Conditions: Inflammation Fatigue
Keywords: Central Nervous System (CNS) Glutamate Breast Cancer Treatment Fatigue Cognitive Dysfunction Behavioral Psychometrics Imaging Technology Magnetic Resonance Spectroscopy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
The goal of the proposed research is to determine whether riluzole, a drug that increases glutamate reuptake, will decrease central nervous system (CNS) glutamate in breast cancer survivors with increased inflammation and fatigue. The researchers will also determine whether decreasing glutamate with riluzole will reverse inflammation-related fatigue and other symptoms including cognitive dysfunction and decreased motivation. To accomplish these goals, the researchers plan to conduct an 8 week, double-blind, randomized control trial of riluzole (100 mg/d) versus placebo in 40 breast cancer survivors (n=20 per group). All breast cancer survivors will have completed treatment within 1-3 years and have a fatigue level of ≥4 (on a 10 point scale) and a plasma c-reactive protein (CRP) concentration \>3mg/L (indicative of high inflammation). Participants will undergo magnetic resonance spectroscopy (MRS) to measure CNS glutamate before and after 2 and 8 weeks of riluzole or placebo treatment. Fatigue and other behavioral assessments including measures of cognitive function and motivation will be conducted before and after treatment and correlated with the change in CNS glutamate.

Detailed description:
Breast cancer is one of the most common cancers among women with \~250,000 new cases diagnosed in the US each year. Significant advances have been made in treating breast cancer, and the current number of women in the US who are considered breast cancer survivors is over 2 million. Despite these advances, breast cancer and its treatment comes at a considerable cost for a significant percentage of women with up to 30% of women experiencing behavioral and/or cognitive symptoms months to years after treatment completion. The mechanisms which contribute to these symptoms are only beginning to be understood, however, mounting data suggest that inflammation may be involved.

Prior research has demonstrated significant relationships between inflammatory markers and inflammatory signaling pathways and symptoms of fatigue and cognitive dysfunction in patients with multiple forms of cancer including breast cancer. There are a number of theories as to how inflammation may influence fatigue and cognition function in breast cancer patients. One neurotransmitter pathway that may be involved is glutamate. Inflammatory cytokines have been shown to decrease glutamate reuptake and increase glutamate release from astrocytes.

The primary objective of this study is to provide the first data on the role of CNS glutamate and symptoms of fatigue in breast cancer patients using MRS and a medication that has been shown to lower CNS glutamate in animal models and human subjects. No previous study has examined the potential connection between increased inflammation, increased CNS glutamate and symptoms in breast cancer patients, although there is strong clinical and preclinical support for an important interrelationship among these variables. Identification of a significant relationship between increased CNS glutamate and symptoms will:

* Enable the development of inflammatory biomarkers to identify patients with altered CNS glutamate.
* Help focus future studies using glutamate stabilizing medications and glutamate antagonists on patients most likely to respond to glutamate-targeted therapies (personalization of trials and treatment).
* Expand treatment studies to include synergistic or sequential targeting of inflammation and glutamate to reduce symptom burden in breast cancer patients.

This study will also serve as a foundation for efforts to link the impact of inflammatory cytokines and their relationship with increased CNS glutamate and behavior to a variety of cancers. Moreover, by testing novel treatment approaches (targeting glutamate), this study may ultimately improve the quality of life of breast cancer and other cancer patients.

Arms:
arm 1: Participants will take a daily oral dose of 100 mg of riluzole (50 mg two times per day). Participants will be instructed to take the study medication on an empty stomach (1 hour before or 2 hours after meals). arm 2: Participants will take a daily oral dose of 100 mg of a placebo that appears identical to riluzole (50 mg two times per day). Participants will be instructed to take the study medication on an empty stomach (1 hour before or 2 hours after meals).

Interventions: intervention 1: Riluzole intervention 2: Placebo
Intervention descriptions: intervention 1: Study participants randomized to this arm will take 100 mg/day of riluzole for 8 weeks. intervention 2: Study participants randomized to this arm will take a placebo, that matches the appearance of 100 mg tablets of riluzole, daily for 8 weeks.

Protocol document:
Prot_SAP_000.pdf: 
Emory IRB#00086271 
PI: AH Miller  
Sponsor: Donor Funds 
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IRB#: 00086271 
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Title: Effects of Riluzole on CNS Glutamate and Fatigue in Breast Cancer Survivors with 
High Inflammation 
 
 
Principle Investigator: Andrew H. Miller MD 
 
 
Co-Investigators: Ebrahim Haroon MD, Xiaoping Hu PhD, Mylin A. Torres MD, Michael T. 
Treadway PhD, Bobbi J. Woolwine MSW, Jennifer C. Felger PhD, Brian Dias PhD, Tanja 
Jovanovic PhD, Seth Norrholm PhD, Vasiliki Michopoulos PhD MS, Wendy Baer, MD, Kelly M. 
Sklare 
 
 
Protocol Version Date: May 21, 2019 
 
 
NCT Number: NCT02796755 
 
 


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1. Title: Effects of Riluzole on CNS Glutamate and Fatigue in Breast Cancer Survivors 
with High Inflammation 
 
Principle Investigator: Andrew H. Miller MD 
Co-Investigators: Ebrahim Haroon MD, Xiaoping Hu PhD, Mylin A. Torres MD, Michael T. 
Treadway PhD, Bobbi J. Woolwine MSW, Jennifer C. Felger PhD, Brian Dias PhD, Tanja 
Jovanovic PhD, Seth Norrholm PhD, Vasiliki Michopoulos PhD MS, Wendy Baer, MD, Kelly M. 
Sklare 
 
 
Version: May 21, 2019 
 
2. Précis/Abstract:  
The goal of the proposed research is to determine whether riluzole, a drug that increases 
glutamate reuptake, will decrease CNS glutamate in breast cancer survivors with increased 
inflammation and fatigue. We will also determine whether decreasing glutamate with riluzole will 
reverse inflammation-related fatigue and other symptoms including cognitive dysfunction and 
decreased motivation.  To accomplish these goals, we plan to conduct an 8 week, double-blind, 
randomized control trial of riluzole (100 mg/d) versus placebo in 40 breast cancer survivors 
(n=20 per group).  All breast cancer survivors will have completed treatment within 1-5 years 
and have a fatigue level of ≥4 (on a 10 point scale) and a plasma c-reactive protein (CRP) 
concentration >3mg/L (indicative of high inflammation).  Patients will undergo magnetic 
resonance spectroscopy (MRS) to measure CNS glutamate before and after 1 and 8 weeks of 
riluzole or placebo treatment.  Fatigue and other behavioral assessments including measures of 
cognitive function, motivation, and startle reactivity will be conducted before and after treatment 
and correlated with the change in CNS glutamate.  
 
3. Introduction and Background:  
Breast cancer is one of the most common cancers among women with ~250,000 new cases 
diagnosed in the US each year. Significant advances have been made in treating breast cancer, 
and the current number of women in the US who are considered breast cancer survivors is over 
2 million. Despite these advances, breast cancer and its treatment comes at a considerable cost 
for a significant percentage of women with up to 30% of women experiencing behavioral and/or 
cognitive symptoms months to years after treatment completion.[1-4] The mechanisms which 
contribute to these symptoms are only beginning to be understood, however, mounting data 
suggest that inflammation may be involved.  
 
Work from our group and others have demonstrated significant relationships between 
inflammatory markers and inflammatory signaling pathways and symptoms of fatigue and 
cognitive dysfunction in patients with multiple forms of cancer including breast cancer 2,7-11.[2, 
5-8] In addition, polymorphisms in genes for inflammatory cytokines have been associated with 
cancer-related fatigue in breast cancer patients.[9, 10] Moreover, blockade of the inflammatory 
cytokine TNF-alpha was found to reduce symptoms of fatigue in patients with advanced cancer, 
suggesting a cause and effect relationship between inflammation and behavioral change.[11]  
 
There are a number of theories as to how inflammation may influence fatigue and cognition 
function in breast cancer patients. One neurotransmitter pathway that may be involved is 
glutamate.[12, 13] Inflammatory cytokines have been shown to decrease glutamate reuptake 
and increase glutamate release from astrocytes.[14-16] Excess glutamate has been shown to 


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have a neurotoxic effect on neurons through direct excitotoxicity and inhibition of neuronal 
growth factors such as brain derived neurotrophic factor. [12, 17] In addition to direct effects of 
inflammatory cytokines on glutamate reuptake and release, inflammatory cytokines can also 
lead to the activation of the kynurenine pathway.[18, 19] The kynurenine pathway involves 
stimulation of the enzyme indoleamine dioxygenase which breaks down tryptophan into 
kynurenine. [18, 19] Kynurenine is then transported into the brain through the large amino acid 
transporter where it is converted to quinolinic acid (QUIN) in microglia as well as activated 
macrophages which can enter the brain during an inflammatory state. [12, 18-20] QUIN not only 
directly binds the glutamate [N-Methyl-D-aspartate (NMDA)] receptor, but also inhibits glutamate 
reuptake. [19, 21] Interestingly, in a recent study in rats, the NMDA antagonist ketamine was 
found to block the development of depressive-like behavior following administration of the 
inflammatory stimulus lipopolysaccharide.[22] Surprisingly, ketamine (a drug that has also 
shown profound efficacy in patients with treatment resistant depression)[23] had no effect on the 
inflammatory response or activation of the kynurenine pathway in LPS-treated animals, 
indicating that the “end game” of inflammation and activation of the kynurenine pathway may 
indeed be glutamate.[22] 
 
