Clinical trial NCT02019940
Conditions: PTSD
Sponsor: Yale University
Start date: 2014-01-01; Completion date: 2020-01-01
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This open label study will evaluate the safety and efficacy of riluzole in patients with PTSD. Patients will receive riluzole 50mg twice per day orally for 12 weeks as outpatient, with a one month follow up at week 16.

Detailed description:

Arms: arm 1: Riluzole 50 mg orally twice per day
Interventions: intervention 1: Riluzole
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
1/30/18 
1 
1. Principal Investigator: 
 Chadi Abdallah, M.D.* † 
Other Investigators and Study Personnel:  
Ismene Petrakis, M.D. †, M.D., Robert Pietrzak, Ph.D., M.P.H., Brenda Martini, M.A.* 
James Yaffe, A.P.R.N. †, Elizabeth O’Donnell, R.N.*, Angelina Genovese RN, BSN, 
 MBA*, Margaret Dion Marovitz, M.S., RN*, Lynnette Averill, Ph.D.,* Erin O’Brien, 
Psy.D., Chris Averill, B.S.*  Gihyun Yoon, M.D. †, Benjamin Kelmendi, M.D. †, Prerana 
Purohit, B.A.*, Timothy Amoroso, B.A.*, Jeremy Roscoe, B.A.*, Selin Goktas, M.A.*, 
Tequetta Valeriano, B.A.*, Teddy Akiki, M.D.*, Hassaan Gomaa, M.D.*, Archana 
Adikey, M.D.*, Evelyn Alkin, M.A.*, Mohsin Raza*, Amanda Brennan, M.S.*, 
Stephanie Argraves, M.S.*, Elizabeth Likins-Graham, MMS*   
* Individuals who will be obtaining consent   
† Individuals authorized to prescribe study medication 
* Individuals who will be obtaining consent   
† Individuals authorized to prescribe study medication 
2. Title of Project: An Investigation of the Effects of Riluzole in Patients with Post-
Traumatic Stress Disorder (PTSD). 
3. Purpose: To conduct a pilot study evaluating the efficacy of riluzole 50 mg twice per 
day in decreasing symptoms of PTSD in patients diagnosed with PTSD.  
Post Traumatic Stress Disorder (PTSD) is a debilitating and chronic mental illness with 
limited treatment options. Currently, there are only two FDA-approved medications both 
of which are monoaminergic antidepressants. Rates of non-response to these medications 
are high. The current study aims to examine the efficacy of a novel drug, riluzole, in 
treating PTSD symptoms. Riluzole is an FDA approved medication for Amyotrophic 
Lateral Sclerosis. Preclinical studies have shown riluzole to modulate glutamate release 
and clearance, and to have potent neuroprotective properties, promoting neuro-resilience. 
Other preclinical data also show the drug to have anxiolytic-like and antidepressant-like 
effects in rodent models of stress used to screen for antidepressant and anxiolytic activity. 
In addition, several open-label clinical studies further suggest riluzole has anxiolytic and 
antidepressant properties, even in patients who do not respond to standard 
monoaminergic antidepressant and anxiolytic medications. However, to date, riluzole has 
not been studied in patients suffering from PTSD. The proposed study will provide pilot 
data on the efficacy of riluzole in PTSD. 
4. Hypothesis: We predict that riluzole will significantly reduce the symptoms of PTSD 
(measured by the Clinician Administered PTSD Scale-CAPS scores). 
SPECIFIC AIM 1: To provide preliminary data about the efficacy of riluzole 
treatment in improving PTSD symptoms. Hypothesis: PTSD subjects treated with 


1/30/18 
2 
 
riluzole (50 mg twice per day for 12 weeks) will have reduction in PTSD symptoms. To 
examine the efficacy of riluzole we will compare the mean change in the CAPS total 
score over the course of 12 weeks of riluzole treatment. 
5. Background:  
PTSD Is a Debilitating Illness with Limited Treatment Options 
The House Veterans Affairs Committee issued a report in mid October 2006 stating that 
the number of Iraq and Afghanistan veterans seeking help for PTSD has gone from 4500 
to 9000 from October 2005 through June 2006.  In the general adult population, PTSD 
has a lifetime prevalence rate ranging from approximately 5 - 10%1, 2.  PTSD tends to be 
a chronic disorder with one third of sufferers having symptoms more than ten years after 
experiencing the traumatic event3, 4. The symptom profile for PTSD includes avoidance, 
arousal and re-experiencing symptoms. 
Despite the disabling and chronic nature of PTSD, only two medications, both of them 
selective serotonin reuptake inhibitors (SSRIs), have FDA-approval for PTSD treatment5-
8. However, accumulating evidence highlights the limitation of SSRI treatment and the 
prevalence of SSRI-resistant PTSD2, 9, 10. 
Riluzole Is A Glutamate Modulating Agent With Anxiolytic And Antidepressant Effects. 
Over the last two decades, convergent lines of research have demonstrated aberrant 
glutamatergic function in mood and anxiety disorders11, 12. These neurobiological 
findings have been underscored by preliminary trials showing promising results for novel 
drugs with glutamate-based mechanisms13, 14. One such medication is riluzole, an agent 
possessing neuroprotective properties 15-17 approved by the United States Food and Drug 
Administration for treatment of Amyotrophic Lateral Sclerosis. Riluzole is believed to 
exert its pharmacological effects primarily by reducing pre-synaptic glutamate release 
and potentiating glutamate reuptake 18. In open-label trials at Yale and other institutions, 
riluzole showed significant anxiolytic properties in patients with major depression 19, 20, 
bipolar depression 21, obsessive-compulsive disorder 22, and generalized anxiety disorder 
(GAD) 23 (for review see references. 18, 24). However, to date, riluzole was not studied in 
patients with PTSD. 
6. Significance of proposed research: Our	  proposed	  study	  is	  the	  first	  to	  examine	  the	  
effect	  and	  feasibility	  of	  riluzole	  treatment	  for	  PTSD.	  Data	  from	  this	  pilot	  study	  will	  
inform	  the	  design	  of	  future	  larger	  double-­‐blind	  controlled	  studies.	  For	  e.g.,	  if	  PTSD	  
veterans	  showed	  full	  early	  response	  to	  riluzole	  following	  1-­‐4	  weeks,	  this	  will	  affect	  
the	   design	   of	   future	   definitive	   (likely	   multisite)	   studies.While	   placebo-­‐controlled	  
studies	   are	   standard	   for	   FDA	   approval	   and	   definitive	   clinical	   trials	   confirming	  
efficacy,	  an	  open	  label	  approach	  is	  appropriate	  for	  pilot	  studies	  seeking	  early	  signals	  
of	  efficacy	  and	  optimal	  treatment	  regimen.	  Pilot	  open	  label	  studies	  are	  essential	  for	  
early	  phase	  of	  drug	  development.	   
 


