD (DoD-VA Practice Guideline for 
the Management of Posttraumatic Stress, 2010)).
 
Medication Treatments for PTSD
 
Selective serotonin re-uptake inhibitors (SSRIs) are currently the only class of FDA-approved 
medications available for the treatment of PTSD.  Although studies demonstrating the efficacy of SSRIs 
in PTSD use well-designed, double-blind strategies, the results are inconsistent, producing low to 


moderate effect sizes (0.3 to 0.5) (Van der Kolk et al., 1994; Conner et al., 1999; Marternyi et al., 2002; 
Brady et al., 2000; Davidson et al., 2002; Marshall et al., 2001; Tucker et al., 2007), or no significant 
effect at all (Friedman et al., 2007; Zohar et al., 2002; Martenyi et al., 2007; Van der Kolk et al., 
2007),  compared to placebo (Pitman et al., 2002).  Prazosin, a centrally active alpha-1 adrenoreceptor 
antagonist, reduced nightmares associated with PTSD in addition to overall PTSD symptoms when used 
as an adjunct to other psychotropic medications in PTSD (Raskind et al., 2007; Peskind et al., 
2003).  Other novel pharmacological strategies, including low dose cortisol (Aerni et al., 2004) have 
provided limited reduction in PTSD symptoms, but need further investigation.
 
In summary, for patients with PTSD, existing medication treatment options are suboptimal.  Therefore, 
there is an urgent need for the development of novel interventions for PTSD that rapidly and robustly 
improves PTSD symptoms with minimal side effects.  
 
The Role of Glutamate in acute and chronic stress: Pre-clinical models
 
Glutamate is an excitatory amino acid that has been implicated in the pathophysiology of major 
depression, TBI, Huntington’s disease, and Alzheimer’s disease (Hynd et al., 2004; Benn et al., 
2007).  Glutamate plays a crucial role in acute and chronic neurodegeneration, as well as neural 
plasticity (Einat & Manji, 2006; Parsons et al., 2007; Du et al., 2004).  The stress-related effects of 
glucocorticoids and the excitatory effect of glutamate on the hippocampus make this brain region 
susceptible to damage following the experience of a stressor.  For example, corticosterone has been 
found to prolong NMDA receptor-mediated calcium activation (Sato et al., 2004) and reduce plasticity of 
the hippocampus, also via NMDA receptors (McEwen et al., 2000).  It appears that stress increases levels 
of glutamate which may be neurotoxic, particularly to the hippocampus; whereas drugs that reduce 
glutamatergic neurotransmission are neuroprotective and improve symptoms in preclinical models of 
chronic stress and depression. While there have not been studies of the direct effects of cortisol 
administration on PTSD,  drugs that more tightly regulate glutamate brain concentrations by either 
decreasing glutamate release or activity or enhance its uptake could provide a novel strategy to reduce 
symptoms of PTSD and alleviate distress in this chronic stress disorder.
 
Is PTSD associated with impairment of neural plasticity and cellular resilience?
 
Yes, a very rough outline of this connection is based on increased glutamate levels triggering prolonged 
LTP causing stressful or highly emotional memories to become associated with non-stressful events.  This 
results in someone displaying heightened stress responses to otherwise mundane situations, a hallmark 
symptom of PTSD. 
 
Structural magnetic resonance imaging has been used to measure the volume of crucial structures 
implicated in the pathophysiology of PTSD.  Several (Carrion et al., 2007; Pavic et al., 2007; Bremner et 
al., 2005; Vythilingam et al., 2005), but not all (Jatzko et al., 2006; Woodward et al., 2006; Pederson et 
al., 2004), morphometric studies have confirmed smaller hippocampal volume in PTSD patients, 
compared to controls.  A recent meta-analysis of valid structural MRI studies in PTSD also confirmed a 
smaller hippocampal volume in this disorder (Karl et al., 2006).  Volumetric reduction in the anterior 
cingulate appears to be a consistent finding in PTSD, as well (Kasai et al., 2007; Kim et al., 2007; Rauch 
et al., 2003).  The only postmortem study in PTSD confirmed neuronal loss in the locus coeruleus (LC) in 
combat veterans, compared to controls (Bracha et al., 2005).
 
Proton magnetic resonance spectroscopy ( H MRS), an in vivo imaging technique, provides direct 
1
neurochemical information in the brain.  NAA levels that were measured using H MRS served as a 
1
surrogate marker for neuronal integrity and reflected the extent of neuronal loss or injury (Sager et al., 
2001; Ebisu et al., 1994).  Reduced levels of NAA/Cr ratio in the hippocampus and anterior cingulate 
have been reported in patients with PTSD due to mixed traumas (Mahmutyazicioglu, 2005), in fire 
survivors (Li, 2006) and in combat veterans (trend) (Villarreal et al., 2002).  Reduced NAA/Cr ratio was 
also reported in the anterior cingulate of maltreated children (De Bellis, 2000) and in the basal ganglia of 
adolescent fire survivors with PTSD (Lim et al., 2003).  Studies that attempted to differentiate 
traumatized subjects with and without PTSD using NAA/Cr ratio reported no differences; however, small 
sample sizes may have been a limitation (Seedat et al., 2005; Kimbrell et al., 2005).
 
Patients with ALS demonstrated a significant increase in NAA/Cr ratio in the motor cortex following 3-
week treatment with 100mg of riluzole daily (Kalra et al., 1998).  Riluzole may result in rapid 
improvement of neuronal integrity, as an increase in the NAA/Cr ratio was found as early as 1 day 
following treatment with riluzole in ALS patients (Kalra et al., 2006).  Patients with Generalized anxiety 
disorder (GAD) who responded to 8 weeks of riluzole treatment (9 of 14, 64%) demonstrated a 
significant increase in hippocampal NAA using H  MRS in contrast to a decrease in NAA levels in non-
1
responders (Mathew et al., 2008).  The effects of riluzole treatment on hippocampal and anterior 
cingulate NAA levels in PTSD have not yet been assessed.
 
Structural MRI studies of the pathophysiology of PTSD have not established a correlation between LC 
neuronal loss and volumetric loss for the hippocampus and the ACC, possibly due to methodologies with 


study sampling and design.  While several of these studies investigated mixed traumas, these were in 
exclusively in civilian settings.  Few studies have considered the subset of combat-trauma exposure, 
which we believe is an entirely unique presentation.  The 2005 Bracha et al. finding of postmortem LC 
neuronal loss in combat veterans could indicate such a correlation, hence the decision to pursue 
structural MRI analysis in this trial.
 
Taken together, current data suggest the loss of neuronal integrity and possible focal atrophy in regions 
of the brain are implicated in the pathophysiology of PTSD.  Drugs that alter neuronal survival pathways 
through reduction of glutamate activity may play a role in reversing these effects and improving 
symptoms of PTSD, as well as TBI.  Given that the neuropsychiatric community continues to refine 
clinically significant diagnostic points of departure for co-morbidity, it remains challenging to distinguish 
clearly PTSD and TBI with regard to symptomology and clinical outcomes.  Nowhere is this more clearly 
evident than in the overlapping associated symptoms of PTSD and Persistent Post-concussive Syndrome 
(TBI), which include depression, anxiety, insomnia, irritability/anger, poor concentration, fatigue, hyper-
arousal, and avoidance.  As research into this field continues, characterization of the neurological change 
from each diagnosis may become more likely. 
 
TBI is frequently diagnosed in comorbidity with PTSD and, as a result, it is nearly impossible to find a 
sufficient sample of PTSD patients in combat veteran populations.  Because the goal of this study is to 
provide an empirical assessment of whether riluzole is an effective treatment in real world, combat 
veteran PTSD populations, the effect of riluzole on TBI symptoms is not one of our objectives.  This is 
why we are concerned only in the efficacy of treating PTSD in patients regardless of their TBI 
history.  However, there is ample evidence within the field that brain injury is associated with increased 
glutamate concentrations in the brain.  Chamoun et al (2010) provides strong evidence that increased 
levels of glutamate following a traumatic brain injury are strongly predictive of poorer outcomes. 
 
Riluzole (Rilutek®)
 
Riluzole, a neuroprotective agent with anticonvulsant properties, is a member of the benzothiazole 
class.  Chemically, riluzole is 2-amino-6-(trifluoromethoxy) benzothiazole. Riluzole is the only drug 
currently approved (by the FDA in US, CPMP in Europe and MHW in Japan) for the treatment of 
ALS.  Riluzole is an antagonist at a subset of Glu receptors (Benavides 1985), functional antagonist at 
NMDA and kainate receptors (Debono, 1993), and noncompetitive antagonist of AMPA receptors in the 
rat spinal cord (Albo, 2004) and cortex (Zona, 2002).  Riluzole also inhibits the release of Glu in vivo 
(Cheramy, 1992) and in vitro (Doble, 1992; Martin, 1993; Jehle, 2000).  Riluzole interacts with a large 
number of ion channels (voltage-activated sodium channels) (Benoit, 1993; Hebert, 1994; Zona, 1998; 
Urbani, 2000), voltage-gated calcium channels (VGCCs) (Huang et al., 1997; Stefani et al., 1997), and 
voltage-gated potassium channels (Zona, 1998; Duprat, 2000; Xu, 2001; Ahn, 2005; Ahn, 2006) that 
may contribute to a reduction in Glu release (Chéramy et al., 1992) and its neuroprotective effects.  It 
enhances AMPA trafficking and increases glial uptake of glutamate (Azbill, 2000; Dunlop, 
2003).  Upregulation of glial Glu reuptake results in decreased extrasynaptic Glu concentrations and a 
release from the tonic inhibition of these neurons by activation of the presynaptic mGluR 2/3 
receptors.  This finding could offer an explanation for how riluzole induces trophic factors, including BDNF 
(Mizuta, 2001; Katoh-Semba, 2002).  The interaction of BDNF  with other trophic factors is a matter is 
scientific debate in the published literature and is beyond the scope of a clinical trial.  Elucidation of BDNF 
biochemistry would be more appropriate in a cell culture or rodent model investigation.  As such, a more 
descriptive presentation would neither strengthen the protocol nor provide necessary information for the 
participant in their process of granting informed consent.  Further, any attempt would be beyond the 
reading comprehension level implicit and necessary in the Consent Form.  While we consider it a fair 
point for the Reviewer to raise, we respectfully submit that it is beyond the scope of this trial.
 
In summary, preclinical and clinical data suggest that dysfunction in glutamatergic neurotransmission is 
a prime candidate in the pathophysiology of PTSD.  The antiglutamatergic agent riluzole appears to have 
significant neuroprotective effects and the potential to be a novel agent in the treatment of PTSD.  This 
study will permit us to determine the therapeutic benefit of reducing glutamate activity in subjects with 
PTSD.
 
   
Scientific Justification.
Scientific justification for the proposed research, as well as rationale for the research hypotheses, is 
detailed in the preceding Section.
Human Subjects Justification.  
For patients with PTSD, existing medication treatment options are suboptimal.  Current research 
suggests that the loss of neuronal integrity and possible focal atrophy in regions of the brain are 
implicated in the pathophysiology of PTSD, and drugs that alter neuronal survival pathways through the 
reduction of glutamate activity may play a role in reversing these effects and improving symptoms of 
PTSD, as well as TBI.  Riluzole is an FDA-approved drug for the treatment of ALS, and research indicates 


that it may result in rapid improvement of neuronal integrity, as an increase in the NAA/Cr ratio was 
found as early as 1 day following treatment with riluzole in ALS patients (Kalra et al., 2006).  However, 
the effects of riluzole treatment on hippocampal and anterior cingulate NAA levels in PTSD have not yet 
been assessed, despite the drug appearing to have significant neuroprotective effects and the potential 
to be a novel agent in the treatment of PTSD.  This study will permit us to determine the therapeutic 
benefit of reducing glutamate activity in subjects with PTSD with minimal side effects.
 
9.4  
Objectives/Specific Aims/Research Questions:
Describe the purpose and objective(s) of the study, specific aims, and/or research questions/hypotheses
Objective:  To evaluate the efficacy of acute riluzole treatment (100-200mg/day) in 158 active duty and 
returning OIF, OEF, and OND veterans, aged 18 to 65 with a diagnosis of PTSD, with or without mTBI, 
who are sub-optimally responsive to their current medication treatment (8 weeks). 
 
Hypothesis 1:  Subjects with PTSD, with or without mTBI, who are only partially responsive to initial 
therapy (e.g., CAPS score greater than or = 40 at the completion of an adequate trial of medication 
therapy) who are subsequently randomized to augmentation therapy with riluzole will have a superior 
response rate compared to subjects randomized to placebo.
 
Hypothesis 2:  PTSD patients randomized to augmentation with riluzole therapy will have significant 
improvement in depression, anxiety and global functioning compared to those who receive placebo in 
addition to their pre-study PTSD medication. 
 
Hypothesis 3:  The N-acetyl aspartate to creatine ratio (NAA/Cr) in the hippocampus and anterior 
cingulate, measured using magnetic resonance spectroscopy ( H MRS), will increase after 8-week 
1
treatment with riluzole.
 
In addition to indicating simple change in severity, the change in CAPS total score will be the primary 
outcome variable at the end of Phase II (Visit 10).  We believe this study is powered to detect a 9 point 
or greater difference in CAPS total score from baseline between riluzole and placebo augmentation (after 
Phase I) to the last measured value of Phase II.
 
The following scales are proposed for primary and secondary outcome measures:
 
i.   Primary Outcomes Assessment:  Clinician-Administered PTSD Scale (CAPS), Clinical 
Global Impression of Severity (CGI-Severity), Clinical Global Impression of Improvement 
(CGI-Improvement).
ii.  Secondary Outcomes Assessment:  Montgomery-Asberg Depression Rating Scale 
(MADRS), Hamilton Anxiety Rating Scale (HAM-A), Sheehan Disability Scale (SDS), PTSD 
Checklist (PLC-C), UKU Side Effect Rating Scale, Self-rating version.    
iii. Additional secondary outcome measure:  Changes in NAA levels in the hippocampus 
and anterior cingulate cortex following riluzole or placebo administration measured using H 
1
MRS.
 