Consistent with impact of inflammation on glutamate metabolism in laboratory animals, recent 
work by our group has shown that administration of the inflammatory cytokine, interferon (IFN)-
alpha, to patients with hepatitis C leads to increases in CNS glutamate in the basal ganglia and 
dorsal anterior cingulate cortex (dACC) as measured by magnetic resonance spectroscopy 
(MRS).[24] The basal ganglia and dACC are well known targets of inflammatory cytokines on 
the brain, and cytokine effects on these brain regions have been associated with symptoms of 
fatigue and cognitive dysfunction as well as reduced motivation.[25] Increases in glutamate as 
measured by MRS correlated with both symptoms of fatigue (including reduced motivation) and 
peripheral markers of inflammation including sTNFR2.[26] Interestingly, our most recent data 
indicate that in patients with major depressive disorder, there is a stepwise relationship between 
CRP and basal ganglia glutamate with patients with a CRP >3mg/L, which is considered high 
inflammation, exhibiting significantly higher basal ganglia glutamate than patients with a 
CRP<1mg/L.[27]  In addition, similar to what was found in IFN-alpha-treated patients, increased 
basal ganglia glutamate in depressed patients was correlated with decreased motivation and 
cognitive dysfunction as manifested by psychomotor slowing.[27] Relevant to the translational 
relevance of the potential relationships among inflammation, glutamate and fatigue and 
cognitive symptoms, a recent study in cancer patients receiving whole brain radiation 
demonstrated that the glutamate antagonist memantine was able to attenuate the effects of 
radiation on cognitive function, indicating that blocking glutamate may treat symptoms in cancer 
patients with an increased inflammatory load.[28] Like memantine, riluzole is a glutamate 
stabilizing agent that increases the reuptake of glutamate and is used for treatment of 
amyotrophic lateral sclerosis.[29]  Riluzole has also been shown to improve symptoms of 
depression while decreasing extracellular glutamate in preclinical models and human subjects.[29]  
Of note, riluzole-induced decreases in glutamate in bipolar depressed subjects were observed 
within 1 week of riluzole administration.[29]   Taken together, the data support that: 
 
•  A significant percentage of breast cancer patients have symptoms of fatigue and cognitive 
dysfunction during and after treatment. 
•  Inflammation has been associated with symptoms in breast cancer patients during and 
after therapy. 
•  Inflammation activates a cascade of events that can lead to excess CNS glutamate which 
can be measured by MRS in humans. 


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• 
Excess glutamate has been associated with multiple symptoms related to fatigue and 
cognitive dysfunction including decreased motivation and psychomotor slowing. 
• 
Riluzole is a drug that can rapidly (within 1 week) reduce extracellular glutamate 
(quantified by MRS) and like memantine, a glutamate receptor antagonist, may reduce 
symptoms of fatigue and cognitive dysfunction in breast cancer patients. 
 
No study has examined whether riluzole can reverse inflammation-induced glutamate changes 
and the associated behavioral alterations in breast cancer patients. Based on our preliminary 
data and previous literature, there is reason to believe that riluzole may lower glutamate in 
breast cancer patients with increased CNS glutamate, and by lowering glutamate reduce fatigue 
and other related symptoms including decreased motivation and psychomotor slowing. 
Therefore, the goals of the proposed research are to test the following hypotheses: 
 
• Compared to placebo, the glutamate stabilizing drug riluzole will decrease CNS 
glutamate in a population of breast cancer survivors with fatigue and high inflammation 
(Aim 1). 
• Decreased CNS glutamate in breast cancer patients treated with riluzole will be 
associated with decreased symptoms of fatigue and cognitive dysfunction including 
anhedonia and psychomotor slowing (Aim 2). 
 
4. Objectives:  
The primary objective of the proposed research is to provide the first data on the role of CNS 
glutamate and symptoms of fatigue in breast cancer patients using MRS and a medication that 
has been shown to lower CNS glutamate in animal models and human subjects. No previous 
study has examined the potential connection between increased inflammation, increased CNS 
glutamate and symptoms in breast cancer patients, although there is strong clinical and 
preclinical support for an important interrelationship among these variables. Identification of a 
significant relationship between increased CNS glutamate and symptoms will: 
 
•  Enable the development of inflammatory biomarkers to identify patients with altered CNS 
glutamate. 
•  Help focus future studies using glutamate stabilizing medications and glutamate 
antagonists on patients most likely to respond to glutamate-targeted therapies 
(personalization of trials and treatment). 
•  Expand treatment studies to include synergistic or sequential targeting of inflammation and 
glutamate to reduce symptom burden in breast cancer patients. 
 
This study will also serve as a foundation for efforts to link the impact of inflammatory 
cytokines and their relationship with increased CNS glutamate and behavior to a variety of 
cancers.  Moreover, by testing novel treatment approaches (targeting glutamate), may 
ultimately improve the quality of life of breast cancer and other cancer patients. 
 
5. Specific Aims: 
Breast cancer patients experience significant behavioral alterations including fatigue and 
cognitive dysfunction that persist in up to 30% of patients for months to years after therapy. 
Data from our group and others have demonstrated that alterations in behavior both during and 
after breast cancer treatment are associated with increased inflammation. One mechanism that 
may mediate the relationship between inflammation and behavioral changes in breast cancer 
patients is central nervous system (CNS) glutamate. Recent work from our laboratory using 


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magnetic resonance spectroscopy (MRS) has found that chronic exposure to the inflammatory 
cytokine interferon (IFN)-alpha leads to increased CNS glutamate [as reflected by the 
glutamate/creatine (Glu/Cr) ratio] which correlated with symptoms of fatigue and cognitive 
dysfunction. Similar relationships among increased inflammation (as measured by CRP), 
increased CNS glutamate and symptoms of anhedonia and psychomotor slowing were also 
observed in patients with depression.  Glutamate changes are likely secondary to the capacity 
of inflammatory cytokines to block glutamate reuptake and increase glutamate release from 
astrocytes, while also activating the kynurenine pathway, leading to increased quinolinic acid, 
which can bind glutamate receptors and block glutamate reuptake. Excessive glutamate can in 
turn lead to neuronal damage. 
 
Thus, CNS glutamate may serve as a final common pathway to CNS pathology and behavioral 
and cognitive disturbances in breast cancer patients after treatment. Interestingly, memantine, a 
drug that antagonizes glutamate signaling was found to preserve cognition in cancer patients 
undergoing whole brain radiotherapy, indicating that blocking glutamate may have 
neuroprotective effects under conditions of an increased inflammatory load.  Taken together, 
these data suggest that glutamate may be an outstanding target for reversing the behavioral 
pathology associated with inflammation during breast cancer and its treatment. Demonstration 
that targeting glutamate to reverse fatigue and cognitive changes in patients with high 
inflammation and could potentially help treat the long-term toxicities of breast cancer and its 
treatment. The goal of the current proposal is to test the hypothesis that reduction of glutamate 
in breast cancer survivors with fatigue and high inflammation will be associated with decreased 
CNS glutamate and decreased symptoms of fatigue and cognitive function including anhedonia 
and psychomotor slowing. To test these hypotheses the following aims are proposed: 
 
Aim 1: To study the impact of 8 weeks of riluzole treatment on CNS glutamate 
concentrations in breast cancer patients with increased fatigue and high inflammation.  
Using a double-blind randomized controlled trial design, 40 female breast cancer patients with 
increased fatigue (≥4 on a 10 point scale) and high inflammation (CRP>3mg/L) will be treated 
for 8 weeks with either riluzole or placebo (n=20 per group).  At baseline and at 1 and 8 weeks 
of treatment, all subjects will undergo single voxel MRS to measure CNS glutamate.  Voxels will 
be placed in the right and left basal ganglia and the dACC. In addition, chemical shift MRS 
imaging will be employed to explore potential glutamate changes in other brain regions of 
interest. 


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Hypothesis 1: Breast cancer patients administered riluzole will exhibit greater decreases in 
basal ganglia and dACC glutamate compared to women treated with placebo. 
 
Aim 2: To determine whether decreased CNS glutamate correlates with improved 
symptoms of fatigue and cognition dysfunction. Behavioral assessments of fatigue and 
cognitive function including measures of motivation and psychomotor processing speed, 
attention, executive function, and memory will be assessed in the patients indicated in Aim 1 
and correlated with glutamate measures in the basal ganglia and dACC as well as other brain 
regions as an exploratory analysis using chemical shift imaging. 
Hypothesis 2: Decreased glutamate in the basal ganglia will be associated with decreased 
fatigue and improved motivation and processing speed.  Decreased glutamate in the dACC will 
be associated with improved executive function and improved memory performance. 
 
The proposed research will help elucidate a novel pathway to behavioral pathology in patients 
with breast cancer, while also identifying peripheral biomarkers of risk as well as a novel 
treatment. 
 
6. Study design and methods:  
 
Participant Selection 
Breast cancer research participants will be referred by physicians in the Glenn Family Breast 
Center at Winship Cancer Institute of Emory University, recruited through social media 
campaigns, or recruited through letters from the Georgia Center for Cancer Statistics. We plan 
to enroll 120 female breast cancer patients between the ages of 21-65 inclusive (to obtain 40 
patients with analyzable data). All breast cancer patients will have completed surgery 
(lumpectomy or mastectomy) with or without neoadjuvant or adjuvant chemotherapy and with or 
without radiation between 1-5 years prior to enrollment.  
 