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7. Experimental subjects: We anticipate approximately 20 male and female subjects 
with  PTSD, between the ages of 18-75 years, to complete all study procedures. In order 
to account for screenings failure and subject drop outs, and retain a sample of 20 subjects 
completing the treatment phase, approximately  50  eligible subjects will be enrolled.  
Inclusion Criteria: 
• Male or female subjects between the ages of 18-75 years; 
• Able to provide written informed consent; 
• Current Post Traumatic Stress Disorder, as determined by the Clinician 
Administered Scale for PTSD, or the presence of sub-threshold PTSD. Individuals 
with sub-threshold PTSD will be included at the discretion of the PI; 
• Clinician Administered PTSD Scale (CAPS) score of 23 or higher; 
• Be able to understand and speak English. 
• Subjects taking FDA-approved antidepressant medications may enter the study if 
they have been on a stable dose for at least 4 weeks prior to starting the study 
drug.  
Exclusion Criteria: 
• Breastfeeding women and pregnant women, or women of child bearing potential 
who are not using a medically accepted means of contraception (to include oral, 
injectable, or implant birth control, condom, diaphragm with spermicide, 
intrauterine device, tubal ligation, abstinence, or partner with vasectomy); 
• 
Current, ongoing serious suicidal risk as assessed by evaluating investigator or by 
scoring 5 or more on the item-10 of the MADRS. 
• Unstable medical illness as determined by the investigator; 
• Patients with schizophrenia or schizoaffective disorders (current or past); 
• 
Substance use disorder during the 3 months prior to screening; except for 
Cannabis and Alcohol use Disorders. 
• Clinical evidence of untreated hypothyroidism; 
• Patients with any evidence of clinically significant liver abnormalities, or any 
liver transaminase level > 1.5 x ULN at initial screening, or > 5 x ULN during 
treatment; 
• Axis II personality disorders that are the primary purpose of treatment, or would 
interfere with a patient's safety or compliance, as determined by the investigator 
during open-ended psychiatric interview; 
• Patients currently being treated for a respiratory disorder (including asthma or 
COPD); 
• For participants over the age of 60, evidence of dementia as determined by the St. 
Luis University Mental Status Exam (SLUMS; participants with total scores less 
than or equal to 20 will be excluded and referred to their Primary Care Physician 
for follow-up/dementia evaluation); 


1/30/18 
4 
 
Structured psychotherapy focused on treatment of PTSD is exclusionary unless 
the subject has had at least 8 weeks of treatment prior to starting the study 
medication; 
8. Privacy: All reports generated from the data obtained through this study will protect 
the confidentiality of the subjects who participate in this study. All subjects will be given 
a “wallet card” which identifies them as a study participant and lists the emergency 
contact numbers.  If a subject shows clinical deterioration (worsening of PTSD 
symptoms), Dr. Abdallah will determine whether: 1) the subject can remain in the study, 
or; 2) a higher level of care (e.g. referral back to treating psychiatrist or referral to 
emergency or inpatient care) is needed. 
9. Selection: Subject eligibility will first be assessed via telephone screening and if 
records are available, by a preliminary medical record review.  If the subject seems to be 
a likely candidate for inclusion in this protocol, he or she will be evaluated for study 
eligibility in person.  Telephone screens will occur by experienced research personnel 
adept with this process. Following a face-to-face evaluation and discussion with the 
research team, an experienced study investigator will determine suitability for enrollment. 
10. Recruitment: Subjects will be recruited through flyers, public advertisement 
(newspaper, radio, internet posting), by word of mouth, contact with community service 
groups, our local IRB-approved screening protocol (KW0003), and clinics and local 
treatment facilities (e.g., VA Hospital, Community-Based Outpatient Clinics, local 
private practices). Subjects will be identified via their response to advertisementsand/or 
internal recruiting through the research clinics. Subjects will be asked to call us at the 
number provided on the flyers if they are interested in participating in the research study. 
Subjects will be contacted for follow-up appointments via the most convenient means and 
personal preference, e.g. telephone. All available research staff is responsible for 
recruiting potential subjects. 
11. Research Plan: This study will be conducted at the VA Hospital, West Haven, CT.  
Overview: This is a diagnosis-informed study designed to provide preliminary data 
regarding the efficacy and tolerability of riluzole to treat symptoms of PTSD. Subjects 
diagnosed with PTSD will receive riluzole, 50 mg taken twice daily (BID) for 12 weeks.   
PTSD subjects will be followed closely on a weekly basis and their liver function and 
pregnancy tests will be repeated (see Table 1).  
Dosing: Following confirmation of eligibility, the dosing regimen for the first week of 
study medication is 50 mg twice a day (BID). Subjects who are unable to tolerate the 
study medication will be allowed to take a lower dose. For these subjects, the dose may 
be lowered to 50 mg taken once a day (QD). Subjects who are unable to tolerate the once 
a day 50 mg (QD) dosing regimen will be discontinued from the study. Riluzole should 
be taken 1 hour before or 2 hours after a meal to avoid food-related decreases in 
bioavailability. 