Further, these scales are proposed as 
:  Liebowitz Social 
Additional Measurement Instruments
Anxiety Scale (LSAS), Pittsburgh Sleep Quality Index (PSQI), Dissociative Experience Scale (DES), 
World Health Organization Quality of Life (WHOQOL-BREF), Connor-Davidson Resilience Scale (CD-
RISC), Childhood Trauma Questionnaire, Short Form (CTQ-SF), Symptom Checklist, 90 items, Revised 
(SCL-90-R), Peri Traumatic Distress Inventory (PDI).
9.5  Study Design:
Describe study design in one to two sentences (e.g., prospective, use of existing records/data
/specimens, observational, cross-sectional, interventional, randomized, placebo-controlled, cohort, etc.). 
Specify the phase – Phase I, II, III, or IV – for FDA-regulated investigational drug research
The study design is a 1:1 randomized, double-blind, placebo-controlled, parallel trial.  The ongoing 
assessment and monitoring of subjects enrolled in the study will be conducted by a Masters-level Clinical 
Research Psychologist under the supervision of a credentialed provider within the WRNMMV Behavioral 


Health Clinic.  Blinded study medication will be manufactured by the WRNMMC Investigational & 
Research Pharmacy and will be identical and indistinguishable.  The WRNMMC Investigational and 
Research Pharmacy will administer, blind, and distribute all study medications, including secondary 
distribution to the Syracuse VA Medical Center Pharmacy and maintain the list indicating whether a 
participant is receiving placebo or study drug in a locked cabinet within the research pharmacy.
 
All members of the research team and treatment staff will be blinded.  Randomization into the treatment 
and placebo arms will be determined by the Research Pharmacy and is outlined in their Memorandum of 
Support.  Stratification by center will be performed prior to a 1:1 randomization.  As explained by the 
staff of the Research Pharmacy, randomization may be by computer generated random number or 
random table assignment, and volunteers for the post-treatment magnetic resonance spectroscopy 
portion of the study will be allotted 1:1 for treatment comparison.  Blinded subjects will be asked post-
treatment to guess their treatment assignment and the responses statistically analyzed to evaluate the 
success of the study blinding.  Additionally, subjects and providers will be asked at week 2 to guess 
treatment assignments to assess the similarity of the drug and placebo in appearance, taste and 
composition.
9.6  Target Population:
Describe the population to whom the study findings will be generalized
See Legacy Protocol
9.7  Benefit to the DoD:
State how this study will impact or be of benefit to the Department of Defense
See Legacy Protocol
10.0
 
Study Procedures and Data management
10.1  Study Procedures:
Describe step-by-step how the study will be conducted from beginning to end
The clinical component of this study is 10 weeks (although there is an option for subjects to enter a 3 
month open label continuation phase, detailed in Section 2.3).  The anticipated duration of study 
including regulatory review and approval, participant recruitment and enrollment, and data analysis, 
report writing, and dissemination is 36 months.
 
The 
 lists the clinical assessments conducted at baseline and those carried out at 
Schedule of Events
various points during Screening and Study Phases I and II.
 
Study Period/Phase I
                 Study Period/Phase II 
                 
b                           
  
 
Screening for all Subjects and 
Washout for Subjects on Medication
Randomized, Double-Blind, Placebo Controlled Clinical 
Trial
 
S1Description of 
Data
Scr
Stabil
V1
V2
V3
V4
V5
V6
V7
V8
V9ª
SOC
Week
-2
 
0
1
2
3
4
5
6
7
8
 
Informed consent
X
 
 
 
 
 
 
 
 
 
 
 
Demographics/ 
Hollingshead
X
 
 
 
 
 
 
 
 
 
 
 
Vital signs - body 
temperature, pulse 
rate, blood pressure, 
and respiration rate
X
 
X
X
X
X
X
X
X
X
X
Yes


Weight/ Height
X
 
X
 
 
 
 
 
 
 
X
Yes
Psychiatric 
examination
X
 
 
 
 
 
 
 
 
 
X
Yes
Physical 
examination
X
 
 
 
 
 
 
 
 
 
X
Yes
Chemistry panel 
and CBC w/dif
X
 
 
 
 
 
 
 
 
 
X
Yes
 Thyroid function, 
HIV, HCG, hepatitis 
screen and urine 
drug screen
X
 
 
 
 
 
 
 
 
 
X
Yes
 Liver function panel
X
 
X
X
X
X
X
X
X
X
X
Yes
 Menstrual history 
(women)
X
 
 
 
 
 
 
 
 
 
 
Yes
 Family History Screen X
 
 
 
 
 
 
 
 
 
 
Yes
SCID-IV-TR
X
 
 
 
 
 
 
 
 
 
 
 
 Placebo lead-in
 
 
 
 
 
 
 
 
 
 
 
 
Study drug/ Placebo
 
 
X
X
X
X
X
X
X
X
X
 
Efficacy Measures  
 
 
 
 
 
 
 
 
 
 
 
  CAPS
X
 
X
 
 
 
X
 
 
 
X
 
   CGI,
X
 
X
X
X
X
X
X
X
X
X
 
  MADRS
X
 
X
X
X
X
X
X
X
X
X
 
  HAM-A
 
 
X
 
 
 
X
 
 
 
X
 
  SDS
 
 
X
 
 
 
X
 
 
 
X
 
   PCL-C
 
 
X
X
X
X
X
X
X
X
X
 
   UKU-SERS-Pat
X
 
X
X
X
X
X
X
X
X
X
 
   LSAS
 
 
X
 
 
 
X
 
 
 
X
 
   PSQI, DES
 
 
X
 
 
 
X
 
 
 
X
 
   WHOQOL BREF, CD-
RISC
 
 
X
 
 
 
X
 
 
 
X
 
   CTQ
 
 
X
 
 
 
 
 
 
 
 
 
   SCL-90
 
 
X
 
 
 
X
 
 
 
X
 
   PDI
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Description of Data
Scr
Stabil
V1
V2
V3
V4
V5
V6
V7
V8
V9ª
 
SOC
Week
 
 
0
1
2
3
4
5
6
7
8
 
Safety Measures
 
 
 
 
 
 
 
 
 
 
 
 
  Adverse events
X
X
X
X
X
X
X
X
X
X
X
 
MRS
 
 
X
 
 
 
 
 
 
X
 
 
 Sc = Screening Visit; Sta = Stabilization Visit; CAPS = Clinician-Administered PTSD 
Abbreviations:
scale; CD-RISC = Connor-Davidson Resilience Scale; CGI = clinical global impression scale; CTQ = 
Childhood Trauma Questionnaire; DES = Dissociative Experience Scale; F/U = Follow-up visit; HAM-A = 
Hamilton Anxiety Rating Scale; HCG = blood pregnancy test; Hollingshead = Hollingshead 4 Factors of 
Social Status Scale; LSAS = Liebowitz Social Anxiety Scale; MADRS = Montgomery Depression Rating 
Scale;; PLC-C = PTSD Checklist; UKU-SERS-Pat = UKU Side Effect Rating Scale, Self rating version; PDI 
= Peri Traumatic Distress Inventory; PSQI = Pittsburgh Sleep Quality Index; SCID-IV-TR = Structure 
Clinical Interview for DSM-IV; SCR = screen; SCL-90 = Symptom Checklist, 90 items; SDS = Sheehan 
Disability Scale; WHOQOL BREF = World Health Organization Quality of Life WO = washout phase.
Exit visit to be performed at Visit 9 or sooner if the patient is discontinued from the study. 
a
WO = washout phase. May vary depending on drug but in general is 51/2 lives. If the subject is 
medication free, they may proceed to Study Period I.
Visits during Study Period II may happen within 2 days of the scheduled visit.  SCO = Standard of Care 
b
activity – Affirmative notation; Default notation is left blank indicating an activity that is research-related.


 
The 10-week clinical study will be conducted in two phases, a minimum of 2-weeks and maximum of 4-
weeks screening and stabilization phase (Phase I) and an 8-week double-blind placebo controlled 
treatment (Phase II).  
 
In Phase I, indicated as the “Screening Period” 
, patients 
in Figure 1 Riluzole Augmentation for PTSD
who are suboptimal responders (see inclusion/exclusion criteria) to other psychotropic drugs will 
continue these at stable dosage for at least 2 weeks prior to study randomization (dose 
stabilization).  Use of antidepressant and sedative/hypnotic drugs at stable dose is permitted.  Subjects 
will be contacted by phone after 1 week to assure that no medication changes were made and to 
schedule the first Phase II visit.  
 
Subjects will also complete the screening visit where they will be evaluated for study entry and 
enrollment.  Psychiatric history and diagnosis will be administered by study staff at each site using the 
SCID-P (First et al., 1995) and the DSM-IV Diagnostic Criteria (American Psychiatric Association, 
1994).  Patients who meet DSM-IV criteria for PTSD must have a Clinician Administered PTSD Scale 
(CAPS) of 40 at Visits 1 and 2 to be included in the study.  Those entering the study at the completion of 
a referring INTRuST or other medication trial for PTSD will also receive a CGI assessment, and must have 
a score indicating “NOT improved” or “NOT very much improved” on the CGI scale at the completion of 
their medication trial to be eligible.  The screening visit will include the screening tests, patient history, 
and psychiatric and physical examinations, as well as menstrual history in females.  Subjects will 
undergo a physical exam, supine and standing vital signs, complete blood cell counts (CBC) with 
differential, electrolytes, thyroid function test, liver function tests, fasting blood sugar, hematology 
profile, urinalysis (including screens for substances of abuse), hepatitis screen, SCID, and CAPS.  Women 
of childbearing capacity will have a baseline serum ß-HCG.  A positive ß-HCG will exclude them from 
participating in the study.  Subjects must also have a negative Human Immunodeficiency Virus (HIV) 
test.  Results of these tests will identify patients who should be excluded because of active medical 
problems or substance abuse that might affect the clinical phenomenology or treatment response and to 
identify conditions that might make randomization into one of the treatment arms less safe.  The CGI will 
be used to collect information on overall improvement, and the UKU side effect rating scale will be used 
to collect information on side effects.   Finally, eligible subjects who consent to participate in the baseline 
H MRS portion of the study will undergo the scan during the screening visit.
1
 
The time commitment for the telephone confirmation is estimated to be 10 minutes.  The screening visit 
will take 4 hours.  The time commitment for the baseline H MRS scan is estimated to be 60-90 minutes.
1
 
Phase II, indicated as the “Acute Double-Blind Period”, in 
, 
Figure 1 Riluzole Augmentation for PTSD
begins after the completion of the stabilization phase, where subjects will be randomized at a ratio of 1:1 
to receive an 8-week double-blind treatment of either riluzole or placebo.  Riluzole or placebo will be 
administered in two divided doses (two tablets twice a day).  During the clinical trial, all blinded study 
medication will be manufactured to identical appearance.  All members of the research team and 
treatment staff will be blinded.  Subjects will be assessed weekly from Visit 1 through Visit 9 (see 
Schedule of Events, 
).  Riluzole therapy will be initiated at a dose of 
Section 5.5.8 Study Time Line
50mg twice daily, as will matching placebo for those subjects randomized to placebo.  Riluzole may be 
increased to 200 mg/day thereafter if the subject’s weekly case history (subject self-reported 
symptomatology and CAPS score and/or additional psychological clinical battery diagnostics) indicate that 
the increased dose may have therapeutic benefit.  The maximal allowable dose of riluzole permitted is 
200 mg/day.  The minimal allowable dose of riluzole permitted is 100 mg/day.  Those subjects unable to 
tolerate the lowest allowable dose will be discontinued from the study.  Eligible subjects who consented 
to participate in the baseline 1H MRS portion of the study will undergo a post-treatment scan between 
visits 8 and 9.
 
The time commitment for the weekly scheduled visit is estimated to be 2-4 hours.  The time commitment 
for the post-treatment H MRS scan is estimated to be 60 to 90 minutes.
1
 
10.2   Data Collection:
Describe all the data variables, information to be collected, the source of the data, how the data will be 
operationally measured, and approvals needed for use of information from DoD databases
a.      Method of Collection from Study Participants.
 
Primary Outcomes Assessment – All study assessment materials are in the public domain and will not 
be altered.  Each measure includes a minimum of one citation attesting to the reliability and validity of 


the questionnaire based on the consensus of researchers published in the field of behavioral science.  In 
general, each measure has a minimum assessment level of ‘adequate’, with the majority assessed at a 
level of ‘good’ or higher. 
 
Instruments selected are well established neuropsychological questionnaires with extensive clinical and 
research validation and are structured to ensure the highest levels of clarity and ease of 
administration.  Participants will have no difficulty in reliably completing these instruments in a clinical 
setting.  This instrument battery is currently in use in several WRNMMC-approved research projects 
conducted by the Investigator in both the inpatient ward and outpatient clinics at WRNMMC.  Further, 
this instrument battery is in use by the INTRuST Clinical Consortium, which is a multi-site research 
collaboration on PTSD and TBI, which will allow de-identified data from this study to be compared across 
a nationally-representative dataset.   Assessments not directly related to the primary outcome are being 
made to allow for comparability with these other ongoing trials in this population, and all questionnaires 
were selected and rigorously reviewed to ensure that content overlap was minimized in the interest of 
participant welfare.  As such, no unnecessary measures are included, and all data collected will be 
analyzed and results reported and disseminated.
 
1.Clinician-Administered PTSD Scale (CAPS):  The CAPS (Blake et al 1995; Blake et al., 
1990) is a lengthy structured interview based on the DSM-IV that assesses the presence 
and severity of PTSD and associated symptoms.  Changes from baseline to endpoint in the 
CAPS total score will serve as the primary efficacy measure for the double blind phase.  The 
CAPS is widely accepted as the Gold Standard for establishing PTSD diagnosis with excellent 
reliability and validity (Blake et al., 1990; 1995), (Weathers et al., 1999).
 
2.Clinical Global Impression of Severity (CGI-Severity):  The CGI-Severity scale 
(Guy, 1976) will be administered to assess the clinician's global impression of the severity 
of the patient's PTSD at each visit over the course of treatment.  It is a 7-point scale in 
which 1 = normal and 7 = extremely severe case of PTSD.  The CGI is a core metric for 
psychiatric research and has demonstrated adequate psychometric properties (Berk et al., 
2008).
 