Participants 
40 female patients with Stage I-III breast cancer that are between 1-5 years post treatment and 
are between the ages of 21 and 65, unless otherwise approved by the PI, will be enrolled in this 
clinical trial. Participants will have completed surgery (lumpectomy or mastectomy) with or 
without neoadjuvant or adjuvant chemotherapy and with or without radiation.  Subjects must 
have a CRP>3mg/L and a Single Item Screening Scale for Fatigue score of ≥4 (out of 10 points, 
0 being no fatigue and 10 being severe, incapacitating fatigue) to be eligible for the trial. Based 
on projections that ~50% of recruited subjects will have a CRP>3mg/L and a Fatigue score ≥4 
and ~20 of subjects will drop out during the clinical trial, we anticipate that we will need to recruit 
120 subjects to yield analyzable data for 40 breast cancer subjects.  No patients will be enrolled 
from vulnerable populations, including neonates, children, prisoners, or institutionalized 
individuals. No use will be made of fetal tissue. Potential subjects will be excluded for a number 
of medical conditions that might represent a risk for riluzole (including history of allergic reaction 
to riluzole and evidence of liver disease) and potentially confound the relationship among CNS 
glutamate, inflammation and behavior/cognition, including autoimmune or inflammatory 
disorders, chronic infectious diseases (e.g. HIV, hepatitis B or C), pregnancy, neurologic 
disorders (including a history of serious head trauma or seizures), liver disease (as manifested 
as an elevation in liver transaminases) and uncontrolled cardiovascular, metabolic, pulmonary 
or renal disease (as determined by medical history and laboratory testing). Subjects with a 
current or past history of schizophrenia will also be excluded. Subjects with Bipolar Disorder that 
have experienced a manic episode within 6 months of study entry will be excluded or at the PI’s 
discretion. Subjects receiving antidepressants, mood stabilizers, antipsychotic medications or 


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benzodiazepines or drugs known to affect the immune system (e.g. glucocorticoids, 
methotrexate) will also be excluded,unless otherwise approved by the PI. Subjects who exhibit 
signs of an infection at screening will be rescheduled when symptoms have resolved. Subjects 
who exhibit signs of infection or a significant change from baseline test measurements via 
safety labs will be informed. Her treating physician may be notified for follow-up or results will be 
used by study clinicians to determine appropriate medical care in the case of adverse events 
and/or study continuation. 
Compensation: For the main riluzole study, participants will be compensated at the end of each 
study visit using ClinCard. The ClinCard is a web based, reloadable, debit card that automates 
reimbursements for clinical research participants. However, if ClinCard accessibility is not 
available, participants may be compensated in the form of cash, check or gift card. Participants 
will receive $25 for each screening visit (which could be up to 2 visits) or $50 if they complete 
the consent and all of the screening assessments in a single visit, $25 for each completed study 
visit and $250 for each visit including an MRS scan, if scan is completed, for compensation for 
their time and effort. Participants will receive compensation for completed MRS scans upon 
completion of study participation. Participants will also receive $25 for completing cognitive 
tasks for Baseline I and Baseline II, and $50 for completing cognitive tasks for Week 8. 
Participants will receive additional compensation for completing the Effort-Expenditure for 
Rewards Task and earnings will be rounded to the nearest $5. If participants do not finish the 
study, we will compensate them for the visits completed. Participants can receive a maximum of 
$1100 for study completion. If there is a considerable break between study visit procedures 
(i.e. a lapse of at least 2 hours outside of the structured study schedule), the participant may 
leave and then return to complete the visit and will be compensated an additional study visit’s 
compensation of $25. Further compensation (up to an additional $25 per visit) will be provided 
to cover travel expenses if participants live equal to or greater than 50 miles outside of the 
Atlanta city limits. Payments will be provided as follows: $25 in cash for the screening visit (s), 
$25 in cash for each study visit, $25 in cash for neurocognitive testing at Baseline I and 
Baseline II, and $50 in cash for neurocognitive testing at Week 8. The additional compensation 
for the Effort-Expenditure for Rewards Task will be given in cash for each study visit when the 
task is completed. The remaining $750 will be mailed to participants in a check at the end of 
study completion. Each participant will be asked to fill out a tax form, including their Social 
Security or Taxpayer Identification Number, in order to be reimbursed, depending on the 
amount and method of payment. Some payment methods involve mail coming to a participant’s 
home address, which may be seen by others members of the household. Participants can 
decline payment if concerned about confidentiality or will be told to discuss other payment 
options with the study team. For the startle study, participants will be compensated an additional 
$50 per study visit for your time and effort, totaling to $100 if all parts of the sub-study are 
completed in two visits. 
 
Recruitment and Informed Consent 
Female subjects with breast cancer will be recruited from local (inter-Departmental) referrals, 
medical record queries, and/or completion of a RedCap survey in response to an IRB approved 
social media recruitment campaign(s). Letters will also be sent from the Georgia Center for 
Cancer Statistics to breast cancer survivors who are potentially eligible for the study. If those 
women are interested, they may sign the consent for contact information release through the 


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Georgia Center for Cancer Statistics, after which trained study personnel may contact them for 
study recruitment. An overview of the study will initially be provided in person or over the phone 
by study clinicians or trained study staff.  A telephone prescreening interview will be conducted 
on candidates providing verbal consent. If a subject shows interest in the study, research staff 
members will describe the general procedures involved and will answer relevant questions. If a 
subject remains interested in participation, the detailed nature, purpose, procedures, benefits, 
risks of, and alternatives to this research study will be explained to each subject and written 
informed consent will be obtained by the study clinician who provides this information. Informed 
consent will be documented on the Institutional Review Board-approved form. A copy of the 
signed consent form will be given to the participant and the original document filed in a central 
study consent binder. The consent binder(s) and subject casebooks containing information 
gathered as part of the study will be kept in a locked office and/or cabinet. 
 
 
 
Verbal Consent to Verify Breast Cancer Information  
For participants who did not undergo their breast cancer treatment within Emory Healthcare, they 
may verbally consent to having their diagnosis and treatment information (e.g. cancer stage, 
nodal involvement, types and dates of treatment, and receptor status) verified through the 
Georgia Center for Cancer Statistics. This verbal consent process will be recorded on an IRB-
approved verbal consent form by trained study personnel. The study clinician may also obtain a 
written informed consent. 
 
Telephone Prescreen Interview 
A telephone prescreen interview will be conducted with study referrals following verbal consent. 
Candidates eligible to proceed with the study process will be scheduled for an appointment to 
see a study clinician.  
 
Onsite visit (s): Trained personnel will obtain written informed consent from candidates prior to 
initiating study procedures. Screening information will be collected by interview and evaluation, 
as well as obtaining collateral history and data from other relevant sources (e. g. medical 
records, referring physician).  
 
Screening will include the following assessments: (1) History of medical and psychiatric 
conditions (2) screening laboratory evaluations, (3) subject height and weight measurements 
and waist circumference obtained by staff 4) Concomitant Medications 5) Adverse Events 
6) MRI Safety Form 7) Demographics and 8) assessments below: 
 
Mini-Mental State Exam (MMSE) is a 27-item interviewer administered questionnaire widely 
used for the evaluation of general cognitive functioning and identification of altered mental 
status. At screening, subjects will be excluded for score ≤28 (unless otherwise approved by the 
PI), which is evidence of mild cognitive impairment.[30] 
WRAT-3 is a very brief screening measure for reading level. Participants evaluated at less than 
an 8th grade reading level may not participate unless otherwise approved by the PI.  
Child Trauma Questionnaire (CTQ) is a standardized, retrospective 28-item self-report inventory 
that measures the severity of different types of childhood trauma. Participants will not be 
excluded for history of childhood trauma.  
 
 
Description of Study Procedures (Baseline 1, Startle Study, Baseline 2 and Weeks 1-8) 


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All eligible participants with a CRP>3mg/L and a Fatigue Score ≥4 will complete Baseline 1, be 
randomized to receive riluzole (100 mg/d) or placebo atBaseline 2, and proceed to study visits 
at Weeks 1, 2, 4, and 8.  
During the Baseline 1 visit and on Week 1 and Week 8, subjects will undergo magnetic 
resonance spectroscopy (MRS).  Between baseline 1 visit and baseline 2 visit, participants will 
have the option of undergoing a parallel Startle Test Study protocol. This protocol will consist of 
either 1 or 2 visits, for completing psychiatric assessments and self-report forms and for 
completing a psychophysiological startle task. A schedule of all assessments is provided in 
Table 1. Approximately 30 mL of blood will be drawn at the same time of day between 8-10AM 
(to reduce potential circadian effects) under sterile conditions at Baseline 1 and 2 and Weeks 1, 
4 and 8.  Screening/safety labs are not time dependent. Safety labs will be completed at 
Baseline 2, Week 4 and Week 8.  At each visit, self-report forms with urine toxicology will occur 
as well as recording of concomitant medications and adverse events. Neurocognitive testing will 
be completed on Baseline 1, Baseline 2 and Week 8. Where indicated, participants will be 
administered the neurocognitive tests and the scanning sequence of the MRS will be completed 
based on scanner availability and at the discretion of the PI or PI’s designee. Subject will be 
read MRI instructions 48hrs prior to Baseline 1, Week 1, and Week 8 visits to have the subject 
avoid specific foods, medications, alcohol and cigarettes starting 24hrs prior to the MRS scan.  
A light lunch/snack may be provided after the fasting lab work.   
 