1/30/18 
5 
 
A schedule of the study events is provided in Table 1. 
A. 
Participants: Twenty patients with a current diagnosis of PTSD or sub-threshold 
PTSD between the ages of 18-75 will complete the treatment phase of the study. 
Subjects will initially be pre-screened by phone interview and a preliminary 
medical record review. Eligible subjects will then be invited for an in-office visit 
and will complete the written informed consent process. Subjects will be 
thoroughly screened for inclusion and exclusion criteria as described below. 
B. Discontinuation of subjects: Subjects may be discontinued from study treatment 
  and assessments at any time.  Specific reasons for discontinuing a subject from 
  this  study are: 
• Voluntary discontinuation by the subject, who is at any time free to 
discontinue his/her participation in the study without prejudice to further 
treatment; 
• Clinical deterioration: The following are objective criteria for clinical 
deterioration, (1) a 35% increase in CAPS scores at any time during the study, 
(2) Patients with a CGI-I score ≥ 6 at any post-baseline visit, and (3) the onset 
of active suicidality as assessed by the study investigator or by scoring 5 or 
more on the item-10 of MADRS; 
• Evidence of neutropenia (ANC ≤ 1500) or other intolerable adverse reaction, 
or unable to tolerate study drug; 
• Transaminase levels > 5x ULN; 
• Safety reasons as judged by the investigator; 
• Stopping birth control or positive pregnancy test; 
• Evidence of illicit drug abuse (except for cannabis) or problematic alcohol use 
during trial; 
• Non-compliance to protocol as judged by the investigator; Subjects who do 
not take between 75-125% of study medication for two consecutive visits are 
considered non-adherent and are withdrawn from the study medication. 
Figure 1. Study Design  
 Week 12 
D 84 
      Riluzole 50 mg twice per day for 12 weeks 
End of treatment 
1 month 
follow-up 


1/30/18 
6 
 
A subject that prematurely discontinues (i.e. stops study medication or no longer 
wishes to participate) will always be asked about the reason(s) for discontinuation 
and the presence of any adverse events.  If possible, they will be seen and 
assessed by the investigator.  Adverse events will be followed up as medically 
necessary. 
C. 
Screening Procedures and Behavioral Assessments: A waiver of HIPAA 
authorization and written informed consent will be obtained for a brief initial 
phone screen and preliminary medical record review. The phone screen and 
preliminary medical record review will be done to determine obvious exclusions 
from the study protocol and to prevent subjects from making unnecessary travel 
for screening as well as possibily delaying the start of other treatments. 
Potentially eligible subjects will then be invited for an in-office screening visit, 
sign the VA informed consent, the VA HIPAA, be personally interviewed and 
begin the medical assessments. All subjects will have an initial screening 
assessment that includes medical history, physical examination, laboratory 
testing, psychiatric history and standardized psychiatric assessments.  
C.1. Historical and Demographic Information: Each subject will complete a 
demographic information form. This document will elicit information about the 
subjects’ demographics including education level, socioeconomic status, race and 
ethnicity. In addition, it will also request information on the subject’s family 
history of mental illness. 
C.2.  Screening Physical Exam and Laboratories: All subjects will have a standard 
physical examination (including neurological examination) conducted by a 
physician/APRN at the time of the initial screening.  Routine laboratory studies 
include CBC, CMP, baseline HCG, TSH, fT4, RPR, ESR, CRP, urinalysis, and 
urine toxicology screen. An ECG will also be obtained. Additional tests will be 
requested as clinically indicated. 
C.3.   Screening and Behavioral Assessments: PTSD subjects will have an open 
ended psychiatric interview, in addition to a structured clinical interview (i.e. 
SCID or MINI). Baseline and follow-up ratings will also be obtained via 
assessment measures of PTSD, trauma, depression, anxiety, sleep, alcohol use, 
and 
adverse 
effects. 
Subjects 
will 
also 
complete 
a 
computerized 
neuropsychological test battery called ‘Cogstate’ (see Table 1).  
It is estimated that the total amount of time required by the patient to determine 
screening eligibility will be 7 hours. It will require one hour of time to complete 
each of the scheduled CAPS interviews. Repeated follow-up visits (including 
rating scales, blood work, urine screens, etc.) without the above cited assessments, 
will last for approximately 45 minutes to one hour. If necessary due to time 
commitments or difficulties with scheduling, some visits may take place over 
more than one day during the study week. 


1/30/18 
7 
 
Each of the psychiatric, behavioral and cognitive assessment instruments is 
briefly described below. 
1. Clinician Administered PTSD Scale (CAPS): The CAPS is a standardized 
clinician-rated instrument to assess the presence and severity of PTSD 
symptoms. 
2. Post Traumatic Stress Disorder Checklist (PCL): The PCL is used to measure 
PTSD symptoms and is a self-report questionnaire that shares similar 
reliability with the CAPS. 
3. The Combat Exposure Scale (CES): The CES is a self-report instrument that 
measures reports of wartime stressors on a 5 point Likert Scale format. 
4. Early Trauma Inventory (ETI-SR) The ETI-SR is a self-report instrument to 
assess childhood trauma and includes physical, emotional and sexual abuse as 
well as general traumas. 
5. Klein Loss Scale (KLS): The KLS is a self-report of parental loss or separation 
during childhood. 
6. Global Perceived Early Life Stress (GPELS): The GPELS is a self-report of 
perceived stress during childhood. 
7. Montgomery-Asberg Depression Rating Scale (MADRS): The MADRS is a 
standardized instrument to ascertain depressed mood and neurovegetative 
signs and symptoms of depression. 
8. Quick Inventory of Depressive Symptoms – Self-Report (QIDS-SR): The 
QIDS-SR is a patient-rated depression instrument. 
9. Massachusetts General Hospital Antidepressant Treatment History 
Questionnaire (MGH-ATRQ)-This is a self-rated questionnaire used to 
determine treatment resistance in major depressive disorder. 
10. Clinical Global Impressions Scale (CGI) and the Patient Global Impressions 
Scale (PGI): The CGI and PGI are widely used instruments, which assess 
overall severity of illness on a 1 to 7 point scale with 1 indicating “normal, not 
at all ill” and 7 indicating “among the most extremely ill patients.”  These 
instruments also assess global improvement on a 1-to-7 point scale with 1 
indicating “very much improved,” 4 indicating “no change” and 7 indicating 
“very much worse.” 
11. Penn State Worry Questionnaire (PSWQ): The PSWQ is a self-report 
questionnaire to assess for ‘worry’ symptoms that are typical of generalized 
anxiety. 
12. Pittsburgh Sleep Quality Index (PSQI): The PSQI is a self-report 
questionnaire to assess sleep quality and sleep disturbance. 
13. Sheehan Disability Scale (SDS): The SDS is a brief self-rated measure of 
disability and impairment. 
14. Columbia-Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a brief 
clinician administered and standardized measure that uniquely assesses 
essential information about suicide behavior, ideation, lethality and severity, 
and distinguishes between suicidal occurrences and non-suicidal self-injury. 
15. Cogstate is a brief computerized neuropsychological test battery. We will 
administer the following subtests from this battery to assess working memory, 