3.      Clinical Global Impression of Improvement (CGI-Improvement):  The CGI-
Improvement scale (Guy, 1976) will be administered to assess the clinician's global 
impression of the improvement of the patient's PTSD over the course of treatment. It is a 
7-point scale in which 1 = very much improved, 4= no change, and 7 = very much worse. 
A pre-entry score (e.g., for those subjects entering this protocol from other research 
studies will be obtained during the screening phase.  Those subjects who, at the 
completion of the previous research study receive scores of 1, 2, or 3 will be excluded 
from this study.
 
For this study, treatment response will be defined as those who are very much improved 
(score of 1), or much improved (score of 2), or improved (score of 3) on the Clinical Global 
Impressions, improvement item and have a 
 9 point decrease in CAPS score.
>
 
Secondary Outcomes Assessment
 
1.Montgomery-Asberg Depression Rating Scale (MADRS):  The MADRS (Montgomery 
& Asberg, 1979) is a clinician-rated instrument that measures the presence and severity of 
depression.  The MADRS has demonstrated very good reliability and validity in clinical 
applications (Cusin et al., 2009).  This instrument consists of a 10-symptom scale.  Each 
symptom is rated on a defined step scale (0 to 6).  A high numeric rating reflects a greater 
degree of symptom severity.  This outcome will be assessed by the mean change from 
baseline MADRS score.
 
2.Hamilton Anxiety Rating Scale (HAM-A):  The HAM-A is a clinician-rated instrument 
that measures the presence and severity of anxiety.  The HAMA-A has demonstrated 
adequate psychometric properties (Riskind et al., 1987).  This instrument consists of a 14-
symptom scale.  Each symptom is rated on a defined step scale (0 to 4).  A high numeric 
rating reflects a greater degree of symptom severity.  This outcome will be assessed by the 
mean change from baseline HAM-A score.
 
3.Sheehan Disability Scale (SDS):  The Sheehan Disability Scale (SDS) (Sheehan, 1983) 
is a patient-rated instrument designed to assess the impact of perceived problems on work 
productivity, social/leisure activities, and family life/home responsibilities.  The SDS has 
demonstrated adequate psychometric properties (Frischholz et al., 1990).  The Sheehan 
Disability Scale consists of 3 questions rated on a visual analog scale (0 to 10).  Higher 
scores represent greater impairment of activity.  This outcome will be assessed by the mean 
change from baseline SDS score
 


4.PTSD Checklist (PLC-C):  The PCL-C (civilian) is a 17-item self-report measure of the 
17 DSM-IV symptoms of PTSD used for screening individuals for PTSD, diagnosing PTSD, 
and monitoring symptom change during and after treatment.  It asks about symptoms in 
relation to "stressful experiences" and can be used with any population and has 
demonstrated adequate psychometric properties (Weathers et al 1994).
 
5.UKU Side Effect Rating Scale, Self-rating version:  The UKU side effect rating scale, 
self-rating version (UKU-SERS-Pat)  (Lingjaerde et al., 1987), a patient-rated scale, is a 
valid and reliable comprehensive measure to evaluate side effects of psychotropic 
medications (Lindstrom et al., 2001).  Adverse events in the psychic, neurologic, autonomic, 
dermatological, and sexual domains will be assessed.  For symptoms endorsed as present, a 
clinician will further assess their severity, potential causal relationship with the medications, 
and interference with daily performance.
 
6.Additional secondary outcome measures:  These will include evaluating changes in N-
acetyl asparate (NAA) levels in the hippocampus and anterior cingulate cortex following 
riluzole or placebo administration measured using magnetic resonance spectroscopy ( H 
1
MRS) among a sub-sample of WRNMMC participants.
 
Acute Trial Assessments
 
As shown in 
, subjects participating in this study will be rated 
Section 5.5.8 Study Time Line
weekly during the double-blind phase for severity of PTSD using the same scales as were 
obtained at Visit 2.  Week 8 or Visit 9 ratings will be used to determine whether patients meet 
criteria for response.  Side effects will be assessed using the UKU side effect rating scale, self-
rating version (Lindstrom et al., 2001). 
 
Additional Measurement Instruments
 
1.Liebowitz Social Anxiety Scale (LSAS):  A 24-item scale providing separate scores for 
fear and avoidance in social and performance situations over the past week (approx. 8 
minutes to complete) (Liebowitz, 1987).  This measure has demonstrated adequate 
psychometric properties (Fresco et al. 2001).
 
2.Pittsburgh Sleep Quality Index (PSQI):  A 19-item instrument to assesses sleep 
quality and disturbances over a 1-month time interval (approx. 5 to 7 minutes to complete) 
(Buysse et al. 1989).  The PSQI had demonstrated acceptable psychometric properties 
(Carpenter & Andrykowski, 1998).
 
3.Dissociative Experience Scale (DES):  A 28-item questionnaire used to screen for 
dissociative symptoms (approx. 8 minutes to complete) (Bernstein et al. 1986).  The DES 
has demonstrated excellent reliability and validity (Frischholz et al., 1990).
 
4.World Health Organization Quality of Life (WHOQOL-BREF): is a self-report 
measure of quality of life, life satisfaction and personal well-being (Murphy et al., 2000). 26-
items assess the board domains of physical health, psychological health, social relationships 
and environmental factors (e.g., finances, safety).  This measure has strong psychometric 
properties (Skevington et al., 2004) and will be administered at each time point.  The 
overall QOL score will be used as the QOL outcome measure.
 
5.Connor-Davidson Resilience Scale (CD-RISC):  A 25-item scale of ability to recovery 
after a traumatic event (approx. 8 minutes to complete) (Connor & Davidson, 2003).  The 
CD-RISC has demonstrated good psychometric properties (Windle et al., 2011).
 
6.Childhood Trauma Questionnaire, Short Form (CTQ-SF):  A 28-item measure of 
childhood physical, sexual and emotional abuse and physical and emotional neglect (approx. 
8 minutes to complete).  The CTQ-SF has demonstrated good reliability and validity 
(Bernstein et al 2003).
 
7.Symptom Checklist, 90 items, Revised (SCL-90-R):  A 90-item instrument to 
evaluate a broad range of psychological problems and symptoms of psychopathology.  The 
instrument is also useful in measuring patient progress or treatment outcomes (approx. 12-
15 minutes to complete) (Derogatis, 1999).  The SCL-90-R has demonstrated adequate 
psychometric properties (Hardt et al., 2000).
 
8.Peri Traumatic Distress Inventory (PDI):  A 13-item self-report measure to obtain a 
quantitative measure of the level of distress experienced during and immediately after a 
traumatic event (approx. 5 minutes to complete).  The PDI has also demonstrated good 
reliability and validity (Brunet et al 2001).


10.3  At any point in the study, will you request, use, or access PII from the Military Health System 
(MHS)?
  Yes   
  No
10.4  Have you consulted with an MHS data expert to determine the data elements to be extracted or the 
information system(s) to access? 
Consulting with a data expert often saves time later in the compliance process because the data expert 
can advise on the data available in the numerous MHS information systems, the quality of that data and 
the methods for encrypting and collapsing data.  To schedule a consult with an MHS data expert, send 
an email to: (
)
dha.ncr.pcl.mbx.privacyboard@mail.mil
Yes, then complete the questions below according to the data consult 
No, then complete the questions below according to the best of your knowledge (NOTE: It is highly 
recommended that you work with an MHS data expert) 
10.5  Indicate whether you plan to receive a data extract from the MHS or plan to access an information 
system directly to create a data set:
A data extract is when the MHS or a contractor provides the data set directly to the researcher.  When 
receiving a data set through data extract, the researcher may indicate whether the data elements should 
be provided as is, encrypted or collapsed.  In contrast to a data extract, access to an information system 
means that the researcher may directly access an MHS information system and create a data set for the 
research study
Data Extract
Access
10.6  Do you intend to use only de-identified data from the MHS in your research study?
There are different two methods for de-identifying data pursuant to HIPAA:
1) Safe Harbor Method: Removing all of the identifiers listed in Table 1 below, provided that the 
researcher does not have actual knowledge that the remaining data can be used alone or in combination 
with other information to identify the individual who is the subject of the information
2) Statistical Method: An expert, with appropriate knowledge of and experience with generally accepted 
statistical and scientific principles and methods for rendering information not individually identifiable, 
determines that the data is not individually identifiable
  Yes   
  No
10.7  If your research study requires access to an MHS information system, please indicate the system to 
obtain data:
If you do not know which system(s) contain the data elements you need, refer to the Guide for DoD 
Researchers on Using MHS Data or seek guidance from an MHS data expert:
 
PHI Systems:
MHS Information System
Requesting Data
: AHLTA
: Yes
: CHCS
: Yes
PII-Only Systems:
MHS Information System
Requesting Data


No records have been added
De-Identified Data & Other Systems:
Information System
Requesting Data
Expense Assignment System
List other system(s):
List other system(s):
10.8  Do you intend to merge or otherwise associate the requested data with data from any sources 
outside of the MHS, including other DoD systems that are not part of the MHS?
Yes, will merge data  
No, will not merge data 
10.9  Indicate the categories of data that you will request from MHS systems or MHS health care 
providers about research participants or relatives, employers, or household members of the 
research participants.
Data Element(s)
MHS
Non-MHS Systems
1. Names
2. Postal address with only 
town, city, state and zip code
3. Postal address with all 
geographic subdivisions smaller 
than a state, including street 
address, city, county, precinct, 
zip code and their equivalent 
geocodes, except for the initial 
three digits of a zip code if, 
according to the current 
publicly available data from the 
Bureau of Census: 1) the 
geographic unit formed by 
combining all zip codes with the 
same three initial digits 
contains more than 20,000 
people; and 2) the initial three 
digits of a zip code for all such 
geographic units containing 
20,000 or fewer people is 
changed to 000
4. Dates including all elements 
(except year) directly related to 
an individual, including birth 
date, admission date, discharge 
date, and date of death
5. Ages over 89 and all 
elements of dates (including 
year) indicative of such age, 


unless you will only request a 
single category of “age 90 or 
older”
6. Telephone numbers
7. Fax numbers
8. Electronic mail addresses
9. Social Security numbers 
(SSNs)
10. Medical record numbers
11. Health plan beneficiary 
numbers
12. Account numbers
13. Certificate/license numbers
14. Vehicle identifiers and serial 
numbers, including license plate 
numbers
15. Device identifiers and serial 
numbers
16. Web Universal Resource 
Locators (URLs)
17. Internet Protocol (IP) 
address numbers
18. Biometric identifiers, 
including finger and voice prints
19. Full-face photographic 
images and any comparable 
images
20. Any other unique 
identifying number, 
characteristic, or code (DEERs 
ID, EDIPN, Rank)
If you are obtaining SSNs, provide a justification as to why and explain why a substitute cannot be used
Collecting the SSN of participants allows investigators to order required lab tests in CHCS; also required 
for subject payment thru Henry Jackson Foundation.


10.10  Is it possible that the data will become identifiable because of triangulation, a small cell size, or 
any unique data element(s)?
Triangulation means using different data elements that are not themselves identifiable but that when 
combined can be used to identify an individual. For example, triangulation would be using rank and race 
together to determine the identity of an individual with a particular health condition
Small cell size means that there are only a small number of eligible individuals that satisfy the category 
description.  Guidance for acceptable cell size is available from the Centers for Medicare and Medicaid 
Services. For example, the rank category of four star generals with a particular diagnosis may be less 
than 30 so the rank category may need to be expanded to include lower ranks
A unique data element includes any unique features that are not explicitly enumerated in the categories 
of data in rows 1 – 19 of Table 1 above, but that could be used to identify an individual.  Examples of 
unique data elements include: 1) a unique number, such as a medical record number or EDIPN; 2) a 
unique code, such as a diagnosis code or a bar code on an electronic health record; and 3) any unique 
characteristic, such as the rank of general or admiral, or a race or gender combined with another unique 
characteristic
Yes, there is a reasonable possibility the data will become identifiable 
No, there is no reasonable possibility the data will become identifiable 
10.11  HIPAA Privacy Rule and Use of Protected Health Information in Research:
N/A – will not use or disclose protected health information (PHI) 
HIPAA Authorization will be obtained 
Use of a limited data set where a data use agreement will be obtained 
Waiver/alteration of HIPAA Authorization is being requested 
10.12  Managing Data (Data Management and/or Sharing Plan ) and/or Human Biological Specimens for 
this Study:
Include in this section the plan for acquiring data (both electronic and hard copy), access during the 
study, data/specimen storage and length of time stored, shipment/transmission, and the plan for 
storage and final disposition at the conclusion of the study. Describe any data agreements in place for 
accessing data within and/or outside of your institution (e.g., Data Sharing Agreement, Data Use 
Agreement, Business Agreements, etc.)
See Legacy Protocol
10.13  Managing Data (Data Management and/or Sharing Plan) and/or Human Biological Specimens for 
Future Research:
If the study involves collecting, storing, or banking human specimens, data, or documents (either by the 
Investigator or through an established repository) for FUTURE research, address. How the specimens
/data will be used, where and how data/specimens will be stored (including shipping procedures, storage 
plan, etc.), whether and how consent will be obtained, procedures that will fulfill subjects’ request as 
stated in the consent, whether subjects may withdraw their data/specimens from storage, whether and 
how subjects may be recontacted for future research and given the option to decline, whether there will 
be genetic testing on the specimens, who will have access to the data/specimens, and the linkage, the 
length of time that data/specimens will be stored and conditions under which data/specimens will be 
destroyed
See Legacy Protocol
11.0
 
Statistical/Data Analysis Plan
11.1  Statistical Considerations:


List the statistical methods to be used to address the primary and secondary objectives, specific aims, 
and/or research hypotheses.  Explain how missing data and outliers will be handled in the analysis.  The 
analysis plan should be consistent with the study objectives.  Include any sub-group analyses (e.g., 
gender or age group).  Specify statistical methods and variables for each analysis.  Describe how 
confounding variables will be controlled in the data analysis
5.7.1 Data Analysis Table
Independent Variable /
Predictor
Dependent Variable/
Outcome
Statistical Test
Riluzole/placebo
PTSD anxiety symptomatology (CAPS 
total score)
t-test/Mann-Whitney U test
Riluzole/placebo
Clinical Response Rate
Pearson’s chi-square test,  Fisher’s 
exact test
Riluzole/placebo
Effects of treatment status longitudinally Regression Analysis
Riluzole/placebo
Origin, gender, age, dose level, illness 
characteristics
ANOVA, Mantel-Haenszel common 
odds ratio test, Breslow-Day test
Riluzole/placebo
NAA/Cr ratio
t-test/Mann-Whitney U test
Not Applicable
Not Applicable
Descriptive Statistics
 
11.2  Sample Size Estimation:
A power analysis confirms the study will be able to detect a 9 point change in CAPS score in subjects 
receiving riluzole augmentation versus placebo using a sample size of 50, assuming a two-tailed test, an 
alpha = 0.05, and a standard deviation of 15 (based on the PI’s experience in this population seeking 
treatment at WRNMMC). This yields a power of 0.844. Power increases to 0.909, under the same 
assumptions, when a single-tailed test is used. The difference value of 9 is considered the minimally 
clinically significant difference and is supported by recent publications (Krystal et al, 2013; Schnurr et al, 
2001; Weathers et al, 2001; Fontana et al, 1997; Norman et al, 2003; Lunney et al, 2007).
The SAS System 
The POWER Procedure 
Two-Sample t Test for Mean Difference
Fixed Scenario Elements
Distribution Normal
Method Exact
Number of Sides 2
Mean Difference 9
Standard Deviation 15
Group 1 Sample Size 50
Group 2 Sample Size 50
Null Difference 0
Alpha 0.05
Computed Power 
Power 0.844
The SAS System 
The POWER Procedure 
Two-Sample t Test for Mean Difference
Fixed Scenario Elements
Distribution Normal
Method Exact
Number of Sides 1
Mean Difference 9
Standard Deviation 15
Group 1 Sample Size 50
Group 2 Sample Size 50
Null Difference 0
Alpha 0.05
Computed Power 
Power 0.909
To allow for ineligibility (30-40%) and the possibility that more participants will be needed from 


WRNMMC (~2:1 ratio), a total of up to 158 participants will be consented study-wide, with up to 104 
participants recruited at WRNMMC. 
11.3  Data Analysis Plan:
Primary Analysis:  (Hypothesis 1) Subjects with PTSD randomized to acute therapy with Riluzole will 
have a superior response rate acutely compared to subjects randomized to placebo.
 