 


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Table 1. Schedule of Study Procedures and Assessments 
 
+ - for patients with a CRP>3mg/L and a Single Item Screening Scale for Fatigue Score ≥4 
* - for patients completing the main branch of the Riluzole Study 
** - for patients who opt for to complete the Startle Test Study 
 
 
 
 
 
Procedures for 
MRS Controls 
 
 
Intake 
Screen 
Visit 
Baseline 
1+ 
 
Startle  
Study 
(optional)  
Baseline 2+ 
(randomization) 
Week 
1+ 
Week 
2+ 
Week 
4+ 
Week 
8+ 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
Screening/ Safety 
labs* 
 
X 
 
 
X 
 
 
X 
X 
Psychiatric 
Assessments*, ** 
 
X 
 
X 
 
 
 
 
 
Medical History 
and Physical 
 
X 
 
 
 
 
 
 
X 
Concomitant 
Medications 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
MRI Safety Form 
 
X 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
Startle Task** 
 
 
 
X 
 
 
 
 
 
Research Blood* 
 
 
X  
 
X 
X 
 
X   
X 
Urine toxicology 
(Test kit) 
 
X 
X 
 
X 
X 
 
X 
X 
Self-Report 
Forms*, ** 
 
 
X 
X 
X 
X 
X 
X 
X 
Neurocognitive 
Tests* 
 
 
X 
 
X 
 
 
 
X 
MRI Scan Food, 
Drink and 
Cigarette Intake 
Form
 
 
X 
 
 
X 
 
 
X 
MRS 
 
 
X 
 
 
X 
 
 
X 
Placebo or 
Riluzole (100mg/d) 
 
 
 
 
X 
X 
X 
X 
X 


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Key: 
Main Riluzole Study 
*Screening/ Safety Labs: CBC w/Diff, Metabolic Panel, hCG quantitative serum, TSH, Urinalysis w/micro 
at Screening and Week 8 only, Urine drug test all visits (test kit), except week 2 visit; Testing for CRP, 
Hepatitis B and C and HIV will be conducted on the screening visit only, unless otherwise approved by 
the PI. A Rapid C Reactive Protein finger prick may also be obtained by trained research staff using a 
rapid CRP finger prick test at the discretion of the investigator to expedite determining eligibility for 
research participation. 
*Psychiatric Assessments: WRAT-3, MMSE, CTQ, QID-S, Single Item Screening Scale for Fatigue 
*Research Blood: Cytokine Multiplex, TRP, KYN, mRNA analysis, methylation analysis, and gene 
analysis (collected under fasting conditions)  
*Self-Report Forms: IDS-SR, MFI, PROMIS-Fatigue, BAI, PSQI, Assessment of Pain level, PHQ-9, Single 
Item Screening Scale for Fatigue, Baycrest Memory Scale  
*Neurocognitive Tests:  
Baseline 1 - EEfRT,Finger Tapping Task (FTT), The Trail Making Test (TMT), Digit Symbol Task, 
Reaction Time Task (CANTAB) 
 Baseline 2 - Rey Auditory Verbal Learning Test (RAVLT), Delayed Matching To Sample (CANTAB), 
Spatial Working Memory (CANTAB), Stroop Color and Word Test 
Week 8- EEfRT, Finger Tapping Task (FTT), The Trail Making Test (TMT), Digit Symbol Task, Reaction 
Time Task (CANTAB), Rey Auditory Verbal Learning Test (RAVLT), Delayed Matching To Sample 
(CANTAB), Spatial Working Memory (CANTAB), Stroop Color and Word Test 
 
Startle Test Study 
**Psychiatric Assessments: CAPS, MINI, MPSS 
**Self-Report Forms: Demographics Form, Menstrual Cycle Questionnaire, CD-RISC, BDI-II, TEI, Life 
Events Checklist, Post Traumatic Growth Inventory, Saliva Pre-collection Questions, Post-testing 
questions 
**Startle Task: Electromyographic activity, Acoustic startle, Electrocardiogram activity, Electrodermal 
activity, Response keypad, Sniffin’ Sticks, Saliva Collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Riluzole Flowchart: 
 
 
 
CRP>3mg/L and Fatigue Score ≥4  Riluzole Trial  
Screening 
Screening/ Safety labs, psych assessment, medical history, 
concomitant meds, adverse events, MRI safety form, 
demographics, urine toxicology          
 
 
 
Visit week 
1 
Concomitant meds, adverse events, research 
blood, urine toxicology, self-report forms, MRI 
scan, MRS, medication compliance 
Visit week 
4 
Safety labs, concomitant meds, adverse events, 
research blood, urine toxicology, self-report 
forms, medication compliance 
 
Visit week 
2 
Concomitant meds, adverse events, self-report 
forms, medication compliance 
 
Baseline 2 
Safety labs, concomitant medications, adverse 
events, research blood, urine toxicology, self-
report forms, neurocognitive tests, Randomized 
to Riluzole or Placebo 
Baseline 1 
Concomitant meds, adverse events, research blood, urine 
toxicology, self-report forms, neurocognitive tests, MRS scan  
Startle 
Study 
Safety labs, medical history, concomitant meds, 
adverse events, research blood, urine 
toxicology, self-report forms, neurocognitive 
tests,  MRS scan, medication compliance 
 
Visit week 
8 
Psychiatric 
Assessments, Self-
Report Forms, Startle 
Task, concomitant 
meds, adverse events 
Optional 


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Randomization 
Subjects will be randomized to 100 mg of riluzole (50 mg po BID) or an identical appearing 
placebo in a 1:1 fashion with no stratification. Subjects will be instructed to take the study 
medication on an empty stomach (1 hour before or 2 hours after meals). The dosage of riluzole 
is based on several clinical trials that have previously used this medication to treat a number of 
psychiatric disorders ranging from depression to generalized anxiety disorder as well as 
ALS.[31] A randomly generated sequence of assignments to riluzole or placebo will be created 
and maintained by the study pharmacist. Subjects will be randomized in blocks of 4. If a subject 
drops out prior to receiving the first dose of medication, she will not be included in data analyses 
and her randomization assignment will “roll over” to the next recruited subject until 40 subjects 
have received at least one dose of medication or placebo. 
 
Compliance 
Patients will be asked to fill out a medication log and bring in their pill bottles at each study visit.  
Patients who have taken less than 75% of their medication may be excluded from study 
participation. If study removal occurs at or after the Week 4 study visit, the patient will undergo 
exit safety laboratory testing and physical examination. 
 
Main Riluzole Study 
 
Psychiatric Assessments 
 
Quick Inventory of Depressive Symptoms (QIDS) (healthy controls only) is a 16 item self-
report instrument that includes assessment of nine diagnostic symptom domains used to 
characterize a major depressive episode. At screening, subjects will be referred to PI or PI’s 
designee for a QIDS score ≥16. 
Childhood Trauma Questionnaire (CTQ) is a clinician-assisted inventory used to assess 3 
types of childhood abuse: sexual, physical, and emotional.  
Mini-Mental State Exam (MMSE) is a 27-item interviewer administered questionnaire widely 
used for the evaluation of general cognitive functioning and identification of altered mental 
status. At screening, subjects will be excluded for score ≤28 (unless otherwise approved by the 
PI), which is evidence of mild cognitive impairment.[30] 
WRAT-3 is a very brief screening measure for reading level. Participants evaluated at less than 
an 8th grade reading level may not participate unless otherwise approved by the PI. 
 
Self-report Forms  
 
Single Item Screening Scale for Fatigue is a single question self-report screening instrument 
that asks subjects to rate their fatigue on a scale of 0-10 where 0 = No fatigue and 10 = Worst 
fatigue you can imagine. Ratings are categorized as none to mild (0–3), moderate (4–6) or 
Severe (7–10). This screening strategy for fatigue is recommended by the National 
Comprehensive Cancer Network (NCCN) Guidelines. 
Pain assessment scale is a Likert style self-report pain measurement (10 items; 1=no pain; 
10=extreme pain) to be completed by breast cancer participants to gauge their ability to lie 
comfortably in the scanner. Participants reporting a current pain level of >5 may not be 
approved to participate unless otherwise approved by the P.I.  
Inventory of Depressive Symptomatology-Self Reported (IDS-SR) is a 30-item self-report 
instrument with excellent psychometric properties that was designed to measure symptom 
constructs consistent with current psychiatric diagnostic nosology and has been widely used as 
a self-report outcome measure of depression in treatment trials.[32, 33] Of note, the IDS-SR is 


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the patient reported version of the IDS-C used in our other breast cancer study. In the event that 
a subject becomes unduly distressed or scores >32 on the IDS-SR (indicating moderate to 
severe depressive symptoms) or endorses a score >2 on the suicide item of the IDS-SR 
(Question 18), the PI or his designee will be immediately contacted. 
Multidimensional Fatigue Inventory (MFI) is a 20-item scale used to evaluate the presence 
and severity of fatigue among subjects by self-reports.[34] The MFI assesses 5 dimensions of 
fatigue, including general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced 
motivation. The MFI has been used by our group to quantify fatigue in breast cancer patients, 
and a minimal clinically important difference of 10 points has been established.[35, 36] 
PROMIS-Fatigue Short Form is a 7-item scale developed by the Patient-Reported Outcome 
Measurement Information System (PROMIS), a part of the NIH Roadmap Initiative which is 
focused on developing a publicly available resource of standardized, accurate, and efficient 
outcome measures of symptoms, distress, and functioning. The criterion for a minimally 
clinically important difference in patients with advanced-stage cancer is a 3 to 5 point difference 
in raw score.[37]  Recommendations for high priority research on cancer-related fatigue 
recommend use of the PROMIS fatigue scale to allow comparison of results across studies.[38] 
Pittsburgh Sleep Quality Index (PSQI) will be used to assess sleep quality over the past 
month. The scale contains 15 multiple-choice items that inquire about frequency of sleep 
disturbances and subjective sleep quality and 4 write-in items that inquire about typical bedtime, 
wake-up time, sleep latency, and sleep duration. The PSQI generates seven scores that 
correspond to relevant domains of sleep, and each score ranges from 0 (no difficulty) to 3 
(severe difficulty). The component scores are summed to produce a global score (range of 0–
21).  
Beck Anxiety Inventory (BAI) is a 21-item self-report measure of anxiety-related symptoms, 
rated on a 4-point Likert scale based on the patient’s experience in the last two weeks. 
Patient Health Questionnaire (PHQ-9) is a nine-item measurement used to assess depressive 
symptoms and suicidal ideation. Study psychiatrists will be alerted to any participants scoring > 
3 on the suicidal item. 
Baycrest Memory Scale is a 26 item memory scale developed by the Baycrest Centre for 
Geriatric care. 
 