1/30/18 
8 
 
visual motor function,  visual attention executive function,verbal 
learning/memory and visual learning/memory: One Back and  Two Back Test, 
Chase Test, Identification Task, Groton Maze Learning Test (with delayed 
recall), the International Shopping List Task (with delayed recall) and the One 
Card Learning Task. 
16. St. Luis University Mental Status Exam (SLUMS) – The SLUMS is a dementia 
screening instrument. It will be administered to participants who are 60 or 
older during our screening process.  
17. Modified Military Acute Concussion Evaluation (MACE) - The MACE is a 
concussion screening tool for the acute assessment of service members 
involved in a potentially concussive event. 
18. Alcohol and Consumption Habits- This is a brief measure that documents 
alcohol, caffeine and nicotine habits.  
19. Systematic Assessment for Treatment Emergent Events (SAFTEE): The 
SAFTEE is a commonly used instrument originally developed by NIMH and 
adapted into a self-report instrument.  It examines, in systematic fashion, 
possible treatment-emergent side effects and probes for specific adverse 
symptoms, including suicidal thoughts and behaviors, and self-injurious 
behavior. 
20. Drug Attitude Inventory- (DAI):The DAI evaluates how attitudes about 
medications may affect treatment adherence. The items with the most 
potential for discrimination between dosing compliance and noncompliance 
are related to subjective ‘feeling’ factors. 
21. Perceived	  Stress	  Scale	  (PSS):	  This	  is	  a	  10-­‐item	  self-­‐report	  questionnaire	  to	  
assess	  the	  severity	  of	  perceived	  stress	  over	  the	  past	  month. 
22. Cumulative	  Adversity	  Interview	  (CAI):	  A	  multifaceted	  semi-­‐structured	  
assessment	  of	  stressful	  life	  events	  and	  chronic	  subjective	  stress	  used	  in	  
research	  on	  stress	  and	  psychopathology. 
 
Due to the potential of Riluzole to cause elevations in serum aminotransferase 
levels, liver function tests will be reviewed and monitored for medical 
significance (marking NCS for results not clinically significant) by the PI, a co-
investigator or other medical research personnel (A.P.R.N., R.N. etc.). If any liver 
transaminase level is > 5X the UNL, the study investigator will be informed and 
the patient will be discontinued from the study, with appropriate medical follow-
up.  
PTSD subjects receiving the study medication will be seen weekly. Compliance 
with study medication will also be assessed weekly and at each visit. Subjects will 
be given medication diary cards to record the medication that they have taken at 
each daily dosing interval and the medication that was missed at each dosing 
interval. Drug accountability will then be done between the medication that was 
returned and the medication recorded as being taken on the diary cards. A subset 
of the interviews and measures obtained throughout the study will be repeated at a 
one-month, in person follow-up. This follow-up will be used to evaluate any 
lasting effects of the treatment, if any.   


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9 
 
The presence of any spontaneously reported side effect or adverse event is 
carefully documented. Reasons for premature discontinuation of study 
medication, including intolerable side effects, are recorded; however, all willing 
subjects continue to return for weekly evaluations as if they remain on study 
medication. 
All concomitant medications taken during the study are also recorded in the paper 
research chart, along with dosage information and start and stop dates. Medication 
management and clinical ratings are performed by the study physician/APRN and 
the clinical rater, respectively. 
Subjects who are unable to tolerate the study medication after adjusting the dosing 
regimen to the lowest dose of 50 mg QD are withdrawn from study medication. 
Treatment adherence is monitored by pill counts. In order to minimize risks, 
subjects are advised during the consenting process that if they discontinue the 
study medication prematurely, the researchers want them to continue study 
evaluations as if they were still on the study medication for reasons of safety 
monitoring (i.e. to evaluate the possibility of withdrawal effects from abrupt 
discontinuation of the study drug, worsening of psychological symptoms or other 
newly emergent medical symptoms after stopping the study drug).  Non-adherent 
patients are classified as dropouts in the analysis. 
Audio Recording: 
Clinician administered interviews may be audio recorded for inter-rater reliability and 
staff training purposes. Subject identifying information such as name, DOB, SSN, age, 
etc will not be on the audio recording. Recordings will be stored in a locked cabinet when 
not in use. Subjects will be asked on the consent form to indicate whether or not they 
agree to having their clinical interviews audio recorded. If subjects disagree to having 
their clinical interview audio recorded, it will not affect their eligibility to participate in 
study procedures. 
Data Analysis  
Descriptive statistics will be calculated prior to statistical analysis. Distributions of 
quantitative variables will be assessed for normality using normal probability plots and 
Kolmogorov-Smirnov statistics and transformations or non-parametric methods will be 
used as necessary. All statistical tests will be two-sided. Uncorrected alpha level of 0.05 
will be used for testing the primary hypothesis. Pairwise post-hoc comparisons and tests 
of secondary outcome measures will be adjusted using Holm-Bonferroni procedure. All 
analyses will be intent-to-treat. We will using mixed effects regression models, with time 
effects for the primary outcome variable (CAPS). We do not expect significant 
moderating effects of alcohol use comorbidity but will assess the interaction between 
treatment and alcohol use comorbidity and perform follow-up tests as necessary. This 
approach will be applied to most secondary outcome measures as well. Mixed effects 
regression models use all available data on each subject, are flexible in modeling the 
correlation structure of the data and give unbiased results under missing at random 