The PI will be primarily responsible for data analysis in this study.  He will be assisted by a data analyst 
or analysts within the Department of Psychiatry at USUHS and this person (or persons) will be added to 
the protocol as investigators (with IRB approval) prior to any handling of the data. The primary intent of 
this study is to compare the efficacy of riluzole relative to placebo in the treatment of overall anxiety 
symptomatology of subjects who have PTSD.  This will be analyzed by comparing reductions from 
baseline scores on the CAPS total score after up to 8-weeks of double-blind therapy to the original score 
before the start of therapy using t-tests or Mann-Whitney U tests when assumptions for t-tests are not 
satisfied. 
 
In addition to utilizing the CAPS continuous score, scores will also be dichotomized to examine clinical 
responders versus non-responders in the treatment and placebo groups.  A responder will be defined as 
any patient who demonstrates a 30% or greater decrease in CAPS total score from baseline (phase I) to 
the last measured value of Phase II.  Response rate analyses will then be performed by comparing the 
proportion of subjects in each treatment group who met the response criteria.  Response rates will be 
analyzed using Pearson’s chi-square test or Fisher’s exact test when expected cell sizes are less than 5. 
 
In order to more thoroughly assess the effects of treatment status in a longitudinal setting, random 
effects regression will also be used to examine the study groups over time in the presence of additional 
covariates. 
 
In general, variables that are continuous, yet non-normally distributed, will be appropriately transformed 
or will be analyzed using appropriate non-parametric tests. Variables that are non-continuous (ordinal, 
nominal) will be analyzed using appropriate non-parametric tests.   All tests of hypotheses will be tested 
at a two-sided a level of 0.05.
 
Secondary Analyses:
 
Additional analyses will be performed for origin, gender, age, dose level and certain illness characteristics 
(if there are at least 10 subjects in each treatment group).  All subgroup analyses will be considered 
secondary analyses.  Continuous outcomes will be assessed using ANOVA models.  The treatment-by-
subgroup interaction will be tested to determine whether treatment differences in the continuous 
outcomes are the same for each subgroup category.  The Mantel-Haenszel common odds ratio and the 
Breslow-Day test for homogeneity of odds ratio will be used to evaluate differences across the subsets 
for dichotomous categorical outcomes.
 
Secondary Outcomes: (Hypotheses 2 and 3) PTSD patients randomized to augmentation with riluzole 
therapy will have significant improvement in depression, anxiety and global functioning compared to 
those who receive placebo in addition to their pre-study PTSD medication.  The NAA/Cr ratio in the 
hippocampus and anterior cingulate, measured using H MRS, will increase after 8 week treatment with 
1
Riluzole.
 
The analysis techniques described above will also be employed with the additional secondary 
outcomes.  Further, post-hoc analysis will be performed by the PI in the comparison of outcomes from 
this research to other PTSD research being conducted by the PI at WRNMMC, including the INTRuST 
Clinical Consortium.  All comparisons will involve de-identified data.
 
Collaborators from Draper Lab and Brigham and Women Hospital/ Harvard will be responsible for the H 
1
MRS data analysis.
12.0
 
Participant Information
12.1  Subject Population:
The subject population consists of 158 active duty and returning Operation Iraqi Freedom (OIF), 
Operation Enduring Freedom (OEF), and Operation New Dawn (OND) veterans, aged 18 to 65 with a 


diagnosis of PTSD despite adequate trial of medication treatment (8 weeks) (e.g., CAPS score 
greater than or = 40). 
 
Subjects will be recruited from collaborator- and provider-referrals at WRNMMC and the Syracuse VA 
Medical Center, as well as from associated community-based outpatient clinics (CBOCs) and other 
referring research studies.
12.2  Age Range:
0-17
18-24
25-34
35-44
45-54
55-64
65-74
75+
12.3  Gender:
Male
Female
12.4  Special categories:
Minors /Children - “You must also consider the requirements of 45 CFR 46 Subpart D and DoDI 
3216.02, Enclosure 3, paragraph 7.d.”
Students
Employees - Civilian - “You must also consider the requirements of DoDI 3216.02, paragraph 7.e.”
Employees - Contractor
Resident/trainee
Cadets /Midshipmen - “You must also consider the requirements of DoDI 3216.02, Enclosure 3, 
paragraphs 7.e. and 12.”
Active Duty Military Personnel - “You must also consider the requirements of DoDI 3216.02, Enclosure 
3, paragraph 7.e.”
Wounded Warriors - “Depending on your intended subjects’ status, you may also need to consider the 
requirements of DoDI 3216.02, Enclosure 3, paragraph 7.e.”
Economically Disadvantaged Persons - “You must also consider the requirements of 32 CFR 219.111
(b).”
Educationally Disadvantaged Persons - “You must also consider the requirements of 32 CFR 219.111
(b).”
Physically Challenged (Physical challenges include visual and/or auditory impairment)
Persons with Impaired Decisional Capacity - “You must also consider the requirements of 10 USC 
980.”
Prisoners - “You must also consider the requirements of 45 CFR 46 Subpart C and DoDI 3216.02, 
Enclosure 3, paragraphs 7.b. and 7.c.”
Pregnant Women, Fetuses, and Neonates
Non-English Speakers
International Research involving Foreign Nationals - Headquarters Review is necessary
12.5  Inclusion Criteria:
Order 
Number
Criteria


a.  
1 
Inclusion Criteria – Male and female subjects, aged 18 to 65 are eligible for 
inclusion in the study if they satisfy the following criteria:
1.Are an active-duty service member or an Operation Iraqi Freedom (OIF), 
Operation Enduring Freedom (OEF), or Operation New Dawn (OND) veteran.
2.Are diagnosed with PTSD and have not achieved remission with an 
adequate trial of medication treatment (8 weeks) as indicated by self-report 
at referral and confirmed by baseline CAPS score of greater than or = to 40 
after informed consent is obtained.
 
12.6  Exclusion Criteria:
Order 
Number
Criteria
b.
Subjects will be excluded from the study for any of the 
  Exclusion Criteria - 
following reasons:
1. Female subjects of childbearing capacity who test positively for ß-HCG, or 
are either self-reporting as pregnant, planning to become pregnant, or 
nursing.
2. Presence of psychotic features.
3. Unable to provide informed consent or comply with study procedures.
4. Previous treatment with riluzole.
5. Serious, unstable illnesses including hepatic, renal, gastroenterological, 
respiratory, cardiovascular (including ischemic heart disease), 
endocrinologic, neurologic, immunologic, hematologic disease, or HIV.  This 
includes individuals with a history of COPD by diagnosis as well as persons 
taking inhalers for Asthma or Reactive Airway Disease.
6. Clinically significant abnormal levels (3x ULN or greater) of serum 
transaminases (ALT/SGPT; AST/SGOT), current or past blood dyscrasia.
7. Subjects with uncorrected hypothyroidism or hyperthyroidism.
8. DSM-IV alcohol or substance abuse or dependence within 90 days of the 
screening visit.
9. Treatment with a reversible MAOI, guanethidine, or guanadrel within 1 
week, or any change in fluoxetine dosing within 8 weeks prior to visit 2.  Use 
of antidepressant and sedative/hypnotic drugs at stable dose is permitted.
10. Documented history of hypersensitivity or intolerance to riluzole.
11. Subjects with a current or past history of other axis I disorders including 
schizophrenia, schizoaffective disorder, bipolar disorder or 
dementia.  However, those with a co-morbid history of other Axis I disorder 
like major depression, dysthymia or other anxiety disorders will be included; 
the justification for this is that approximately 70% of subjects with PTSD 
have co-morbid depression and or alcohol abuse, and restricting the sample 
to PTSD patients without depression will not accurately reflect the scope of 
this disorder.
12. Patients who are currently at high risk for homicide or suicide, as 
indicated by an affirmative answer to the question: “In the last three 
months, have you attempted to kill yourself, made specific plans to kill 
yourself, or had the intention to kill yourself?”
13. Current or planned litigation regarding the traumatic event.
14. Patients who recently started trauma focused cognitive behavioral 
psychotherapy (Patient's underlying educational or supportive individual or 
group therapy will be included).
15. Patient’s actively enrolled in an evidence based psychotherapy treatment 
(e.g., Cognitive Processing Therapy or Prolonged Exposure Therapy) will be 
excluded until that therapy has concluded, but may be re-approached at that 
time if patient self-report or clinician referral suggests persistent PTSD 
symptoms upon conclusion of that treatment.
16. Subjects with an artificial cardiac pacemaker or metallic implants within 
their body will be enrolled at WRNMMC for the placebo-control clinical trial 
portion of the study only.  These individuals, due to their pre-existing 
medical condition, are medically ineligible to participate in the H MRS 
1
imaging portion of the study.  Further, the Magnetic Resonance (MRI) 
Screening Form is use at WRNMMC will be used for participant screening 
prior to any imaging procedures.
17. Use of benzodiazepines.
Rationale and further discussion for General Inclusion and Exclusion criteria


1 
Age criteria:  The absence of data demonstrating the efficacy and tolerability of 
riluzole in children with PTSD makes their inclusion unethical.
Diagnosis:  Subjects with other co-morbid Axis I disorders except for major 
depressive disorder and other anxiety disorders are excluded because patients with 
this characteristic may constitute a group with a more severe form of illness that 
requires a different treatment approach.  Patients with a co-morbid diagnosis of 
major depressive disorder will be included because of the frequent co-occurrence of 
major depression in patients with PTSD.
Severity criteria:  Only subjects with a certain severity of PTSD will be included to 
increase the likelihood of finding the desired results. That is, PTSD must be 
unremitting and under current treatment on a stable prescriptive dosage for a 
minimum of 8 weeks on either of the two FDA-approved drugs for PTSD (Paroxetine 
– Paxil or Sertraline – Zoloft) or any other  SSRI/SNRI in off-label prescriptive use for 
the management of PTSD.  A score of 40 or more on CAPs is also required.
Exclusion of recent substance abuse or dependence:  We elect to use a narrower 
exclusion criterion of abuse and dependence than DSM-IV (within the past three 
months) in order to allow participation by subjects with a history of substance abuse 
or dependence problems that could be secondary to their mood disorders.  Allowing 
participation by patients with histories of substance abuse/dependence more than 
three months earlier broadens the inclusion criteria to more closely approximate 
patients seen in “real world” settings. Study medications are not associated with 
increased risk of future dependence problems.
To safeguard participants from self-incrimination, two exclusion criteria will be 
grouped and presented using the following script, which will be read aloud to each 
potential participant as part of obtaining informed consent for study enrollment:
“There are two situations that would preclude you from participating in this 
study.  I’m going to read these two to you.  If you believe that either of these is 
relevant to you, you cannot be in this study.  You do not need to state what your 
personal reasons are to me.  And I will not record them in any manner.  If you 
can participate in this study, please state, ‘
’ when I ask you if you’d like to 
YES
be in the study.  You do not need to say, ‘
’ if you cannot be in the 
NO
study.  Simply say ‘
’, and I will understand.  I appreciate your time 
THANK YOU
and consideration in participating.
The two situations are:
1. In the past 90 days, have you struggled with significant alcohol or 
substance abuse?
2. Are you planning to file legal suit or seek litigation regarding your 
traumatic event?
‘
’ ”
WOULD YOU LIKE TO BE IN THE STUDY?
Referral information for alcohol/substance/sedative use and legal counseling in 
use at WRNMMC will be maintained in the clinical area where screenings are 
conducted.  These are commonly posted and displayed for any individual to 
review.  In general, these materials are also maintained with other health and 
welfare referrals so anonymity and privacy is maintained.  As the participant 
leaves, the research clinician will inform the participant that resources are 
available should they be interested.  If the research clinician feels the individual 
is at personal risk, active intervention will be necessary as detailed in Section 6.3.
a.
Exclusion of acute or unstable medical illnesses:  This would prevent subjects from 
tolerating the acute trial target doses of medication.  We will include subjects with 
chronic stable medical illnesses.
Exclusion of women who are pregnant, plan to become pregnant or are breast-feeding
:  The study medication is a Category C drug, and we cannot be certain that it will 
not have teratogenic effects and it may be present in breast milk.  As such, the 
Consent Form advises female participants to avoid becoming pregnant for at least 
one month after last receiving the study drug.  Pregnancy within this time after the 
study drug is given may be a risk to an unborn baby.  No evidence of teratogenic 
effects is found in the literature for males; however, all participants will be advised of 
the pregnancy category of the drug (C) and be informed that they should avoid 
attempting to conceive during participation or for at least one month after last 
receiving the study drug.  Female participants will be given a pregnancy test post-
treatment.
Because it is unknown whether riluzole can adversely affect human sperm, male 
participants will be informed of the possible risk to a child conceived while using the study 
drug and be advised they avoid engaging in sexual activity with the intent to conceive.
 