Neurocognitive Tests 
 
The following neurocognitive test battery was developed to test domains of functioning and 
anatomical regions of interest relevant to the proposed Aims and Hypothesis. 
Baseline 1: 
 
Effort-Expenditure for Rewards Task (EEfRT): In this effort-discounting variant, subjects are 
presented with a choice between two task-difficulty levels in order to obtain monetary 
rewards.[39] In each trial, subjects must make repeated manual button presses within a certain 
period of time.  To succeed in each trial, subjects must meet or exceed the required number of 
button presses within the time allotted. Easy-task trials require 30 button presses within 7 
seconds, while hard-task trials require 99 button presses within or before 21 seconds have 
passed.  There are also probability cues attached to each trial—88%, 50%, and 12%—that 
determine whether a trial may result in compensation, upon completion. This information will be 
made known to the subjects at the start of the task. Upon completion of all trials, three of the 
trials will be randomly selected and the subject will receive compensation from those trials 
based on the choices they made. This payment may range from approximately $3.00- $24. This 


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task lasts approximately 20 minutes, and the number of trials subjects complete is based on 
their choices and button press rate. 
The Trail Making Test (TMT) is a commonly used neuropsychological measure with updated 
norms that has two parts. Part A (TMT-A) requires the patient to connect numbered circles in 
order and reflects a measure of basic attention and processing speed, while Part B (TMT-B) 
requires the patient to alternate between numbers and letters and is considered a measure of 
executive function, including planning and organization. 
Digit Symbol Task: The Digit Symbol Task is a subtest of the Wechsler Adult Intelligence 
Scale (WAIS) and consists of rows of blank squares, each printed with a randomly assigned 
number (1-9).  A key is printed above these rows and shows each number paired with a 
different nonsense symbol. The subject’s task is to fill in the blanks with the corresponding 
symbols as rapidly as possible. This test involves graphimotor speed, visual scanning and 
memory, with about half of the variance being accounted for by graphimotor speed, a third by 
visual scanning and 4-5% by memory [40]. As part of the WAIS, this test is frequently used in 
neuro-psychology and relevant norms and test-retest reliability have been well established [41]. 
Performance on the Digit Symbol Test has been found to correlate with subcortical atrophy 
(esp. as measured by the bi-caudate ratio) in disorders involving the basal ganglia including 
Huntington’s disease and multiple sclerosis.[42, 43]  
Finger Tapping Task (FTT): This task uses a specially adapted tapper that the subject is asked 
to tap as fast as possible using the index finger.  The subject is given 5 consecutive 10-second 
trials for both the preferred and non-preferred hands.  The finger tapping score is the mean of 
the 5 trials and is computed for each hand.   
Reaction Time Task (CANTAB): The reaction time test includes simple and choice reaction 
time tasks and is divided into 5 stages requiring increasingly complex chains of responses and 
providing distinction between reaction (or decision) time and movement latencies 
 
 
 
 
 
 
Baseline 2: 
 
Rey Auditory Verbal Learning Test (RAVLT): A test of verbal memory and learning using list 
learning that measures ability to use strategies to improve learning.  
Delayed Matching To Sample (CANTAB):[44, 45] Variables: Response time, Discrimination 
(Hits/False Alarms). A measure of visual memory where subjects are asked to identify objects 
shown previously at various time points.  
Spatial Working Memory (CANTAB):[46] Variables:  Response time, Correct responses. A 
test of ability to remember spatial localization of objects presented previously 
Stroop Color and Word Test: Subject is requested to name the color of a word both when the 
color of the ink matches the name of the color and when the color of the ink does not match the 
name of the color. Prolongation in reaction time and number of inaccurate responses during the 
name-ink color mismatch condition are measured. 
 
Week 8:  
 
Subjects will complete all neurocognitive testing from baseline 1 and baseline 2. Testing will be 
divided into two sessions with a break of at least ½ -1 hour. 
 
 
 
 


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Startle Test Study (Optional):  
Psychiatric Assessments 
 
Clinician Administered PTSD Scale (CAPS) is an interview-administered diagnostic 
instrument measuring PTSD. The CAPS assesses lifetime and current PTSD. It also yields 
continuous measures for the severity of both overall PTSD and of the three symptom clusters 
(intrusion, avoidance, and arousal). The frequency and intensity of scores for each of the 17 
diagnostic criteria are summed to arrive at a total severity score.[47, 48]    
 
      
Mini International Neuropsychiatric Interview (MINI) is a commonly used psychiatric 
structured diagnostic interview that will be used to assess psychiatric disorders. A cover sheet 
will be used to provide interviewers with an overview of participants’ medical history.  
Modified PTSD Symptom Scale (MPSS) is a 17-item interview used to aid in the detection and 
diagnosis of PTSD. The MPSS will be used in this study as a rapid assessment tool because of 
its reasonably good diagnostic validity for PTSD.[49, 50] 
 
Self-Report Forms 
 
Demographics Form (DF) covers demographics; family composition; living situation; and 
personal and family psychiatric medical, and substance abuse history; and income and 
education.  
Connor-Davidson Resiliency Scale (CD-RISC) is a 25-item scale measuring ability to cope 
with stress and adversity. The CD-RISC demonstrates adequate internal consistency, test-retest 
reliability, and convergent and divergent validity.[51] 
Menstrual Cycle Questionnaire is a self-report measure that covers menstrual cycle history.  
Beck Depression Inventory II (BDI-II) is a 21-item measure of depression symptoms. It is a 
commonly used screening instrument for depressive symptoms.  
Traumatic Events Interview (TEI) is an instrument assessing lifetime history of traumatic 
experiences including experiencing, witnessing, and being confronted with these stressors.  
Life Events Checklist is a self report measure to screen for traumatic events in the 
participant’s life.  
Post Testing Questions will be used to assess participants. 
Post Traumatic Growth Inventory is a 21-item scale that will be used to assess positive 
outcomes as a result of cancer survivorship.[52] 
Post Testing Questions will be used to assess participants’ perception of the tasks.  
Saliva Pre-collection Questions will be used to assess quality of saliva collection.  
 
Psychophysiological Task 
Fear-Potentiated Startle: The following methods will allow us to assess fear acquisition, within- 
and between-session extinction, and conditioned inhibition (learned safety), as well as subjects’ 
awareness of reinforcement contingencies in the experiment. The aversive stimulus (US) in 
these studies will be a 250 ms airblast with an intensity of 140 p.s.i. directed to the larynx as 
described in similar human fear conditioning studies. [53-55] Airblasts will be emitted by a 
compressed air tank connected to polyethylene tubing and controlled by a solenoid switch. 
Conditioned stimuli will be presented as visual stimuli according to our previously published 
methods and will consist of colored geometric shapes presented on a computer monitor 
mounted to the wall of the sound attenuated test chamber. [56] The CSs that are reinforced with 
an airblast US (CS+’s) and those that are not reinforced (CS-‘s) will be counterbalanced across 
subjects. Stimuli will be presented using SuperLab 3.0 for Windows (Cedrus, Inc.) and 


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synchronized with psychophysiological data acquisition using a DIO card (Measurements 
Computing, Inc).  This paradigm has been successfully performed previously in our group. [56] 
Physiological Variables 
Electromyographic activity: We will collect electromyography (EMG) recordings of the 
corrugator supercilii muscle (eyebrow muscle).  According to the guidelines from Cacciopo 
and colleagues [57], two 5 mm Ag/AgCl electrodes will be placed above the right eyebrow.  
EMG activity will be acquired at a sampling rate of 1kHz, amplified and digitized using the 
EMG module of the Biopac MP150 for Windows (Biopac Systems, Inc., Aero Camino, CA). 
Acoustic startle: The acoustic startle response (eyeblink component) will be measured via 
EMG of the right orbicularis oculi muscle. Two 5 mm Ag/AgCl pre-gelled disposable 
electrodes will be positioned approximately 1 cm under the pupil and 1 cm below the lateral 
canthus. The startle probe (noise burst) will be a 108-dB (A) SPL, 40-ms burst of broadband 
noise with a near instantaneous rise time.  
Electrocardiogram activity: Heart-rate and heart-rate variability (HRV) will be measured 
using the ECG module of the Biopac system at a sampling rate of 1 kHz. One 5mm Ag/AgCl 
electrode will be placed on the chest above the right clavicle, another electrode will be 
placed on the chest under the left side of the ribcage. 
Electrodermal activity: Skin conductance level and skin resistance data will be acquired at 
a sampling rate of 1 kHz using the GSR module of the Biopac system.  Two 5 mm Ag/AgCl 
disposable electrodes filled with isotonic paste will be attached to middle phalanges of the 
second and fourth finger of the non-dominant hand. 
Response keypad: To assess subject awareness and US expectancy during each 
experimental session subjects will respond on a response keypad (SuperLab, Cedrus Corp.) 
in coordination with the EMG startle response monitoring system (SR-LAB, San Diego 
Instruments).  During the fear conditioning sessions subjects will press a button marked “+” 
if they expect a CS to be followed by the US, a button marked “-“ if they do not expect a CS 
to be followed by the US, and a button marked “0” if they are uncertain of what to expect.  
Sniffin’ Sticks: Participants’ ability to discriminate odor will be assessed based on 
identification of every-day odors using commercially available, “Sniffin’ Sticks”.[58] 
Saliva Collection: Saliva samples will be obtained during the experiment. These will be 
stored in a -80°C freezer for hormonal analysis and DNA methylation analysis.  
 