1/30/18 
10 
 
assumptions. In addition to testing the potential moderating effect of comorbid alcohol 
use described above, we will also perform exploratory analyses to the assess moderating 
effects of depression, medication status, substance abuse, age, and gender by adding these 
factors one at a time to the models above and testing interactions between each potential 
moderator and treatment group. Effects of intermittent missing data due to non-
compliance with treatment schedule can also be assessed.  
 
 
Table 1. Schedule of Study Events** 
Visit 
Screeni
ng a 
 
Baselin
e 
1 
2&3 
4 
5,6,&7 
8 
9,10,11 
12  
1 
month 
follow-
up 
Day 
0 
0 
7 
14&21 
28 
35,42, & 
49 
56 
63, 70, 
&77 
84 
 
114 
Informed Consent b 
X 
  
  
  
  
  
  
  
  
 
Demographics 
X 
  
  
  
  
  
  
  
  
 
SCID / MINI 
X 
  
  
  
  
  
  
  
  
 
C-SSRS baseline 
X 
  
  
  
  
  
  
  
  
 
MGH ATRQ 
X 
  
  
  
  
  
  
  
  
 
ETI-SR, KLS, GPELS, 
CES 
X 
  
  
  
  
  
  
  
  
 
M-MACE 
X 
  
  
  
  
  
  
  
  
 
Psychiatric Evaluation 
X 
  
  
  
  
  
  
  
  
 
BP, Pulse, Resp., Wt., 
Temp. 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
  
  
  
  
  
  
  
  
 
Physical Exam 
X 
  
  
  
  
  
  
  
  
 
CBC 
X 
  
  
  
X 
  
X  
  
X 
 
CMP 
X 
  
  
  
LFTs 
  
LF
Ts  
  
LFTs 
 
Serum Pregnancy (1)/ 
Urine Pregnancy (2) 
X(1) 
 X (2) 
  
  
X(2) 
  
 X(
2) 
  
X(2) 
 
Urinalysis 
X 
  
  
  
  
  
  
  
  
 
Inclusion/Exclusion 
X 
  
  
  
  
  
  
  
  
 
CAPS 
X 
X c 
  
  
X (visit 6 
only) 
  
  
X 
 
X 
MADRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
PCL, QIDS-SR, PSWQ, 
PSQI, SDS, SAFTEE 
  
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Alcohol Consumption 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Drug Accountability  
  
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collect AEs and SAEs 
  
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
CGI-S/I and PGI-S/I 
  
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urine Toxicology 
X 
X 
  
  
  
  
  
  
X 
 
 
Ethanol Breath Test/DAI 
  
X 
  
  
  
  
  
  
X 
 
 


1/30/18 
11 
 
Cogstate 
Practice 
X 
  
X (Visit 
6 only)  
  
X 
 
 
 
X 
St. Luis University Mental 
Status Exam  
X 
 
 
 
 
 
 
 
 
 
** Day number reflects the approximate date, a window is allowed for scheduling and completion of the 
weekly study visits. a. Screening refers to the period between signing consent and completion of screening. 
As such this visit refers to one or multiple visits. b. Informed consent will be obtained prior to any study 
procedure. c. CAPS will be repeated at the discretion of the investigator or if 4 or more weeks elapsed since 
the prior CAPS. Abbreviations: Structured Clinical Interview for DSM (SCID), Mini International 
Neuropsychiatric Interview (MINI), Columbia-Suicide Severity Rating Scale (C-SSRS), MGH 
Antidepressant Treatment Response Questionnaire (MGH-ATRP), Early Trauma Inventory – Self Report 
(ETI-SR), Klein Loss Scale (KLS), Global Perceived Early-Life Stress (GPELS), Combat Exposure Scale 
(CES), Modified Military Acute Concussion Evaluation (M-MACE), Clinician Administered PTSD Scale 
(CAPS), Post Traumatic Stress Disorder Checklist (PCL), Montgomery-Asberg Depression Rating Scale 
(MADRS), Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR), Penn State Worry 
Questionnaire (PSWQ), Clinical Global Impression Severity/Improvement (CGI-S/I), Patient Global 
Impression-Severity/Improvement (PGI-S/I), Systematic Assessment for Treatment Emergent Events 
(SAFTEE), Pittsburgh Sleep Quality Index (PSQI), Electrocardiogram (ECG), Complete Blood Count 
(CBC), Comprehensive Metabolic Panel (CMP), Drug Attitude Inventory (DAI). 
12. Risks and Benefits: 
General: While subjects are participating in this study, they will temporarily forgo the 
opportunity to receive routine clinical psychiatric care in the community (i.e. patients are 
asked to maintain their treatment regimen throughout the study). 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 
clinicians 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 evaluations are 
minimal. No discomfort is expected to be associated with the physical examination or 
intake interview with the study staff other than the possible stress of answering personal 
questions. Subjects will be answering questions about their symptoms of PTSD and 
filling out questionnaires. They may find this process to be inconvenient, uncomfortable 
or upsetting. The psychological testing may include personal questions about previous 
experiences. The questions will be asked in a private room. Subjects will be informed that 
they do not have to answer any question that they do not want to answer. Subjects will 
also have the option to discuss their concerns with someone on the research staff. One or 
more individuals will be available to talk to the subjects should they become distressed 
during an interview or while filling out questionnaires. 
Risks of ECG test: Sometimes the adhesive pads used to attach the leads for recording the 
electrical activity of the heart (ECG) can cause skin irritation. Such irritation usually 
clears without treatment. 
Blood drawing: Blood samples are taken from a vein in the inside of the elbow or lower 
arm. Blood collection is done using a disposable needle or syringe. The risks or side 