13.0
 


Recruitment and Consent
13.1  Identification and Selection of Subjects:
See Legacy Protocol
13.2  Recruitment Process:
Subjects will be recruited from collaborator- and provider-referrals at WRNMMC and the Syracuse VA 
Medical Center, as well as from associated community-based outpatient clinics (CBOCs) and other 
referring research studies drawing from current patients with PTSD, with or without mild TBI, who are 
sub-optimally responsive to their current medication treatment over a minimum of 8 weeks.  We intend 
to use office space in the WRNMMC Behavioral Health Clinic.  Collaborators and providers will identify 
these potentially eligible patients and discuss with them the possibility of participating in the study. 
 
During the standard of care intake or initial evaluation process, collaborators and providers will give 
referral patients the contact information to reach the study research staff only if they express interest in 
contacting the study research staff and learning more information about participating in the study, 
specifically, the inclusion and exclusion criteria necessary for study participation.  Referral interactions 
with study research staff may occur by telephone, email, text and/or instant messaging, as well as in 
person at WRNMMC.  Patients who then meet inclusion criteria will be scheduled for the Screening Visit 
once informed consent is obtained.  All advertisements and information to be given to potential 
participants regarding how to contact study staff if interested will be approved by the IRB prior to 
dissemination.  Advertisements will include posters, trifold brochures, and provider handouts, which will 
be disseminated at Walter Reed National Military Medical Center services and intranet, and posting on 
clinicaltrials.gov and Facebook.  To ensure confidentiality, on the study Facebook page, only study 
personnel will be permitted to post information; potential participants and providers may privately 
message and “Like” or “Share” the page.  All PI information for participants and enrollees will be 
maintained in secured files or electronic storage under locked quarters.  Only Research Staff will have 
access to these records.  This is further detailed in Section 6.3.c.
 
All subjects will be evaluated for study entry during the Screening Visit by a Masters-level Clinical 
Research Psychologist under the supervision of a credentialed provider within the WRNMMV Behavioral 
Health Clinic using a CAPS assessment; WRNMMC study research staff will recruit, screen, consent and 
enroll subjects at WRNMMC, while Syracuse VA Medical Center study research staff will recruit, screen, 
consent and enroll subjects at the Syracuse VA Medical Center, as well as from associated community-
based outpatient clinics (CBOCs).  CAPS score > or = to 40 will be necessary for study 
enrollment.  Those entering the study at the completion of an INTRuST medication trial will also receive a 
CGI assessment, and must have an assessment determination of “NOT improved” or “NOT very much 
improved” on the CGI at the completion of their medication trial to be eligible for study enrollment.
 
The Screening Visit will include all screening tests, patient and family history, and psychiatric and 
physical examinations, as well as menstrual history in females.  Inclusion and exclusion criteria will be 
assessed.  Subjects will undergo a physical exam, supine and standing vital signs, blood chemistries, 
liver function tests, hematology profile, urinalysis (including screens for substances of abuse), hepatitis 
screen, SCID, and CAPS.  Women of childbearing capacity will have baseline serum ß-HCG, and a 
positive ß-HCG will exclude them from participating in the study.  Subjects must also have a negative 
Human Immunodeficiency Virus (HIV) test.
 
A complete medication list will be compiled prior to dispensing riluzole and verification of the list for 
change will be done at the weekly clinical visit to assess for compounds that may interact with clearance 
of the drug. 
 
Participants will be advised to take riluzole 1 hour before or two hours after meals for optimal 
metabolism of the compound.  Education will be provided that the bioavailability of the compound is 
significantly affected by high fat meals and that charbroiled food may increase the speed of clearance of 
the compound from their bodies.
13.3  Compensation for Participation:
Compensation is provided for off-duty military personnel participating at WRNMMC and for participants 
recruited from the Syracuse VA and associated CBOCs.  Reimbursement is determined by the number of 
hours spent completing study assessments and equates generally to a rate of $15 per 
hour.  Reimbursement will be pro-rated for incomplete research sessions.  Reimbursement is not 


A.  
provided for treatment visits.  Reimbursement will be issued as a gift card given directly to the 
participant (WRNMMC) or as a check mailed to the participant’s home (Central New York Research 
Corporation (Syracuse VA and associated CBOCs).  
 
Participant Reimbursement
Visit
Rate
Hours
Reimbursement
Screening
$15
5
 $                 75
Visit 1
$15
4
 $                 60
Visit 2
$15
2
 $                 30
Visit 3
$15
2
 $                 30
Visit 4
$15
2
 $                 30
Visit 5
$15
4
 $                 60
Visit 6
$15
2
 $                 30
Visit 7
$15
2
 $                 30
Visit 8
$15
2
 $                 30
Visit 9
$15
4
 $                 60
Bonus for attending all clinical sessions
 
 $                 80
Bonus for completing both H MRS imaging 
1
scans (pre and post)
 
5
 
$                 75
Total Reimbursement per participant
 
 $              590
13.4  Eligibility Assessment Process:
See Legacy Protocol
13.5  Consent Process:
Are you requesting a waiver or alteration of informed consent?
  Yes   
  No
Please explain the consent process:
Informed consent will be collected at the start of screening.  Participants will only be assigned a 
study ID number upon randomization after successfully being screened in.  Any participant who is 
found to be ineligible after screening will not be randomized or assigned a study ID number, 
however their consent and screening data will be stored with the rest of the study data files.  The 
stated recruitment goal of 158 participants approximately refers to consented participants and 
does include participants who were not randomized because of screen failure or any other 
ineligibility factor.
Informed consent and HIPAA authorization will be administered by a member of the research 
team at each site prior to screening and psychological testing and is a process that is initiated 
prior to the individual’s agreeing to participate in the study and continuing throughout the 
individual’s study participation.  risks and possible benefits of the study and opportunity to fully 
review the consent form, and ask questions.  The individual will be given sufficient opportunity to 
discuss the study and process the information in the consent process prior to agreeing to 
participate.  As a part of this process, all subjects are informed that they are not obligated to 
participate in this study, and the rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care as well as the care to which they are 
entitled to in their referring research study participation will not be adversely affected or 
penalized if they decline to participate in this study.  If they choose to take part in the study, they 
will be asked to sign the consent form.  This process will be monitored as required at each 
participating institution and in accordance with all regulatory guidelines.  Patients will be informed 
of their right to withdraw from the study at any time prior to obtaining informed consent and at 
subsequent scheduled visits.  This is anticipated to be a time ccommitment of one hour.
 
B. After the subject has been given ample time to read the consent document, the consenter will 
ask him or her to briefly explain the document. At this time, any questions will be answered. If in 
the judgment of the consenter the subject does not understand, the subject will be excluded; the 
consenter will then try to explain the reason for exclusion as best as possible.


 
C. The subject will verbally list health information to be accessed and released to ensure complete 
understanding. If, in the judgment of the consenter, the subject is not able to understand the 
health information to be accessed and possibly released, the subject will be excluded; the 
consenter will then try to explain the reason for exclusion as best as possible.
 
D. A HIPPA waiver will not be requested.
13.6  DoDI 3216.02 requires an ombudsman to be present during recruitment briefings when research 
involves greater than minimal risk and recruitment of Service members occurs in a group setting. If 
applicable, you may nominate an individual to serve as the ombudsman.
N/A 
Propose ombudsman 
13.7  Withdrawal from Study Participation:
Explain the process for withdrawal and specify whether or not the subjects will be given the opportunity 
to withdraw their data their data/specimens in the event they wish to withdraw from the study
See Legacy Protocol
14.0
 
Risks and Benefits
14.1  
Risks of Harm:
Identify all research-related risks of harm to which the subject will be exposed for each research 
procedure or intervention as a result of participation in this study.  Consider the risks of breach of 
confidentiality, psychological, legal, social, and economic risks as well as physical risks.  Do not describe 
risks from standard care procedures; only describe risks from procedures done for research purposes
General:  By agreeing to participate in this study, subjects will be temporarily forgoing the opportunity 
to receive routine clinical care and psychiatric medication in the community.  This will be clearly 
explained to all patients, along with the treatment strategies that are generally used in patients with 
PTSD.  Patients will also be told that riluzole is available for prescription by physicians in the 
community.  However, it has not received FDA approval for the indication of PTSD.
 
Screening and Evaluation:  The risks and discomforts of the screening and baseline evaluations are 
minimal.  No discomfort is expected to be associated with the physical examination or the clinical 
interview.  Venipuncture may be associated with the momentary discomfort of the needle stick, as well 
as a small risk of hematoma (bruise) formation.  Subjects will be exposed to the discomfort of asking 
personal questions that they may find distressing.
 
Stabilization Period and Treatment Trial:  Since it is unknown whether riluzole is effective in the 
treatment of PTSD, participation in this trial could delay additional potentially effective treatments  by 10 
weeks. That is, participation in this study would preclude a subject from receiving other potential 
augmenting medications (although none are FDA approved for PTSD) or additional psychotherapy for his 
or her refractory PTSD.  If the patient is discontinued from the study due to a worsening of their illness, 
they will receive standard care.
 
Risks Due to Riluzole Administration:  Controlled studies in medically ill patients taking multiple 
concomitant medications indicate that it is well tolerated.  The most frequent dose-related adverse 
events included nausea, asthenia, and elevated liver enzyme levels.  Less frequent dose-related adverse 
events include exfoliative dermatitis and tremor.  Nausea was reported by 12 to 21% of riluzole-treated 
patients, compared with 12% for placebo.  Less than 1% of patients with asthenia discontinued 
treatment.  Dizziness, diarrhea, anorexia, and circumoral paresthesia occurred more frequently with 200-
mg/day riluzole.  It should be noted that concomitant medications were permitted in the trials that 
examined riluzole, thus adverse events may be over-reported (approximately 72% took at least one 


concomitant medication, the mean number of concomitant medications per patient during this trial period 
of 6.6).  Elevated ALT levels (>5 X ULN) accounted for the majority of treatment discontinuations based 
on laboratory adverse events.  This event represented less than 4% with any treatment group (50 mg, 
100 mg, or 200 mg riluzole) (Lacomblez et al 1996).
 
Another potential side effect of riluzole that has been reported to rarely occur is neutropenia.  In ALS 
trials, three out of 4,000 patients given riluzole developed marked neutropenia, all seen within the first 2 
months of riluzole treatment.  Because of the risk of an elevation of liver enzymes and neutropenia, we 
will exclude patients with a history of significant liver disease or neutropenia.  Of note, is that in one of 
these trials, approximately 72% took at least one concomitant medication, the mean number of 
concomitant medications per patient during this trial period of 6.6.  It is possible that other medications, 
concomitant medical illnesses, etc could account for these cases of neutropenia.  In our preliminary 
studies, approximately 33 subjects with major depression were exposed to riluzole.  Overall the drug was 
well tolerated and no serious adverse events occurred.  Another potentially serious but very rare event is 
pancreatitis.
 
Our (NIH) experience with riluzole is outlined below:
 
An 8-week open-label study with riluzole in treatment-resistant DSM-IV bipolar depression (Protocol #03-
M-00092) (Zarate et al., 2005).  Eight subjects (57%) completed the 8-week trial. The reasons for 
discontinuation were adverse events (N =3; 2 asymptomatic increase in liver function tests, 1 renal 
calculi) and lack of improvement (N =3).  Patients received riluzole at a mean daily dose of 171.4 + 42.6 
mg (79% took a dose of 150 mg/day or more).  The most common adverse events during the trial were 
fatigue (N = 4), decreased salivation (N = 4), reduced sleep (N = 4), nausea (N = 3), diarrhea (N = 3), 
weight loss (N = 3), decreased sex drive (N = 3), blurred vision (N = 3), and headache (N = 3).  No 
serious adverse events were noted.  Two subjects were discontinued from the study because of increased 
liver function tests (LFTs) that were more than three times the upper normal limit. These subjects were 
asymptomatic for hepatic dysfunction, and LFTs normalized shortly after discontinuing riluzole.  One 
additional subject was discontinued because of renal calculi.  Overall riluzole was well tolerated.
 
A 6-week open-label study with riluzole in treatment-resistant DSM-IV major (unipolar) depression 
(Protocol #02-M-0034) (Zarate et al., 2004).  Patients received riluzole at a mean daily dose of 168.8 + 
27.2 mg (84.2% took a dose of 150 mg/day or more) for a mean duration of 5.4 ± 3.7 weeks.  Sixty-
eight percent (N=13) of subjects completed the 6-week trial.  The reasons for discontinuation were 
adverse events N=3 (1 increased liver function tests, 1 malaise, 1 nausea/vomiting), non-response N=2, 
and administrative N=1.  The most common adverse events during the trial were headache (58%), 
gastrointestinal distress (nausea or vomiting) (43%), decreased salivation (47%), constipation (32%), 
and tension/inner unrest (26%); similar side effects have been observed with riluzole in ALS trials 
(Bensimon et al., 1994).  No serious adverse events were noted.  One subject was discontinued from the 
study because of an increase in liver function tests (LFTs) that was 3 times the upper normal limit.  This 
subject was asymptomatic for hepatic dysfunction, and LFTs normalized shortly after discontinuing 
riluzole.  There was no relationship between dose of riluzole and adverse events or changes in laboratory 
tests.
 
A condition called interstitial lung disease has occurred in some patients who have taken 
riluzole.  Participants will be advised of this risk and informed that should they develop a dry cough with 
shortness of breath or difficulty breathing, they will need to seek medical attention including a chest x-
ray assessment and will need to discontinue taking riluzole immediately. 
 