 
 
Reliability of Behavioral and Neurocognitive Ratings 
The collection of WRAT-3, MMSE, CTQ and medical and psychiatric information (acute status 
and history) will be collected by trained study personnel. Dr. Michael Treadway, Assistant 
Professor of Psychology at Emory University, will train staff on the administration of, Effort- 
Expenditure for Rewards Task (EEfRT). 
 
Laboratory Variables 
 
Blood collection: Research bloods will be collected by venipuncture into EDTA-containing 
vacutainer tube using standard sterile technique. Plasma and buffy coat for the evaluation of 
concentrations of cytokines and their receptors as well as CRP will be obtained by centrifugation 
of whole blood at 1000 x g for 10 minutes at 4°C. Plasma and buffy coat will be removed 


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separately, aliquoted into siliconized polypropylene tubes, and stored at -80°C until batch assay. 
Bloods will also be collected by venipuncture into Tempus mRNA tubes and directly placed in 
freezer storage at -20C. At screening, CRP will be processed in Emory Medical Laboratories 
and/or using the Diazyme hsCRP POC Test Kit. This kit produces rapid results using a finger 
prick method to collect 20 μl of blood and is intended for the in vitro quantitative determination of 
C-reactive protein. Blood and blood plasma will be evaluated in the lab of Dr. Brian Dias at the 
Yerkes National Primate Research Center at Emory University for the evaluation of exosomes, 
RNA, and hormones. Tempus tubes and buffy coats will be sent to the Emory Integrated 
Genomics Core for RNA extraction, gene expression, mRNA profiling, epigenetic evaluation and 
measurement of gene polymorphisms. 
Plasma cytokines and soluble cytokine receptors: Customized high sensitivity Fluorokine 
MAP Multiplex Human Biomarker Panels (R&D Systems, Minneapolis, MN) will be used to 
measure plasma TNF-alpha, sTNFR1 and 2, IL-1ra, IL-6 and sIL-6R. All samples will be 
assayed in duplicate according to manufacturer’s instructions. Quality control plasma of both 
low and high cytokine concentrations will be included with every assay. The mean inter- and 
intra-assay coefficients of variation for control samples are reliably 10% or less. 
C-reactive protein (CRP): Plasma CRP will be assessed with a high sensitivity turbidimetric 
assay. Sensitivity is 0.18 mg/L, range of measure is 0.2 to 80 mg/L, and functional sensitivity (at 
20% CV) is 0.2 mg/ L. 
Tryptophan and Kynurenine: Free tryptophan and kynurenine plasma concentrations will be 
determined by high-performance liquid chromatography in the laboratory of Dr. Dietmar Fuchs 
or other laboratories with equivalent expertise at the PI’s discretion. 
Gene expression and epigenetics: As indicated above, blood will be obtained for analysis of 
inflammatory mediators and signaling pathways. 
Saliva Collection: Saliva will be collected after the startle task by asking participants to spit into 
two tubes. This sample will be analyzed for hormones and DNA methylation changes present at 
time of study visit. 
 
 
MRI Scans  
MRS acquisition and processing: All images will be acquired using a Siemens 3 Prisma 3T 
scanner (Siemens Medical Solutions, Malvern, PA, USA) equipped with a maximum gradient 
strength of 80 mT/m and a rise time of 200 μs, which will provide nearly double the signal-to-
noise ratio enabling high-resolution structural imaging data. The new digital RF system 
equipped with 64-channel RF head-and-neck coil and the two-channel RF excitation coils will 
provide better spectral resolution with improved signal-to-noise ratio while at the same time 
providing more uniform excitation pulses. For image guidance and MRS volume of interest 
prescription, anatomic images will be obtained using a T1-weighted MPRAGE sequence with 
the following parameters: TR/TI/TE =2300/900/3.02 msec; flip angle=8°; FOV read=256 mm; 
matrix=256; slice thickness=1 mm; GRAPPA factor of 0; total scan time=10 minutes.  
Single Voxel MRS Acquisition: Single Voxel Spectroscopy (SVS) is used to quantitate 
neurometabolites of interest in target brain regions. The scanning protocol and post-processing 
methodology will be used in accordance with previously published reports,[24, 27] but modified 
for the Prisma 3T platform. SVS will be acquired using Chemical Shift Selective (CHESS)-based 
MRS sequence using settings of TR/TE = 3000/30 ms, sampling size=128 averages, 
bandwidth=1048Hz with sampling size = 1024, 128 averages. Two voxels with size of 17 x 30 x 
17 mm3 located in the left and right basal ganglia will be used for SVS. Spatial localization will 
be implemented using PRESS technique.[59] Numerically optimized Shinnar-Le Roux (SLR) 


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radio frequency pulses will be used for PRESS (90°, 180°, 180°) and CHESS (90°, 90°, 
90°).[60] Four unsuppressed water FIDs (free induction decay) will be also acquired for eddy 
current and phase correction[61] and to compute metabolite/water ratios if needed (LC Model). 
The FWHM of the unsuppressed water peak will be optimized to <14 Hz by shimming. The 
spectral data will not be apodized. 
Chemical Shift Imaging (CSI): The application of a single voxel to a specific region limits 
evaluation of diffuse or global cortical and subcortical glutamate abnormalities that may occur in 
association with inflammation and have been proposed to occur in unipolar depression.[62] 
Simultaneous sampling from multiple voxels placed bilaterally on the basal ganglia gray matter, 
white matter and adjacent neocortical regions will provide a more expansive evaluation of 
relevant brain structures that have been implicated in the impact of inflammatory cytokines on 
behavior. CSI will be acquired using 2D Point Resolved Spectroscopy (PRESS)-based MRSI 
sequence using settings of TR=1590 ms, TE=30 ms, averages= 7, matrix=16×16, voxel 
size=11. 3×11.3×15 mm3, slice thickness=15mm. The raw files will be processed using LC 
Model package-Version 6.2-2b.[63] 
Post Processing:  
Metabolite Spectral Fitting: The LC Model is an operator-independent commercial software 
package that fits in vivo metabolite spectra using model resonances acquired from multiple 
compounds in standard phantom solutions. The water suppressed time-domain data will be 
analyzed between 1.0 ppm and 4.0 ppm without T1 and T2 correction. The basis set provided 
by the vendor of the LC Model[63] will be used and then scaled to account for receiver gain 
differences. While the entire 18 metabolite basis set would be entered during metabolite fitting, 
the analysis will only include metabolite variances (Cramer Rao Lower Bounds or CRLB) <25. 
Use of a high field strength (Prisma 3T) scanner and short TE (=30 msec) sequence has 
enabled us to calculate Glu/Cr with high reliability and very low metabolite variance (CRLB <10) 
during our previously published MRS studies.[24, 27]  
Water scaling and relaxometry: The post processing pipeline has been developed to yield 
absolute quantitation, metabolite/water and metabolite/creatine values. LC model provides an 
automated water scaling settings which will be used (DOWS). All data (water signal and water 
suppressed data) will be phased followed by quantification of water relaxometry data. The 
relaxometry data will then be fitted to obtain water reference data and in the case of gray matter 
following segregation of the CSF and tissue water constituent. Finally, water signal will be 
scaled to that of the resulting value obtained in previous steps. The water scaling portion of the 
post processing will be done as soon as data is acquired.  
Tissue correction and segmentation: T1-weighted images will be segmented into gray matter 
(GM), white matter (WM), and cerebrospinal fluid (CSF) compartments using FreeSurfer 
(https://surfer.nmr.mgh.harvard.edu/fswiki) on the whole brain T1 images. A volume of interest 
(VOI) will be generated on the T1 images, matching the location and size of MRS voxel. 
Volumes of GM, WM and CSF segments in this volume-of-interest will then be generated using 
FreeSurfer. The absolute metabolite concentrations generated by the LCModel will then be 
corrected for CSF using the formula metabolite C = Co x 1/(1-fCSF), where C is corrected 
metabolite concentrations, Co is metabolite concentrations generated by LCModel output and 
fCSF is fraction of CSF volume.[64, 65]  The final output of the absolute metabolite quantitation 
will be provided in units of molality. Absolute quantitation using CSI data is challenged by 
multiple methodological problems[66] and often requires customized automated programs to 
correct for atrophic tissue changes, B0 field inhomogeneity distortions, and water suppression in 
each subvoxel may be less than optimal.  Consequently, CSI data will be assessed using 
metabolite values normalized to creatine. This will be accomplished after ensuring that raw 
uncorrected concentrations of creatine (Cr) and phosphocreatine (PCr) are not significantly 


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different among the different study groups in the prescribed region of interest. An exploratory 
analysis of the impact of inflammation on other metabolites of interest including choline (Cho), 
myoinositol (InS) and n-acetyl aspartate (NAA) will also be conducted. 
 