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12 
 
effects associated with taking blood from a vein are bruises, local irritation (swelling) 
with itching, slight bleeding and inflammation. In rare cases, it may result in thrombosis 
(blood clots) or an infection. Insertion of the needle can cause localized pain or pain at 
the needle puncture site. Subjects may feel slightly weak or lightheaded, or faint. 
Occasionally, in rare cases, inserting the needle can result in injury to a nerve. Subjects 
are closely monitored and checked for these or other symptoms and we will take 
appropriate measures if they occur.  Normally these problems improve with time and no 
additional medical treatment is needed. Using trained personnel, as well as using sterile 
conditions minimizes these risks. 
The total maximum quantity of blood that may be taken over the entire course of this 
study is less than 300 ml. This is 1.27 cups of blood. The blood is taken slowly over the 
course of the study. As a comparison, during a blood donor session, 450 mL (or less than 
2 cups) of blood is taken in one visit. 
Delay in treatment: By participating in this study, subjects are likely to experience a 
delay in starting other treatment due to the thorough diagnostic evaluation.  Furthermore, 
since it is unknown whether riluzole is effective in the treatment of PTSD, participation 
in this trial could delay potentially effective therapy. During this period, it is possible that 
subjects’ conditions could worsen and lead to increased disturbances in mood, sleep, 
appetite, and cognition. This could result in work loss, loss of social function, and 
possibly increased risk of suicide. However, the risk should be minimized as there are 
several safety precautions in place and subjects will remain in close contact with study 
clinicians. 
Riluzole: Most side effects are usually mild and resolve after stopping the drug. The most 
commonly observed adverse reactions of riluzole, dosed at 100mg/day, in placebo-
controlled trials were asthenia (19.2%), nausea (16.3%), decreased lung functioning 
(10.2%), headache (7.3%), rhinitis (6.4%), hypertonia (6.1%), hypertension (5.1%), 
abdominal pain (5.1%), weight loss (4.8%), vomiting (4.2%), dizziness (3.9%), dyspnea 
(3.8%), pruritus (3.8%), insomnia (3.5%), dry mouth (3.5%), arthralgia (3.5%), back pain 
(3.2%), anorexia (3.2%), peripheral edema (2.9%), diarrhea (2.9%), increased cough 
(2.6%), tachycardia (2.6%), flatulence (2.6%), urinary tract infection (2.6%), somnolence 
(1.9%), vertigo (1.9%), oral paresthesia, and, pneumonia. Cases of interstitial lung 
disease have been reported in patients treated with riluzole, some of them severe; upon 
further investigation, many of these cases were hypersensitivity pneumonitis. If 
respiratory symptoms develop such as dry cough and/or dyspnea, chest radiography 
should be performed, and in case of findings suggestive of interstitial lung disease or 
hypersensitivity pneumonitis (e.g., bilateral diffuse lung opacities), riluzole should be 
discontinued immediately. In the majority of the reported cases, symptoms resolved after 
drug discontinuation and symptomatic treatment. 
Dizziness, diarrhea, anorexia, and circumoral paresthesia occurred more frequently with 
200 mg/day riluzole. In a study with approximately 4,000 patients given riluzole for ALS, 
three cases of neutropenia were reported within the first two months of treatment. Any 


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13 
 
new medication has the potential for a rare, infrequent reaction of hypersensitivity, 
including anaphylaxis.  
Uncommon side-effects: neutropenia – very rarely there is an abnormal drop in the 
number of white blood cells within the first two months of treatment. Rarely, jaundice is 
a side effect as well. Riluzole has also been found to cause elevations in serum 
aminotransferase even in patients without a history of liver disease. Experience with 
riluzole in 800 patients with ALS demonstrated that approximately 50% of riluzole 
treated patients experienced at least one ALT/SGPT level above the ULN, 8% had 
elevations > 3 x ULN, and 2% > 5 x ULN.  A single non-ALS patient with epilepsy 
treated with concomitant carbamazepine and phenobarbital experienced marked, rapid 
elevations of liver enzyme with jaundice four months after starting riluzole that returned 
to normal seven weeks after treatment discontinuation. Another rare side effect is 
pancreatitis. It is estimated that pancreatitis can occur in 4.5/10000 treated patients. A 
recently published Cochrane Database Systems Review 68 states “Adverse effects from 
riluzole are relatively minor and for the most part reversible after stopping the drug” in 
the plain language summary. 
Riluzole is Pregnancy Category C: Riluzole is detected in breast milk of rodents, and the 
recommendation from the PDR is for riluzole not to be used. Women who are 
breastfeeding will be excluded from enrollment. If a woman becomes pregnant during the 
study, the study medication will be discontinued. 
Worsening of symptoms and suicide risk: At any time during the study, subjects may 
experience a worsening of symptoms and possibly have serious thoughts of suicide or of 
harming themselves. 
Unidentified or unforeseen risks: Participation in this study may involve risks that are not 
known at this time. 
Minimizing Risks: We describe below the manner in which the above-mentioned risks 
will be minimized. 
Subject Recruitment and Consent: Subjects will be recruited through flyers, public 
advertisement (newspaper, radio, internet posting), by word of mouth, contact with 
community service groups, the NCPTSD’s approved screening protocol (KW0003), and 
clinics and local treatment facilities (e.g., VA Hospital, Community-Based Outpatient 
Clinics, local private practices). Subjects will be identified via their response to 
advertisementsand/or internal recruiting through the research clinics. Subjects will be 
asked to call us at the number provided on the flyers if they are interested in participating 
in the research study. Subjects will be contacted for follow-up appointments via the most 
convenient means and personal preference, e.g. telephone. All available research staff is 
responsible for recruiting potential subjects. 
After an initial phone screening, consent forms will be given to all prospective subjects, 
which detail all aspects of the project.  The consent form will include the risks of 