H MRS is not associated with any 
Risks Associated with Magnetic Resonance Spectroscopy:  1
known deleterious biological effects in normal subjects.  However, there are risks for subjects who have 
any metallic implants in their body or who have an artificial cardiac pacemaker.  For this reason, they will 
be screened for the presence of any metallic prostheses or cardiac pacemaker both at the time of 
recruitment, and just prior to H MRS imaging.  Subjects will be advised of two potential 
1
discomforts.  The first is that the procedure requires remaining still while lying on their back for an 
extended period of time (up to 60 minutes).  The second is the MRS machine is a tightly enclosed space, 
which may be of concern for those with claustrophobia.
14.2  
Measures to Minimize Risks of Harm (Precautions, safeguards):
For each research procedure or intervention, describe all measures to minimize and/or eliminate risk of 
harms to subjects and study personnel
a. Safety Monitoring Plan


 
Research participants will be continuously monitored throughout the study by the Medical 
Monitor in conjunction with the Principal and Associate Investigators.  During the 8-week 
treatment period, study staff meets weekly with participants to assess their symptom status and 
side effects and to administer the research surveys and questionnaires.  Based on the 
anticipated rate of participant recruitment and study enrollment, the Medical Monitor and 
Investigators will hold a monthly meeting to review the status of enrollment and the overall 
progression of the study.  Records of the meeting will be compiled and maintained by the study 
coordinator.  Meetings of a more frequent interval will be implemented if necessary to account 
for accelerated rates of study enrollment exceeding the baseline estimate.
 
The Safety Monitoring Committee will be comprised of the following members:
 
Chair:  COL David Benedek, MD, MC
Medical/Research Monitor: COL (Ret.) Michael Roy, MD MPH
Data Monitor:  David Kopp, MPH
Member, at-large:  Kyle Possemato, PhD; Larry Lantinga, PhD
 
The Medical Monitor and Investigators define three event triggers, which will result in the 
unscheduled review and potential discontinuation of the participant from the study.  These 
triggers are:
 
1.      signs of increasingly severe physiological or psychological symptoms as evidenced 
by clinical observation during the scheduled weekly visit as well as participant self-
report or disclosure;
2.      exhibited distress or objection raised during the administration of the research 
questions;
3.      and study-related medical complications experienced while taking the assigned 
medication as determined by physical examination and supporting laboratory report.
 
Further, if during the weekly visit, a participant’s response to the research battery indicate 
increasingly severe physiological or psychological symptoms that require an immediate 
intervention or they express suicidal ideation, intent, or plan, study staff will promptly notify the 
Principal Investigator for referral and treatment management of the individual.  As part of study 
enrollment, participants will be given the 24-hour emergency contact information for the 
Investigators and will receive careful instruction on how to reach members of the research team 
for assistance.  Finally, before enrolling in the study, participants will be asked to complete a 
Treatment Contract.  In the Treatment Contract participants will identify a doctor, family 
member or friend who is aware of their participation in this research study and is willing to be a 
part of their support system.  The Investigator may contact the person(s) who have agreed to 
act as the participant’s support system in the case their symptoms worsen during the study or 
there is an emergent medical issue that requires immediate contact. 
 
End of treatment/early discontinuation for the trial:
 
Participants may withdraw at any time or be removed from the study at the discretion of the 
Investigator, should medical contraindications to the assigned medication develop, if intolerable 
adverse reactions occur, if mood or anxiety worsens, or if in the clinician’s judgment the patient 
has worsened to such a degree that further participation would put the individual at risk.  If a 
participant begins evidence based psychotherapy (such as CPT or prolonged exposure 
therapy) or if any of the medications the participant takes for PTSD or other psychiatric 
conditions are changed after they begin the study, the participant may be withdrawn from the 
study.  Participants are at no risk of losing their right to medical care and some period of 
observation by the investigators may be recommended for the participants to safely stop taking 
part in the study because of the study drug.
 
Continuous monitoring of the participant’s health while taking the assigned medication is 
performed by the Medical Monitor in conjunction with the Principal and Associate Investigators 
during the scheduled weekly visits.  Participants will have clinical biochemistry laboratory blood 
assays performed to monitor their liver state and function.  Liver Function Test (LFTs) will be run 
first at the Screening Visit and then weekly while taking the assigned medication.  In the period 
between screening and randomization, the participant will be instructed not to begin taking 
study medication until the Investigator confirms that LFTs are within normal limits.  Specifically, 
their alanine transaminase (ALT), aspartate transaminase (AST), total/direct bilirubin, and 
alkaline phosphate, will be monitored on a weekly basis during Study Period II to ensure that 
participants do not have liver function tests elevated over 3x normal ranges.  If elevated LFTs 
are encountered, the test will be repeated, and if levels remain elevated at or above 3x upper 
limit of normal, the participants on the higher dose will have their dose reduced to 100mg per 


day and participants on the low dose will be removed from the study. If a participant's LFTs ever 
exceed 5x upper limit of normal, the study drug will be discontinued and the subject will be 
withdrawn from the study.
 
Elevated LFTs of only 2xs level are not clinically uncommon and are often associated with any 
number of unrelated medical conditions or complications.  A mild elevation in LFTs is quite often 
temporary in nature, and quickly reversible.  Initial studies in riluzole established the 3x level as 
diagnostic for liver enzyme impairment or disruption to ensure that unrelated medical conditions 
and complications do not compromise the study while still ensuring the highest safeguarding of 
the participant.
 
Participants requiring removal from the study will receive immediate medical treatment and 
follow up care as necessary.  As this is an augmentation trial, we will not taper off medications 
that have been even minimally effective for the participant’s current depression or PTSD (as 
indicated by CGI-Severity/Improvement assessment score at the completion of a previous 
referring trial or baseline assessment).   If participants are outpatients but their deteriorating 
condition requires hospitalization, they will be admitted to the specific site’s appropriate 
inpatient treatment facility until stable for outpatient care.  Participants removed from the study 
because of a worsening of their illness will have the option to continue care at the study sites as 
necessary for up to 90 days.  Since subjects are either active duty military or veterans and may 
move during or shortly after the study, continued care will be coordinated at the appropriate 
military treatment facility or veteran’s administration hospital, since this is more convenient as a 
result of change of duty location or medical separation from service.  Should they choose not to 
receive standard clinical treatment that the study psychiatrist recommends; the participants will 
be discharged to the care of the primary physician or psychiatrist who followed them prior to 
enrollment.  If they do not have a primary provider we will assist them in finding an appropriate 
referral in the community for further treatment and follow-up.
 
b. Safety Analysis Plan
 
 
Exposure to dangerous interventions will be minimized by the discontinuation criteria described 
above, as well as monitoring of laboratory tests by the Medical Monitor in conjunction with the 
Principal and Associate Investigators to ensure that liver function is not elevated over 3x normal 
ranges. 
14.3  
Confidentiality Protections (for research records, data and/or specimens):
Describe in detail the plan to maintain confidentiality of the research data, specimens, and records 
throughout the study and at its conclusion (e.g., destruction, long term storage, or banking). Explain the 
plan for securing the data (e.g., use of passwords, encryption, secure servers, firewalls, and other 
appropriate methods). If data will be shared electronically with other team members/collaborators 
outside the institution, describe the method of transmission and safeguards to maintain confidentiality. 
Explain whether this study may collect information that State or Federal law requires to be reported to 
other officials or ethically requires action, e.g., child or spouse abuse
i. The Principal Investigator at each site maintains adequate and accurate records in order for 
the conduct of the study to be fully documented and study data subsequently verified.  All 
records pertaining to the identity of the subjects will be kept private and confidential.   For 
documentation containing personal identifying information that is to be retained locally, on-site, 
it will be maintained in a locked file cabinet.   After study closure, Investigators retain all source 
documents and study-related documents pertinent to protocol compliance.  Because the length 
of time required for retention of records depends upon a number of regulatory and legal factors, 
Investigators will store documents until they receive notification that documents can be 
destroyed.  In general, study records are retained and securely stored for a minimum of 7 years 
after the completion of all study activities.
 
ii. When will you destroy the research source documents, data file, and the master code?
 
In general, study records are retained and securely stored for a minimum of 7 years 
after the completion of all study activities.
 
iii. Will research data including 
 be sent outside of 
Identifiable Protected Health Information
WRNMMC?


  x   Yes – Please explain assurances you have received from the outside party that they 
will appropriately follow confidentiality protections, follow the HIPAA requirements, and 
abide by the provisions of your Authorization.
___ No
 
 
Only where necessary, research data may be sent outside of WRNMMC.  Principal and 
Associate Investigators in consultation with the Medical Monitor will review all research 
data prior to release to ensure that only the minimum amount of necessary information is 
released.  In their review, all records pertaining to the identity of the subjects will be kept 
private and confidential and the research data will be password protected and encrypted 
using National Institute of Standards and Technology (NIST)-certified 
cryptography.   Transmission of research data will occur through a secured carrier 
recognized in the transport of confidential materials with delivery exclusively to a 
designated individual or agent required.  Prior to release, all necessary assurances will be 
obtained and agreements established and entered into as required by regulation and 
institutional standard of practice.
14.4  
Potential Benefits:
Describe any real and potential benefits of the research to the subject and any potential benefits to a 
specific community or society
If the individuals in the research are considered experimental subjects (per 10 USC 980), and they 
cannot provide their own consent, the protocol must describe the intent to directly benefit all subjects
There may be no direct benefits from participating in this study.  It is unknown if riluzole will decrease 
PTSD symptoms.  Information obtained from the study of all participating subjects will benefit society in 
the way of increased knowledge and understanding of PTSD.
14.5  
Privacy for Subjects:
Describe the measures to protect subject’s privacy during recruitment, the consent process, and all 
research activities, etc.
See Legacy Protocol
14.6  
Incidental or Unexpected Findings:
Describe the plan to address incidental findings and unexpected findings about individuals from 
screening to the end of the subject’s participation in the research. In cases where the subject could 
possibly benefit medically or otherwise from the information, state whether or not the results of 
screening, research participation, research tests, etc., will be shared with subjects or their primary care 
provider. State whether the researcher is obligated or mandated to report results to appropriate military 
or civilian authorities and explain the potential impact on the subject
See Legacy Protocol
15.0
 
Study Monitoring
15.1  Data Monitoring Plan:


Describe the plan to monitor the data to verify that data are collected and analyzed as specified in the 
protocol. Include who will conduct the monitoring, what will be monitored and the frequency of 
monitoring
See Legacy Protocol
15.2  Safety Monitoring Plan:
Describe the plan to monitor the data to ensure the safety of subjects
See section 14.2 of the protocol application
15.3  Does your study require independent data and safety monitoring?
  Yes   
  No
16.0
 
Reportable Events
16.1  Reportable Events:
Consult with the research office at your institution to ensure requirements are met
• Describe plans for reporting expected adverse events. Identify what the expected adverse events will 
be for this study, describe the likelihood (frequency, severity, reversibility, short term management and 
any long term implications of each expected event)
• Describe plans for reporting unexpected adverse events and unanticipated problems. Address how 
unexpected adverse events will be identified, who will report, how often adverse events and 
unanticipated problems will be reviewed to determine if any changes to the research protocol or consent 
form are needed and the scale that will be used to grade the severity of the adverse event
Expected adverse events which are not serious are reported on the Continuing Review (CR) Progress 
Report is generally performed on a 12-month cycle. More frequent Progress Reports may be required 
at the discretion of the IRB.
 
For multi-center studies, a summary of adverse events study-wide or the report of the Data Safety 
Monitoring Board (DSMB) should be included with the CR.
 
Serious Adverse Events: The PI, within 24 hours, must report all related or possibly-related AND 
serious adverse events (SAE) occurring in subjects enrolled at FBCH.  This is accomplished by 
submitting an adverse event report to the IRB via IRBNet.  For protocols involving investigational 
drugs or devices, the investigator must also report a serious adverse event to the sponsor of the IND 
or IDE immediately (within 24 hours). Serious adverse events must be reported even if the PI 
believes that the adverse events are unrelated to the protocol.
 
Unexpected (but not serious) adverse events occurring in subjects enrolled at FBCH which, in the 
opinion of the PI, are possibly related to participation AND places subjects or others at a greater risk 
of harm that was previously known or recognized in the protocol must be reported by the PI within 
24 hours of discovery by email or phone to the IRB and the Research Monitor.  A follow-up written 
report within 5 business days to the IRB and the Research Monitor through IRBNet is required. 
 
Unanticipated problems involving risks to subjects or others (UPIRTSOs) must be reported to the IRB 
and Research Monitor via email or telephone within 24 hours of discovery and a written follow up 
report within 5 business days.
 
When a deviation occurs, the investigator shall report the occurrence to the IRB. The investigator is 
required to make the determination whether the deviation meets the criteria for an unanticipated 
problem involving risks to subjects or others.  The IRB Chair or IRB staff member shall also make 
the determination if the protocol deviation meets the definition of an unanticipated problem involving 
risks to participants or others.  If the IRB Chair or IRB Staff member determines and documents that 
the deviation is an unanticipated problem involving risks to subjects or others or the deviation 
resulted from serious or continuing noncompliance, the IRB staff member shall place the deviation 
on the agenda of the next available IRB meeting for review.  If the IRB Chair or IRB Staff member 


determines and documents that the deviation is not an unanticipated problem involving risks to 
subjects or others, the IRB Chair or staff member shall acknowledge the submission and complete 
the review through an administrative review procedure.
 
As a reminder, according to DoDI 3216.02 (November 8, 2011), the IRB shall approve an 
independent research monitor by name for all DoD-conducted research involving human subjects 
determined by the IRB to involve more than minimal risk to human subjects.  Additionally, the 
research monitor may be identified by an investigator or appointed by an IRB or IO for research 
involving human subjects determined to involve minimal risk.
     