Management of MRS Incidental Findings 
The purpose of these scans is not to make a clinical determination of patients’ brain health.  
However, if any incidental finding is noticed during the scan, the information will be provided to 
patients or their medical provider-of-record for further management.  Incidental findings are 
those abnormalities seen in patients’ brain images during the scanning process, which may or 
may not be of clinical importance.  Follow-up of the scan findings will be the responsibility of the 
patients’ Emory Healthcare provider-of-record.  
 
 
7. Data Quality Monitoring Plan:  
Periodic chart monitoring will be conducted by study personnel to validate integrity of the 
data. Chart reviews will take place after each block of five subjects and may include, but 
not be limited to, the presence of a signed informed consent document, documentation that 
the informed consent was obtained prior to performance of any study-related evaluations, 
documentation related to billing compliance, treatment calendars, enrollment reported to 
OCR, enrollment recorded in Oncore ®, treatment order and/or prescription form copies, 
and source documentation as defined in the Winship Clinical Trials Office’s Standard 
Operating Procedure. 
 
The project will be subject to random chart audits conducted by the Winship Clinical 
Trials Office in accordance with Standard Operating Procedures. A minimum of 5 
subject charts may be randomly audited as requested by the PI, the Associate 
Director for Clinical Research, the Director of the CTO, the IRB, the ORC, or other 
Emory research compliance personnel, or the assistant director on an as needed 
basis. 
 
1. Any of the above persons may request a random audit of clinical trials records for 
the subjects enrolled on any study managed by this office. 
2. When records are requested they will be made available to the person listed above 
within 2 hours. 
3. Chart review may include, but not be limited to, the presence of a signed informed 
consent document, documentation that the informed consent was obtained prior to 
performance of any study-related evaluations, documentation related to billing 
compliance, treatment calendars, enrollment reported to OCR, enrollment recorded 
in Oncore ®, treatment order and/or prescription form copies, and source 
documentation. 
4. Audit will be performed by the persons listed above in "Procedure" or the 
internal monitors. 
5. Audit results may be reviewed by the Winship CTO Director, the Assistant Director of 
Regulatory/Compliance, the Assistant Director for Clinical Research and the Office of 
Research Compliance. Significant findings will be discussed with the nurse, 
coordinator, principal investigator, and Director. 
6. Deficiencies will be corrected within five working days and presented to the Assistant 
Director for review at that time. A corrective and preventive action  plan will be 
developed as indicated by the audit results. 


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Quality Improvement 
Charts with significant deviations from Winship CTO policy will indicate the need for further 
audit of records belonging to the involved nurse or coordinator. Limited findings of 
noncompliance will signal a need for increased education and/or quality monitoring. 
Significant noncompliance can lead to disciplinary action. 
 
Failure to comply with this policy may be grounds for discipline by the University. Any 
disciplinary action taken by the University will follow the rules governing the individual's 
employment category. 
 
8. Sources of Materials: 
Research materials to be obtained will include clinician-administered psychiatric assessments, 
neurocognitive assessments, self-report questionnaires, blood sampling, MRS scans, 
physiological variables, and saliva sampling, Material for evaluating baseline medical status will 
be obtained from blood, urine, patient report and their medical record when available. Data to be 
recorded from subjects will include standardized ratings of fatigue, depression and cognitive 
function, as well as clinical information derived from medical records regarding tumor, patient, 
and treatment characteristics. Data to be obtained from peripheral blood will include complete 
metabolic panel; CBC with differential; hCG quantitative serum; plasma concentrations of 
cytokines and their soluble receptors, gene expression, gene polymorphisms, exosome, and/or 
hormonal anaylsis. Data obtained from urine will include urinalysis and toxicology screen. Data 
obtained from saliva will be used to assess hormone levels and DNA methylation changes at 
time of study visit. Clinical data will be used to assess eligibility and safety and will be collected 
via interview and documented by study clinicians. Standardized clinician-administered and self-
report assessments will be administered and collected by study physicians or his designees.  
Blood will be obtained in the clinic laboratories by trained phlebotomists, and the samples will be 
collected and processed by study personnel. 
 
All data, including questionnaires and blood will be coded by unique identifying numbers. 
Subjects’ names will not be linked to their biological samples or clinical data in REDCap. 
Subject name and identifying number will be kept in a casebook in a locked cabinet and/or 
office. Only IRB qualified research staff and study physicians will have access to subject 
identifiers. Research personnel analyzing blood or clinical data will not be provided information 
from which they could identify subjects. All information will be obtained solely to determine 
eligibility for study participation or for research purposes. Nevertheless, any significant 
abnormalities uncovered will be reported to the subject and his/her treating physician for follow-
up or will be used by study clinicians to determine appropriate medical care and/or study 
termination in the case of adverse event 
 
9. Data Collection and Management:  
The data management team will use REDCap.[67] REDCap allows database construction, an 
interface for collecting data, data validation, and automated export procedures for data 
downloads to statistical packages (SPSS, SAS, Stata, R). Scales will be completed securely via 
the internet via standard web access. Research staff will enter scale responses directly into the 
REDCap electronic assessment forms. Electronic assessments will be completed on computer 
terminals under supervision of study staff. Dr. Miller is currently using REDCap for 2 of his 
funded projects, and he and his staff have extensive experience with its usage. Data will be 
stored indefinitely in a secure location until no longer needed by investigator.  


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10. Statistical Analysis:  
 
Aim 1: To study the impact of 8 weeks of riluzole treatment on CNS glutamate 
concentrations in breast cancer patients with increased fatigue and high inflammation. 
Hypothesis 1: Breast cancer patients administered riluzole will exhibit greater decreases in 
basal ganglia and dACC glutamate compared to women treated with placebo. 
Mixed-effects models for repeated measures (MMRM) will be employed to examine effects of 
group, time and their interaction on left and right basal ganglia glutamate or dACC controlling for 
baseline glutamate concentrations in separate analyses for each brain region. Relevant 
covariates including age, sex, race (white/non-white) and body mass index (BMI),  
socioeconomic status (as measured by household income), educational status, tumor stage, 
tumor receptor status (where appropriate), timing (adjuvant versus neoadjuvant) of 
chemotherapy and radiation (yes/no) will be sequentially tested in the models for goodness of fit 
(Akaike Information Criterion) and included as appropriate.  
 
Aim 2: To determine whether decreased CNS glutamate correlates with improved 
symptoms of fatigue and cognition dysfunction.  
Hypothesis 2: Decreased glutamate in the basal ganglia will be associated with decreased 
fatigue and improved motivation and processing speed.  Decreased glutamate in the dACC will 
be associated with improved executive function and memory performance. 
Random intercept linear mixed models will be used to assess whether change in left or right 
basal ganglia or dACC glutamate predict change in fatigue scores or change in neurocognitive  
function over time. Models will be adjusted for relevant clinical covariates (including IDS-SR, 
PSQI, BAI) as indicated above.  Separate analyses will be run for each behavioral outcome 
(MFI, PROMIS) as well tests of cognition (HVLT-R, TMT PASAT COWAT RT FTT, RTT, and 
DSST) and motivation (DDT, EEfRT, Subjective Value Task, Effort and Delay Task, Daily 
Assessment/Mobile App Task, Gamble Task, and Go No-Go Variant Task.).  Type I errors as a 
result of multiple testing will be controlled by using a step down Bonferroni procedure.[68]  
 
11. Power Analysis: 
A power analysis was conducted using our preliminary data examining a cohort of 50 
unmedicated patients with major depression.[27] The study sample size was powered on the 
basis of Aim 1, which represents the primary hypothesis of the study that riluzole will decrease 
basal ganglia glutamate. Given a sample size of 40, an alpha of 0.05, a power of 0.80, we will 
be able to detect an effect size of Cohen’s d=0.5 which falls in the moderate range (computed 
using G*power).  This effect size is well within the range of the effect size (d) of the differences 
in basal ganglia glutamate concentrations between high (CRP>3mg/L) and low (CRP<1mg/L) 
inflammation, which are expected in this study. 
 