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14 
 
participation, assurance of efforts to maintain confidentiality, and will state that patients 
are free to refuse participation or to withdraw from the project and receive open 
uncontrolled treatment according to clinical indication, without loss of benefits to which 
they are otherwise entitled. The informed consent procedures will comply with the 
standards of the Institutional Review Boards at the VA. 
A member of the research team will obtain written consent from the participants after 
explaining the procedures and risks involved.  The original signed consent form is kept in 
a separate file from the subjects’ research chart.  The consent makes it explicit that the 
protocol involves return visits at specified times.  Participants are informed of the amount 
of blood (less than 300mL or 1.27 cups) that will be drawn in the various procedures and 
the nature of the assays that will be performed. In particular, the consent form indicates 
that the nature of treatment is determined by the protocol, and that the study is a trial to 
evaluate efficacy of riluzole. Subjects will be informed that if their clinical condition 
deteriorates during the study, they may be hospitalized. The consent procedure is viewed 
as a process rather than a single event, and patients will be encouraged to discuss the 
study with the research team. 
Protection Against Risks: All clinical raters have experience in clinical psychiatric 
assessment and will make every effort to implement protocol procedures in a sensitive 
and supportive manner. Research interviews will be interrupted if subjects become 
distressed or object to answering questions.  Other measures to minimize risks include the 
careful assessment of each subject before the study, and close clinical scrutiny during all 
aspects of the study.  Screening for suicide risk factors and suicidality is described in the 
research design.   
Weekly contact is maintained throughout the clinical trial. A study staff member will call 
participants, during any week in which there is no clinic visits, to help ensure subject 
safety and protocol adherence. 
We have included safety measures such as discontinuation of the study drug and 
transition to standard clinical treatment should subjects worsen to a sufficient degree. 
These precautions are likely to be highly effective in minimizing risks. Subjects may be 
hospitalized if they have a worsening of their symptoms, including becoming suicidal. In 
this case or if subjects discontinue study medication they will receive standard short-term 
clinical treatment as indicated. 
Due to the potential of riluzole to cause elevations in serum aminotransferase levels, 
subjects will have liver function tests performed prior to initiating the trial and monthly 
for the duration of the study, or more frequently if clinically indicated. Patients with any 
evidence of clinically significant liver abnormalities or any liver transaminase level > 1.5 
x ULN at baseline will be excluded from the study. Subjects will be discontinued from 
the study if any LFT measure rises above 5 x the ULN once treatment has been initiated.  
This is the recommendation in the PDR and is what has been used in previous studies. If 
treatment is terminated due to physical risks, subjects will be followed carefully until 
resolution of symptoms and treated with the follow up care described in the protocol. 


1/30/18 
15 
 
Subjects will also be asked to report any cough, difficulty breathing or chills to the study 
staff in order to monitor for the possible emergence of interstitial lung disease or 
hypersensitivity pneumonitis. The study investigator, physician/APRN, and rater ask 
patients about any new symptoms at every visit. 
Suicidal Ideation and Imminent Harm: Despite treatment, people with PTSD may get 
worse. All communications about suicide and threats are taken seriously.  It is important 
to assess the risk of suicide carefully when working with these individuals. Many subjects 
may admit to fleeting thoughts of death or briefly wishing for death; these thoughts need 
to be considered in context of the subject’s overall history, along with a consideration of 
other risk factors for suicide.  Study clinicians will assess patients at each visit for suicide 
risk and potential. Individuals at such risk will be treated appropriately, including options 
such as increased contact, more frequent clinical visits, or emergent psychiatric 
hospitalization. Subjects who score > 5 on the MADRS item 10 (suicide) at screening 
will be excluded from the study. In addition, a serious suicide or homicide risk, as 
assessed by evaluating clinician will be considered an exclusion criterion. 
Throughout the study, any subject who scores ≥ 5 on the MADRS item number 10 will 
be discontinued from the study. Any subject with scores of ≥ 6 on the CGI-I will be 
discontinued from the study.   
Subjects will be informed of any important discoveries made during this study, which 
may affect their condition or willingness to participate in this study by leaving a message 
(with subject permission) to contact the study team or by letter, if the subject cannot be 
reached by phone.  
Possible Benefits: 
Subjects may not receive any benefit from participating, though it may help patients in the 
future by giving important information about the study medication and PTSD. Subjects 
may benefit from initial screening procedures that will include careful examination of 
their physical status and psychiatric condition. In the event that clinical abnormalities are 
discovered, subjects will be informed of the finding and referred for appropriate care. 
Subjects’ conditions may improve from taking the study drug.  However, we cannot and 
do not guarantee or promise that they receive any benefits from participating in the study. 
Study personnel will offer a referral to treatment after completion of this study. The 
relative risks and inconveniences associated with participation in this study are balanced 
by the potential benefits to society, particularly patients suffering from PTSD. 
13. Data Safety Monitoring Plan: 
The investigator’s assessment of the overall risk for subjects participating in this study is 
moderate. 
Moderate Risk DSMP 
1. Personnel responsible for the safety review and its frequency: 