The research monitor may perform oversight functions and will report their observations to the IRB 
or a designated official.  The research monitor may discuss the research protocol with the 
investigators, interview human subjects, and consult with others outside of the study about the 
research.  The research monitor shall have the authority to stop a research protocol in progress, 
remove individual subjects from a research protocol, and take whatever steps are necessary to 
protect the safety and well-being of human subjects until the IRB can assess the monitor’s 
report.  Research monitors shall have the responsibility to promptly report their observations and 
findings to the IRB or other designated official.  The research monitors shall have expertise 
consonant with the nature of risk(s) identified within the research protocol and they shall be 
independent of the team conducting the research involving human subjects.
17.0
 
Equipment/non-FDA Regulated Devices
17.1  Does the study involve the use of any unique non-medical devices/equipment?
  Yes   
  No
18.0
 
FDA-Regulated Products
18.1  Will any drugs , dietary supplements, biologics, or devices be utilized in this study?
Drugs
Dietary Supplements
Biologics
Devices
N/A
18.2  Drug Details:
Are drug(s) in this research being used in accordance to the approved labeling?
Are drug(s) in this research being used in a manner other than its approved labeling?
When adding a drug indicate in the details section of the drug if the use is either used in accordance to 
the approved labeling or in a manner other than it's approved labeling
View 
Details
Drug Name
FDA Approved
A new drug or a 
new use of 
approved drug:
IND Number
Trade Drug 
Name: Riluzole
Generic Drug 
Name:
Investigational 
Drug Name:
Yes 
Yes 
 
Trade Drug Name:
Riluzole 


Generic Drug Name:
 
Investigational Drug Name:
 
Identify the name of the 
manufacturer or source of 
investigational drug/biologic:
Rilutek  
Is the drug supplied at no cost?
Yes  
Is the Drug FDA Approved:
Yes  
Is this a new drug or a new use 
of an already approved drug
Yes  
Is an IND necessary
No  
IND Number
 
Who holds the IND:
N/A  
IND details:
 
If FDA Approved and an IND is 
not required, Please provide a 
rationale for exemption:
 
Are you currently using this IND 
in another research project?
No  
If yes, list the IRB Number(s):
 
Dose Range:
 
Frequency:
 
Route of administration:
 
Will the investigational pharmacy 
be dispensing?
Yes  
If the source is not a FDA 
licensed facility, provide details 
regarding the purity, quality, 
stability and sterility of the 
investigational drug/biologic:
 
Identify who will be preparing the 
investigational drug/biologic for 
administration and describe in 
detail how it will be prepared:
 
Indication(s) under Investigation:
 
Where will the drug be stored
 
Drug Storage Restrictions 
(including temperature, etc.):
 
Administration Instructions:
 
Possible Untoward Effects, Their 
Symptoms & Treatment:
 
Potential or Actual Antidotes for 
Excessive or Adverse Drug Effect:
 
Contraindications and 
Interactions, If Known:
 
Investigators Authorized to 
Prescribe:
 
18.4  Reporting Requirements for FDA-regulated research under IND and IDE:
Describe the process for complying with FDA regulatory requirements for adverse event reporting and 
adverse device effects reporting to the sponsor


Riluzole (Rilutek®) is FDA-approved (December 1995) for the treatment of amyotrophic lateral sclerosis 
(ALS).  It is taken in oral dosage form (tablets) - 50mg every 12 hours.  The Package Insert is provided 
as an addendum.  Because of its anti-glutamatergic effect and its relative safe profile, riluzole has been 
evaluated for off-label usage in a number of trials for adult psychiatric conditions in which glutamate 
excess has been proposed as part of the pathologic mechanism. Seven open-label trials of riluzole in 
adult subjects are reported in a recent review including three in major depressive disorder (MDD), one in 
bipolar depression one in generalized anxiety disorder (GAD), and two in the treatment of obsessive-
compulsive disorder (OCD) (Grant et al, 2010).
18.5  Sponsor (organization/institution/company):
N/A
If applicable, provide sponsor contact information:
19.0
 
Research Registration Requirements
19.1  ClinicalTrials.gov Registration:
Registration is not required 
Registration pending 
Registration complete 
19.2  Defense Technical Information Center Registration (Optional):
Registration is not required 
Registration pending 
Registration complete 
20.0
 
References and Glossary
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73.Xu L, Enyeart JA, Enyeart JJ. Neuroprotective agent riluzole dramatically slows inactivation of Kv1.4 
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75.Ahn HS, Kim SE, Jang HJ et al. Interaction of riluzole with the closed inactivated state of Kv4.3 
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79.Katoh-Semba R, Asano T, Ueda H et al. Riluzole enhances expression of brain-derived neurotrophic 
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20.2  Abbreviations and Acronyms:

ICF_001.pdf: 
Page 1 of 10
Protocol No.   380797
Current Version: v.15.5 – 28 July 2017
WALTER REED NATIONAL MILITARY MEDICAL CENTER 
BETHESDA, MD
This consent form is valid only if it contains the IRB stamped date
Consent for Voluntary Participation in a Research Study Entitled: “Riluzole for PTSD: Efficacy 
of a Glutamatergic Modulator as Augmentation Treatment for Posttraumatic Stress Disorder”.
Principal Investigator:
COL David Benedek, MD, MC
Professor/Deputy Chair, Psychiatry; Associate Director/Senior Scientist, Center for the Study of 
Traumatic Stress, USUHS
Service and Department:  Psychiatry 
USUHS, Building B
4301 Jones Bridge Road 
Bethesda, MD 20184
Phone Number: (301) 295-9888
Mobile Number: (240) 204-0562
E-mail: david.benedek@usuhs.edu
Study site:  x WRNMMC,  
FBCH,  USUHS,  
WRAIR,  x  OTHER
List OTHER study sites: Syracuse VA Medical Center 
“A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At most, 
the Web site will include a summary of the results. You can search this Web site at any time.”
1. INTRODUCTION OF THE STUDY
You are being asked to be in this research study because you are receiving treatment for 
posttraumatic stress disorder (PTSD) at WRNMMC, yet your symptoms have not improved. Your 
participation is voluntary. Refusal to participate will not result in any punishment or loss of 
benefits to which you are otherwise permitted. Please read the information below, and ask 
questions about anything you do not understand, before deciding whether to take part in the study.
2. PURPOSE OF THE STUDY
The purpose of the study is to learn and evaluate how using the drug riluzole (sold by the 
name Rilutek®) might improve the symptoms of PTSD in people who are not having 
improvement with their current medication.  This is called an off-label study because although 
riluzole is approved to treat Lou Gehrig’s disease, it is not presently approved for PTSD.
IRB NUMBER: 380797
IRB APPROVAL DATE: 08/10/2017
IRB EXPIRATION DATE: 04/21/2018


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Protocol No.   380797
Current Version: v.15.5 – 28 July 2017
Other studies have shown that certain types of nerve cells in the brain, as well as specific areas of the 
brain are affected in people that experience PTSD. These affects may be caused by changes in the 
amount of glutamate that is normally found in the brain.  Glutamate is a simple amino acid that acts as a 
messenger for nerve cells.  Glutamate does this by binding to a nerve cell and
telling it whether or not to activate.  A medication like riluzole may lower the activity of glutamate in 
the brain, which may improve the symptoms of PTSD.
3. PROCEDURES TO BE FOLLOWED
If you agree to be in this study, you will be asked to take either riluzole or an identical looking but 
inactive placebo along with your current PTSD medication. You have a 50/50 chance of receiving 
riluzole or the placebo. Neither you, nor the study investigators, will know to which group (riluzole or 
placebo) you will be randomly assigned. The randomization process is like a coin toss done by 
computer.  It will be conducted at the WRNMMC research pharmacy where you will go to receive your 
study drug (riluzole or placebo). You will take the study drug twice a day for 8 weeks.
At the Screening Visit, you and the study clinician will discuss the study and you will have a chance to ask 
any questions you might have about participating in the study.  If you agree to participate you will be asked to 
sign this consent form. Then you will be evaluated by the study clinician for enrollment into the study.  This 
medical evaluation will include your medical history, completion of
six screening tests, surveys, and questionnaires, and a psychiatric and physical examination that includes 
blood tests for a profile of your blood, the functioning of your liver and thyroid, a pregnancy test for females 
and for HIV (Human Immunodeficiency Virus) and hepatitis. You will also give a sample of your urine for a 
urinalysis test (a common medical screening test) and a drug screen.  This screening process is designed to 
ensure you are a good candidate for the study, have no major health complications and to provide information 
that can help the researchers determine whether or not the study drug is effective.
There is also an optional brain imaging portion of the study for which you can volunteer.
This imaging is called a proton magnetic resonance spectroscopy, and it does not have any of the risks 
associated with X rays.  It uses the same machine as an MRI, and if you are bothered by tight spaces 
(claustrophobia) you might not want to volunteer for this part of the study. There is one scan at the end 
of the screening visit, and the other after the trial. Each scan takes about an hour. Comparison of these 
scans may show if the study treatment improves parts of the brain that PTSD can adversely affect.  If 
you want to volunteer for this we will ask you to sign another line at the end of the consent that is 
specific to the brain imaging portion of the study.
You will schedule the first Clinical Visit for two to four weeks after the Screening Visit. A number of tests will 
be conducted that day and it is when you will begin taking the study drug.  During the two to four weeks after 
the Screening Visit you should continue taking your current PTSD medicine at the same dosage.  You will be 
contacted by telephone after 1 week to confirm that no medication changes were made.  Throughout the study 
you will continue taking the same amount of your original PTSD medicine while taking the study drug.
With your daily PTSD medicine dose stable and consistent, you will begin taking the study drug for 
PTSD.  You will take two to four tablets twice a day of either riluzole or a placebo.  You will begin by 
taking two tablets twice a day, but your dose may be increased if no improvement is noted during weekly 
IRB NUMBER: 380797
IRB APPROVAL DATE: 08/10/2017
IRB EXPIRATION DATE: 04/21/2018