12. Potential Study Risks: 
 
Main Riluzole Study Risks: There are 4 major areas of potential risk in the proposed study 
stemming from 1) neuropsychiatric assessments, 2) blood drawing, 3) MRS scanning and 4) 
riluzole treatment. Neuropsychiatric assessments may uncover unpleasant feelings about the 
subject’s present emotional state. The risks of blood drawing include discomfort, bruising, 
infection, bleeding and fainting. Undergoing MRS scan poses no more risk than undergoing a 
routine MRI scan. Nevertheless, physical discomfort due to lying in the scanner, occasional 
headaches due to scanner sounds and previously unrecognized claustrophobic attacks are the 


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prominent adverse effects of the procedure.  Major complications of riluzole (Rilutek) include an 
allergic reaction to riluzole or the components of the tablet and hepatic toxicity. Riluzole is 
contraindicated in individuals who have a history of hypersensitivity reactions to riluzole or any 
of the tablet components and in individuals who have hepatic disease or who have baseline 
transaminases greater than 3 times the upper limit of normal.  The drug is also contraindicated 
in women who are pregnant. Subjects of childbearing ability must agree, with the study doctor or 
PI’s designee, on a method of birth control to use throughout the study. To ensure no 
contraindications with alcohol, participants will be told not to consume more than 1 alcoholic 
drink per day while on study medication (12 fl oz of beer, 5 fl oz of wine, 1.5 fl oz shot of distilled 
spirit, and also not to consume any alcohol within 24 hours of a study visit brain scan. Of the 
most commonly observed adverse events associated with the use of RILUTEK in 1,396 
individuals with amyotrophic lateral sclerosis, those reported more frequently than with placebo 
treatment were: asthenia, nausea, elevations in liver function tests, dizziness, decreased lung 
function, diarrhea, abdominal pain, pneumonia, vomiting, vertigo, circumoral paresthesia, 
anorexia and somnolence. Table 2 shows the most common treatment-emergent adverse 
reactions considered possibly related to medication and for which the incidence was ≥1% in an 
open label Phase IV confirmatory trial for amyotrophic lateral sclerosis of 414 patients.  
 
Startle Study Risks: 
The most common risks and discomforts expected in this study are: 
Risks associated with interviews: Psychological tests and interviews can sometimes bring up 
painful emotions. These emotions may include sadness, worry, or increased anxiety. If you have 
trauma-related stress symptoms, you may have an increase in nightmares or flashbacks related 
to your traumatic experiences. You are free not to answer any questions you wish. You may 
stop participating in the study at any time. This will not in any way affect your future care. 
Risks associated with the acoustic startle test: During the startle measurement, scrubbing your 
skin with cleanser or application of skin tape may cause skin irritation. The noise level you will 
hear during the startle test session is about what you hear on a train. For most people, this 
sound level is not uncomfortable. If the sounds or airblasts cause you discomfort, you can stop 
the test session at any time. Withdrawal from the study will not affect your future care. There 
also may be unknown risks, discomforts or side effects 
The less common risks and discomforts expected in this study are: 
Risks associated with the psychophysiological procedure: You may become tired from sitting in 
front of the computer, or may become uncomfortable sitting in one position for a long period of 
time. You can take a break at any point during these tasks and you can stop at any point during 
the visit. 
Risks associated with the saliva collection: You may feel uncomfortable producing saliva and 
spiting into the collection tube. You are free to take as long as you need for this process, you 
can take a break at any point, or discontinue the process if you wish. 


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At screening, study clinicians will discuss benefits and risks of study participation. Alternatives 
include not participating in the proposed study. 
 
Adequacy of Protection Against Risks 
Protection Against Risk: 
Every effort will be taken to prevent injury or distress that may result from this study. Care will 
be taken to avoid bringing about undue psychological distress during the self-reported 
questionnaires. In the event that a subject becomes unduly distressed or scores >32 on the 
IDS-SR (indicating moderate to severe depressive symptoms) or endorses a score >2 on the 
suicide item of the IDS-SR (Question 18) or a score > 3 on the PHQ-9 suicide item, the PI or his 
designee will be immediately contacted, and an appropriate clinical intervention plan will be 
developed. Emory has inpatient, outpatient and emergency room psychiatric services at all 
recruitment and evaluation sites. In addition, the PI Dr. Andrew H. Miller is a Board-certified 
psychiatrist and has extensive experience in administering standardized clinical assessments 
and handling psychiatric emergencies. As for blood drawing, standard sterile procedure for 
blood withdrawal will be used. Blood draws will be conducted by trained phlebotomists with 


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significant experience in the technique. In addition, the volume of blood withdrawn for this study 
will not exceed 40 mL over the course of the study (including screening and assessment 
visits).To minimize discomfort during the MRS scanning, patients will be provided with a head 
cushion and earplugs. Patients will also be informed about the progress of the procedure 
through a remote microphone. In the case of patients developing acute anxiety or panic, the 
scanning session will be terminated and patient provided enough support to cope with the 
feelings induced by the scanner. If a patient is uncomfortable with the skin cleansing during the 
psychophysiological task, it will be omitted. Patients will be told about the airblast prior to 
beginning the task. If they are uncomfortable with this or any part of the task, the task will be 
stopped.  To reduce the likelihood of adverse reactions to riluzole, all patients will have a 
thorough history of allergic reactions reviewed and their first dose of riluzole will be administered 
under supervision of a study physician or nurse practitioner. In addition, all patients will be 
screened for evidence of liver disease including a screen for liver transaminases as well as 
hepatitis B and C and HIV.  Liver transaminases will also be monitored at weeks 4 and 8, and 
subjects will be instructed to inform staff of any gastrointestinal symptoms.  
 
Data and Safety Monitoring Plan (DSMP) 
Although no high risk procedures are being conducted as part of this study, we will be following 
patients on an FDA approved study medication for 8 weeks. For this reason, we have elected to 
utilize the Data Safety Monitoring Board of the Department of Psychiatry and Behavioral 
Sciences as a third-party oversight committee. The DSMB is described in detail below. In 
addition, study clinicians will be available by pager 24 hrs/7 days a week during the period 
between screening and study completion. Should a subject experience a study related 
emergency or should active suicidal ideation develop, either Dr. Miller or Haroon will be 
immediately notified. Drs. Haroon and Miller are board certified psychiatrists with extensive 
experience in the treatment of psychiatric emergencies. If the assessment in question was done 
by a clinician other than either of them, one of them will immediately contact the subject and will 
evaluate the need for further medical or psychiatric treatment and will arrange medical or 
psychiatric follow-up if indicated. They will evaluate each case individually to make a 
determination regarding whether the subject can remain in the study or whether the subject 
should be terminated in addition to receiving a mental health referral.  
Adverse Event Reporting 
Enrolled participants will be monitored closely by study clinicians for any adverse events. All 
adverse events will be collected using the NCI Common Terminology Criteria for Adverse 
Events version 4.0. If any overt study-related adverse events occur, a decision will be made 
about study continuation. Additionally, a record of adverse events for study participants will be 
reported to the DSMC on a regular basis. Subjects will be closely monitored during the course 
of the study for development of any serious or unexpected adverse reactions. Those events 
meeting Emory IRB criteria for a reportable event will be reported to the IRB or the Winship 
Cancer Institute DSMC according to standard regulations and procedures. The Emory IRB 
Reportable Events Guidelines are included in an attachment.  
Stopping rules 
Individuals who exhibit significant suicidal ideation as indicated above will be discontinued from 
the study.  Individuals who exhibit any evidence of an allergic reaction including rash, hives or 
difficulty breathing and individuals who exhibit more than a two-fold elevation in liver 
transaminases will be discontinued from the study and followed until the allergic reaction 


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resolves or the transaminases return to baseline.  Individuals who exhibit suicidal ideation or a 
serious adverse reaction to riluzole will be unblinded by the study pharmacist, and clinical 
management will be supervised by an unblinded study physician. Patients who have taken less 
than 75% of their medication may be excluded from study participation. If study removal occurs 
at or after the 4 week study visit, the patient will undergo exit safety laboratory testing and 
physical examination. Urine drug tests will be conducted at each visit (except week 2) using test 
kits. Individuals who test positive for drugs of abuse may be terminated at the discretion of the 
PI. 
 Composition of the Data Safety Monitoring Board (DSMB) 
Frequency of DSMB review for this protocol will follow recommendations from the IRB based on 
the assessed risk status of the study. The DSMB for this study will consist of the Clinical 
Research Oversight Committee with members including Boadie Dunlop, M.D. Chairman, Larry 
Tune M.D., Marian Evatt, MD and Tanja Mletzco MA. They have agreed to serve as the external 
DSMB for investigator initiated clinical trials conducted by Emory researchers in the Department 
of Psychiatry & Behavioral Sciences. If the DSMB requires additional specialized expertise to 
evaluate safety issues related to the performance of this study, a relevant specialist will be 
consulted by the DSMB.  
Procedures and Responsibilities of the DSMB 
 
The DSMB will meet monthly. This protocol will be submitted to the DSMB 
simultaneously with the initial submission to the Emory IRB. The DSMB will review the research 
protocol and plans for data and safety monitoring. Once per year (or after 6 months if the 
protocol is considered 'high risk' by the IRB), the DSMB will review a report from the study’s 
data manager that includes: the number of participants who signed consent for the study and 
were randomized, the number of post-randomization dropouts, reasons for these dropouts, and 
any safety concerns, adverse events, an up-to-date consent form, and measures taken to 
protect confidentiality (e.g., data and tape storage, use of coded ID numbers, etc.). The DSMB 
will also review the Principal Investigator’s summary of any new data or evidence that might 
alter the risk/benefit ratio for participating in the study (e.g., newly published studies, etc.). After 
reviewing this information, the DSMB will issue its own report summarizing any serious and 
unexpected adverse events or other unanticipated problems that involve risk to study 
participants, and whether these appear related to the study-based interventions or research 
assessment protocols.  
 
There will be regular, ongoing communication between the PI, Emory’s IRB, and the 
DSMB. The PI will take responsibility for submitting reportable serious and unexpected adverse 
events or other unanticipated study problems to Emory’s IRB according to standard regulations. 
A copy will be sent to the DSMB. Actions taken by the IRB in response to adverse event reports 
will be immediately reported to the DSMB. 
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