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16 
 
The principal investigator, Chadi Abdallah, M.D., will be responsible for 
monitoring the data, assuring protocol compliance, and conducting the safety 
reviews at the specified frequency, which must be conducted at a minimum of 
every 6 months (including when reapproval of the protocol is sought). During the 
review process, the principal investigator (monitor) will evaluate whether the 
study should continue unchanged, require modification/amendment, continue or 
close to enrollment. Either the principal investigator or the IRB have the authority 
to stop or suspend the study or require modifications. 
2. The risks associated with the current study are deemed moderate for the 
following reasons:  
1. We do not view the risks associated with riluzole as minimal.  
2. Given the established safety and validity of the use of riluzole, we do not 
view the proposed study as high risk. 
Although we have assessed the proposed study as one of moderate risk, the 
potential exists for anticipated and/or unanticipated adverse events, serious or 
otherwise, to occur since it is not possible to predict with certainty the absolute 
risk in any given individual or in advance of first-hand experience with the 
proposed study methods. 
Therefore, we provide a plan for monitoring the data and safety of the proposed 
study as follows: 
3. Attribution of Adverse Events: 
Adverse events will be monitored for each subject participating in the study and 
attributed to the study procedures / design according to the following categories: 
a. Definite: Adverse event is clearly related to investigational 
procedures(s)/agent(s). 
b. Probable: Adverse event is likely related to investigational 
procedures(s)/agent(s). 
c. Possible: Adverse event may be related to investigational 
procedures(s)/agent(s). 
d. Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s). 
e. Unrelated: Adverse event is clearly not related to investigational 
procedures(s)/agent(s). 
4. Plan for Grading Adverse Events: 
The following scale will be used in grading the severity of adverse events noted 
during the study: 


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17 
 
1. Mild adverse event 
2. Moderate adverse event 
3. Severe 
 
5. Plan for Determining Seriousness of Adverse Events:  
Serious Adverse Events: 
In addition to grading the adverse event, adverse events are evaluated to 
determine whether they meet the criteria for a Serious Adverse Event (SAE). An 
adverse event is considered serious if it: 
1. is life-threatening 
2. results in in-patient hospitalization or prolongation of existing hospitalization 
3. results in persistent or significant disability or incapacity 
4. results in a congenital anomaly or birth defect OR 
5. results in death 
6. based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition, or 
7. adversely affects the risk/benefit ratio of the study 
An adverse event may be graded as severe but still not meet the criteria for a 
Serious Adverse Event. Similarly, an adverse event may be graded as moderate 
but still meet the criteria for an SAE. It is important for the PI to consider the 
grade of the event as well as its “seriousness” when determining whether 
reporting to the IRBs is necessary. 
6. Plan for reporting serious AND unanticipated AND related adverse events, 
anticipated adverse events occurring at a greater frequency than expected, 
and other unanticipated problems involving risks to subjects or others to the 
IRBs 
The investigator will report the following types of adverse events to the IRB: a) 
serious AND unanticipated events; b) adverse events occurring with a greater 
frequency than expected; and c) other unanticipated problems involving risks to 
subjects or others. 
These adverse events or unanticipated problems involving risks to subjects or 
others will be reported to the IRB within 5 business days of it becoming known to 
the investigator, using the appropriate forms.  
7. Plan for reporting adverse events to co-investigators on the study, funding 
and regulatory agencies 


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18 
 
For the current study, the following individuals, funding, and/or regulatory 
agencies will be notified: 
• All Co-Investigators listed on the protocol. 
The principal investigator, Chadi Abdallah M.D., will conduct a review of all adverse 
events upon completion of every study subject. The principal investigator will evaluate 
the frequency and severity of the adverse events and determine if modifications to the 
protocol or consent form are required. 
14. Informed consent: A VA waiver of written informed consent and VA HIPAA 
authorization is requested for a pre-screening phone interview and medical record review. 
Following the phone screen, if an individual appears to meet enrollment criteria and is 
interested in participating, the subject is invited for a face-to-face interview and VA 
informed consent and HIPAA authorization is obtained by one of the project 
investigators. A release of information is obtained for review of any available historical 
and clinical data. A written authorization form is obtained from each subject, permitting 
the research team to use, create, or disclose the subject's PHI for research purposes. The 
nature of the project, procedures, relative risks and benefits, and alternatives to 
participation in the project are discussed with the individual. Following this discussion, 
the individual is given a copy of the consent form to review at their leisure, and any 
questions are answered. 
If the individual is interested in the project, written informed consent is obtained, and 
medical and psychiatric screening procedures are undertaken to confirm eligibility. A 
copy of the consent form is provided to all participants. If the individual decides not to 
participate in this study, the decision not to participate does not affect eligibility to 
participate in future studies, to receive treatment at the VACHS or to receive treatment on 
a private basis from a referring clinician. 
15. Confidentiality: Reports generated from this study will not contain any identifying 
information about the participants. Research records are coded only by a number, and are 
stored in locked cabinets. Research records will be stored with the Clinical Neuroscience 
Division at the VA. Consent forms, HIPAA forms, enrollment logs and release of 
information forms will be kept locked in a place separate from subject data collection 
forms.  Subjects will be informed their name and social security number will appear on 
subject payment vouchers that will be sent to Fiscal Service and the Agent Cashier for 
approval and reimbursement.  Subjects will also be informed that medical evaluations, 
including physicals, EKGs, and urine/blood tests will be administered through the 
hospital and will become part of their permanent record.  Finally, subjects will be 
informed that a hard copy of the consent form will be placed in their paper record.  An 
electronic progress note citing subjects’ participation in this research study will be 
entered in their VA electronic medical record upon entry into and exit from, the study. 
16. Location of Study:  West Haven VACHS.  
 


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19 
 
17. Payment to Subjects:  Subjects will be paid $15.00 per hour for their participation in 
the screening visit (up to $75).  During the clinical trial, subjects will be paid $50 per 
visit. Subjects will also be paid $50 for the one-month follow-up visit. At the discretion 
of the investigator, subjects may be reimbursed for additional costs including travel, 
parking, transportation, meals, or other expenses.  Participants may receive a possible 
total of $825.00 if they participate in all aspects of the study.  
 
18. Sources of Funding:  
National Center for PTSD  
19. Probable duration: The study will be conducted over 5 years. 


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