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Protocol No.   380797
Current Version: v.15.5 – 28 July 2017
follow-up visits to the clinic.  If on the higher dose, you experience any intolerable side effects or your 
liver functions exceed 3x the Upper Limit of Normal (ULN), your dose will be reduced to 100 mg/day. If 
your liver function test exceeds 3x ULN after a repeat test while on 100 mg/day, you will be removed 
from the study.  If a participant's LFTs ever exceed 5x upper limit of normal, the study drug will be 
discontinued and the subject will be withdrawn from the study.
Remember, your chance of being assigned to either the riluzole or placebo group is equal. The 
placebo will look identical to riluzole, but it will not contain any amount of the active drug.  You will not 
know whether you are taking the placebo or riluzole. Your clinician and the research staff
will also not know whether you are taking the placebo or riluzole. This is called double blinding with a 
placebo and it is considered the best way to study the effect of drug. The research pharmacy will maintain 
a record of whether you are receiving study drug or placebo, so that the research team or external monitors 
could be informed in the event of an emergency (such as if you are admitted to the hospital and the 
treatment team needs to know what medications you are taking).
You will return for Clinical Visits weekly.  You will meet with the study clinician to discuss any 
questions you have about the study. You will also give your medical history and complete several 
screening tests, surveys, and questionnaires as well as a psychiatric and physical examination.  Finally, 
if you volunteered to participate in the brain imaging portion of the study, you will undergo a post-
treatment scan between visits 8 and 9.  At the end of your 10-week trial, you will be given the option of 
an additional 3-month, open-label treatment period with riluzole.  If you choose to enter the additional 
open-label treatment period, an open-label letter will be provided to you to offer to your healthcare 
provider with guidance on appropriate monitoring.
4. ALTERNATIVES TO PARTICIPATION
Alternatives to participation may be available to you.  You will need to consult with your primary care 
provider for other alternatives.  Choosing not to participant in the study is an alternative to participation in 
the study.  There may be other research studies involving experimental treatments that could help your 
condition.  
5. AMOUNT OF TIME FOR YOU TO COMPLETE THE STUDY
You will be part of this study for 10 weeks and at the end of study participation you will be given 
the option of receiving riluzole for an additional 3-month period of treatment. This option is available 
to everyone whether or not you believe you received the placebo or the study drug during your 10 
weeks of study treatment.
During the 10 weeks of the study, you will be asked to visit the clinic 9 times.  In the first two 
weeks, you will visit the clinic for your first visit, the Screening Visit, which will take 4 hours, and 
you will have a follow-up telephone interview, which lasts approximately 10 minutes.  In the 
remaining 8 weeks, you will visit the clinic weekly, which may take between 2 to 4 hours, each.
The time commitment for the participants who volunteer to complete the imaging part of the study 
at the Screening Visit and the last visit, is estimated to be 60 to 90 minutes for each scan.
IRB NUMBER: 380797
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Protocol No.   380797
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6. NUMBER OF PEOPLE THAT WILL TAKE PART IN THIS STUDY
This study is called a multi-site study because participants from two hospitals will be in the study.  
There will be up to 104 people taking part in this study at WRNMMC and up to 54 people taking part 
in this study at the Syracuse VA Medical Center. A total of 158 people will be in the study from the 
two hospitals involved.
7. POSSIBLE RISKS OR DISCOMFORTS FROM BEING IN THIS STUDY
The possible risks and discomforts from being in this research study include:
Screening and Evaluation: The risks and discomforts of the screening and baseline evaluations are minimal.  
No discomfort is expected to be associated with the physical examination or the clinical interview.  
Venipuncture, drawing a small amount of blood at each visit, may be commonly associated with the 
momentary discomfort of the needle stick, as well as a small, but rare risk of a bruise forming. You will be 
exposed to the discomfort of asking personal questions that you may find distressing.
While uncommon, if you experience significant psychological stress while answering study 
questionnaires, the study clinician will evaluate your immediate needs and provide you with 
appropriate mental health referrals and resources.  There are no social, legal, or financial risks or 
discomforts expected with your participation in this study.
Risks Due to Taking Riluzole: The risks and discomforts of taking riluzole are rare. Earlier studies on 
individuals taking riluzole found most people having minimal problems even when taking multiple, 
different medications at the same time.
Those people that did have trouble with riluzole commonly experienced nausea and overall
weakness and fatigue or tiredness.  While rare, some individuals had higher laboratory test results for the 
functioning of their liver (their liver enzyme levels had increased), but these levels returned to normal once 
they stopped taking riluzole. We will be testing the functioning of your liver each week while you are taking 
riluzole to watch for this condition and you will stop taking riluzole if this happens to you.
You should know that alcohol use is discouraged while taking riluzole because the combination of the two 
can affect the functioning of your liver (your liver enzyme levels could increase).  If you have an abnormal 
(high) liver function test result while taking riluzole, and it’s possible the result occurred due to your alcohol 
consumption while taking riluzole, be sure to inform the clinician that your test result is not due exclusively 
to your taking riluzole. The clinician will discuss with you confidentially your options.
Rarely, a condition called interstitial lung disease (scarring of the lung tissue) has occurred in some 
patients who have taken riluzole.  If you develop a dry cough with shortness of breath or difficulty breathing, 
you need to see a doctor and get a chest x-ray and you may have to stop taking riluzole immediately.  If this 
happens, in most cases, the symptoms end after stopping the drug and receiving treatment for the symptoms.
While rare, some of the people who took the highest dose of riluzole per day in past studies also had 
dizziness, diarrhea, anorexia, tremor, exfoliative dermatitis or had unknown skin sensations like burning, 
prickling, itching, tingling.  Another rare possibility is pancreatitis, or inflammation of the pancreas.  If 
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Protocol No.   380797
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untreated pancreatitis may result in severe abdominal pain or even death, however these reported cases were 
resolved by withdrawing Riluzole treatment. Very rarely (3 reported cases out of 5,000 patients) there have 
been reports of neutropenia, a condition in which certain white blood cell counts are decreased and may 
result in a weakened immune system without treatment. You will meet weekly with the study clinician, and 
the two of you will discuss any symptoms or feelings or side effects you are having while taking riluzole.  If 
you experience these rarer symptoms, the study clinician will discuss with you the possible changes that can 
be made in your study participation.
Risks Associated with Magnetic Resonance Spectroscopy: The magnetic resonance imaging scan that 
some participants in the study will volunteer to do for brain imaging is not associated with any known 
harmful effects.  However, there are risks for people who have any metallic implants in their body.  For 
this reason, you will be asked whether you have any metallic implants at the time of recruitment and just 
prior to the imaging scan. Also, since the imaging study requires that a person lie relatively still in 
relatively narrow cylindrical tube, some persons may experience uneasiness or discomfort from being in 
such a space.  If you experience these feelings and they become excessive, you can request that the study 
be stopped.
General: By agreeing to participate in this study, you are agreeing to receive an unproven treatment 
(a 50% chance because you could receive the placebo) for your PTSD symptoms, which may not 
decrease, lessen or otherwise improve these symptoms. Alternatively, you may be able to receive this 
treatment from your physician.  Riluzole is available for prescription by a physician.  However, it 
does not have FDA-approval for the treatment of PTSD. Your participation in this study could help 
physicians know whether riluzole is effective in treating PTSD symptoms.
8. POSSIBLE BENEFITS FROM BEING IN THIS STUDY
You may or may not benefit from taking part in this study, but the information we learn may help us 
learn about the active study drug for the treatment of PTSD that might improve the symptoms of this 
condition in people who are not having improvement under their current medication.
9. CONFIDENTIALITY/PRIVACY OF YOUR IDENTITY AND YOUR RESEARCH 
RECORDS
The principal investigator will keep your research records secured at all times. These records will be 
stored in locked cabinetry in a locked room accessible only by the research study team. All electronic 
research information and data will be maintained under password protection and data encryption.  These 
records may be looked at by staff from the Walter Reed (WRNMMC) Department of Research Programs, 
the Walter Reed (WRNMMC) Institutional Review Board (IRB), the DoD Higher Level Review, the 
Veterans Health Administration Research and Development Institutional Review Board (IRB), and other 
government agencies as part of their duties. These duties include making sure that the research 
participants are protected.  Confidentiality of your records will beprotected to the extent possible under 
existing regulations and laws but cannot be guaranteed.
Complete confidentiality cannot be promised, particularly for military personnel, because information 
bearing on your health may be required to be reported to appropriate medical or command authorities. 
Your research records may be disclosed outside of WRNMMC, but in this case, you will be identified only 
IRB NUMBER: 380797
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Protocol No.   380797
Current Version: v.15.5 – 28 July 2017
by a unique code number. Information about the code will be kept in a secure location and access limited to 
authorized research study personnel. 
By signing this consent document, you give your permission for information gained from your participation in 
this study to be published in medical literature, discussed for education purposes, and used generally to further 
medical science. You will not be personally identified; all information will be presented as anonymous data. So, 
your name will not appear in any published paper or presentation related to this study.
This research study meets the confidentiality requirements of the Health Insurance Portability and 
Accountability Act (HIPAA).
10.CONDITIONS UNDER WHICH YOUR PARTICIPATION IN THIS STUDY MAY BE 
STOPPED WITHOUT YOUR CONSENT
Your taking part in this study may be stopped without your consent if remaining in the study 
might be dangerous or harmful to you.  Your taking part in this study may also be stopped without 
your consent if the military mission requires it, or if you lose your right to receive medical care at a 
military hospital.  Lastly, your taking part in this study may be stopped without your consent if you 
do not take the study drug or your preexisting PTSD medication.  If you begin evidence based 
psychotherapy (such as CPT or prolonged exposure therapy) or if any of the medications you take for 
PTSD or other psychiatric conditions are changed after you begin the study, you may be withdrawn 
from the study.
11. ELIGIBILITY AND PAYMENT FOR BEING IN THIS STUDY
You will be compensated for the time you spend completing the study assessments.  If you are 
active-duty military, you must be off-duty during participation to receive compensation. This 
compensation will be a gift card given to you by a study member at the end of each visit.
Compensation will be as follows:
Screening:
$75 (5 hours)
Visit 1:
$60 (4 hours)
Visit 2:
$30 (2 hours)
Visit 3:
$30 (2 hours)
Visit 4:
$30 (2 hours)
Visit 5:
$60 (4 hours)
Visit 6:
$30 (2 hours)
Visit 7:
$30 (2 hours)
Visit 8:
$30 (2 hours)
Visit 9:
$60 (4 hours) Bonus 
for attending all sessions: $80
Bonus for completing both the pre- and post- 1H MRS imaging scans:  $75 (5 hours)
Total possible compensation: $590
Compensation will be prorated as a percentage of the full payment for incomplete research sessions.
IRB NUMBER: 380797
IRB APPROVAL DATE: 08/10/2017
IRB EXPIRATION DATE: 04/21/2018


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Protocol No.   380797
Current Version: v.15.5 – 28 July 2017
12. COMPENSATION IF INJURED AND LIMITS TO MEDICAL CARE
You will not receive any compensation (payment) if you are injured as a direct result of being in 
this study. You should understand that this is not a waiver or release of your legal
rights.  You should discuss this issue thoroughly with the principal investigator before you enroll in 
this study.
Should you be injured as a result of your participation in this study, you will be given medical 
care for that injury at no cost to you.
Medical care is limited to the care normally allowed for Department of Defense health care 
beneficiaries (patients eligible for care at military hospitals and clinics). Necessary medical care does 
not include in-home care or nursing home care.
If at any time you believe you have suffered an injury or illness as a result of participating in this 
research project, you should contact the Department of Research Programs at Walter Reed National 
Military Medical Center at 301-295-8239.
13. COSTS THAT MAY RESULT FROM TAKING PART IN THIS STUDY
There is no charge to you for taking part in this study.
14. IF YOU DECIDE TO STOP TAKING PART IN THIS STUDY AND THE 
INSTRUCTIONS FOR STOPPING EARLY
You have the right to withdraw from this study at any time.  If you decide to stop taking part in 
this study, you should tell the principal investigator as soon as possible; by leaving this study at any 
time, you in no way risk losing your right to medical care. Some period of observation by the 
investigators may be recommended for you in order for you to safely stop taking part in this study 
because of the study drug.
15. STEPS TAKEN BEFORE AND DURING THIS STUDY TO PROTECT YOU
Riluzole has been classified by the FDA as a Class C drug, which means animal testing has 
shown an adverse effect on the fetus but there is no available data from human studies.  If you are 
pregnant or breast feeding, you cannot take part in this study. Females of childbearing age must take 
a urine or blood pregnancy test before starting this study.  If this test is positive, you cannot take part 
in this study.  If you are a female, you should avoid becoming pregnant for at least one month after 
last receiving the study drug.  Female participants will also be required to take a pregnancy test upon 
completion of the study. Male participants should understand that studies have not shown what 
effect riluzole can have on human sperm. Since it is not known if
riluzole can adversely affect human sperm, there could be a risk to a child conceived while a man is 
taking riluzole.  If you are a male, you should avoid trying to conceive for at least once month after 
last receiving the study drug.
IRB NUMBER: 380797
IRB APPROVAL DATE: 08/10/2017
IRB EXPIRATION DATE: 04/21/2018


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Protocol No.   380797
Current Version: v.15.5 – 28 July 2017
16. YOUR RIGHTS IF YOU TAKE PART IN THIS STUDY
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time. No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits.  Leaving the study will not affect your medical care.
17. AUTHORIZATION FOR RESEARCH USE OF PROTECTED HEALTH 
INFORMATION
The Federal Health Insurance Portability and Accountability Act (HIPAA) includes a Privacy 
Rule that gives special safeguards to Protected Health Information (PHI) that is identifiable, in other 
words, can be directly linked to you (for example, by your name, Social Security Number, birth date, 
etc.). We are required to advise you how your PHI will be used. This authorization is effective until 
this study is closed.
(1) What information will be collected?
For this research study, we will collect information about your overall health status, any side 
effects that you are experiencing while taking the study drug, and how the study drug is affecting your 
PTSD symptoms. The PHI we will collect from you includes your name, address, phone number, date 
of birth, and email address and social security number.
(2) Who may use your PHI within the Military Healthcare System?
The members of the research team will have access to your health information in order to find out 
if you qualify to participate in this study, to administer the study drug, to monitor your progress, and 
to analyze the research data. Additionally, your PHI may be made available to research oversight 
groups such as the WRNMMC Department of Research programs and the WRNMMC Institutional 
Review Board.
(3) What persons outside of the Military Healthcare System who are under the HIPAA 
requirements will receive your PHI?
The Principal Investigator or designee will send your PHI to the company that makes riluzole only 
under extreme circumstances, such as a medical emergency or court order.  If you experience a 
complication, we may need to send a copy of your medical record (with your name and other personal 
identifying information blacked out) to the company that makes riluzole and the Food and Drug 
Administration.  Finally, your PHI may be made available to research oversight groups such as the 
Syracuse VA Medical Center, and the Veterans Health Administration Research and Development 
Institutional Review Board (IRB).
(4) What is the purpose for using or disclosing your PHI?
a.
The members of the research team need to use your PHI in order to analyze the information to 
IRB NUMBER: 380797
IRB APPROVAL DATE: 08/10/2017
IRB EXPIRATION DATE: 04/21/2018


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Protocol No.   380797
Current Version: v.15.5 – 28 July 2017
find out whether the study drug we are testing is effective and to monitor your safety.
(5) How long will the researchers keep your PHI?
The research team will keep the research data for a minimum of seven (7) years after the end of the 
study. At that time, all the information will be destroyed. This consent form and HIPAA
authorization will be maintained for a minimum of six (6) years after the study is completed.
(6) Can you review your own research information?
a.
You will not be able to look at your research information until the study has ended.
(7) Can you cancel this Authorization?
Yes.  If you cancel this Authorization, however, you will no longer be included in the research 
study.  The information we collected from you can be destroyed at your request.  If you want to cancel 
your Authorization, please contact the Principal Investigator in writing at the following:.
David M. Benedek, MD
Uniformed Services University of the Health Sciences Department of 
Psychiatry
4301 Jones Bridge Road Bethesda, 
Maryland 20814-4799
(8) What will happen if you decide not to grant this Authorization?
If you decide not to grant this Authorization, you will not be able to participate in this research 
study.  Refusal to grant this Authorization will not result in any loss of medical benefits to which you 
are otherwise entitled.
(9) Can your PHI be disclosed to parties not included in this Authorization who are not 
under the HIPAA requirements?
There is a potential that your research information will be shared with another party not listed in 
this Authorization in order to meet legal or regulatory requirements.  Examples of persons
who may access your PHI include representatives of the DoD Higher Level Review, the Food and 
Drug Administration, the Department of Health and Human Services (DHHS) Office for Human 
Research Protections (OHRP), and the DHHS Office for Civil Rights. This disclosure is unlikely to 
occur, but in that case, your health information would no longer be protected by the HIPAA Privacy 
Rule.
(10) Who should you contact if you have any complaints?
If you believe your privacy rights have been violated, you may file a written complaint with the 
WRNMMC Privacy Officer, located at 8901 Wisconsin Ave, Bethesda, MD 20889, Telephone: 301-
IRB NUMBER: 380797
IRB APPROVAL DATE: 08/10/2017
IRB EXPIRATION DATE: 04/21/2018


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Protocol No.   380797
Current Version: v.15.5 – 28 July 2017
319-4775,
Your signature at the end of this document acknowledges that you authorize WRNMMC personnel 
to use and disclose your Protected Health Information (PHI) collected about you for research purposes 
as described above.
18. CONTACTS FOR QUESTIONS ABOUT THE STUDY
If you have questions about the study, or if you think you have a study-related injury you 
should contact David Benedek, MD at 301-295-9888 or after hours at 240-204-0562. For 
questions about your rights as a research participant, contact the Human Protections 
Administrator, Department of Research Programs in Building 17 at (301-295-8273) or Staff 
Judge Advocate Office at 301-295-2215.
If you believe you are experiencing a medical emergency, please contact 911 or your local 
emergency medical service.
A signed copy of this consent form will be provided to you.
SIGNATURE OF RESEARCH PARTICIPANT
You have read (or someone has read to you) the information in this consent form. You have been 
given a chance to ask questions and all of your questions have been answered to your satisfaction.
BY SIGNING THIS CONSENT FORM, YOU FREELY AGREE TO TAKE PART IN 
THE RESEARCH IT DESCRIBES.
Participant’s Signature
Date
Time
Participant’s Printed Name
If you wish to volunteer for the brain imaging part of the study please sign below.
“I wish to volunteer to participate in the proton MRS imaging portion of the study.”
Participant’s Signature
Date
Time
Participant’s Printed Name
SIGNATURE OFRESEARCH TEAM MEMBER OBTAINING CONSENT
You have explained the research to the participant and answered all of his/her questions. You believe that 
the volunteer subject understands the information described in this document and freely consents to participate.
IRB NUMBER: 380797
IRB APPROVAL DATE: 08/10/2017
IRB EXPIRATION DATE: 04/21/2018


Page 11 of 10
Protocol No.   380797
Current Version: v.15.5 – 28 July 2017
_
_
Signature of Person Obtaining Consent
Date (must be the same as the participant’s) Time
Printed Name of Person Obtaining Consent
IRB NUMBER: 380797
IRB APPROVAL DATE: 08/10/2017
IRB EXPIRATION DATE: 04/21/2018