Clinical trial NCT01703117
Conditions: Alzheimer's Disease
Keywords: Alzheimer's Disease Dementia
Sponsor: Icahn School of Medicine at Mount Sinai
Start date: 2013-11-01; Completion date: 2020-05-26
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Cognitive aging is a major source of disability in an increasingly aging population. The paucity of effective treatments for cognitive aging disorders, and most importantly in Alzheimer's disease instigates a need for further research into novel therapeutic possibilities. Alzheimer's disease is the most common neurodegenerative disorder and its prevalence steeply increases. Glutamate-mediated excitotoxicity in neuropsychiatric disorders and in particular in Alzheimer's disease has been shown to cause significant cerebral damage. Early effective therapeutic intervention in Alzheimer's disease is critical in order to prevent or at least slow down neuropathological progression that will lead to widespread irreversible neuronal loss and significant cognitive dysfunction. Riluzole, a glutamate modulator agent, will be tested in mild Alzheimer's disease patients. Cognitive functional changes along with two established in vivo biomarkers, namely, Magnetic Resonance Spectroscopy (MRS) and Fluorodeoxyglucose (18F) positron emission tomography (FDG-PET) will be evaluated.

Detailed description:
A double-blinded, randomized, placebo-controlled study will be performed. Forty-two individuals with a diagnosis of mild Alzheimer's disease between 50-95 years old will complete the study. All forty-two individuals will have been on an acetylcholinesterase inhibitor, which is FDA approved for the treatment of Alzheimer's disease, for at least 2 months prior to initiating the study, unless the medication was not previously tolerated. Twenty to twenty-two mild Alzheimer's disease patients will receive riluzole and another 20-22 will receive a placebo. All patients will have a neurological evaluation and neuropsychological tests performed to confirm that they meet criteria for probable Alzheimer's disease set out by the National Institute on Aging - Alzheimer's disease Association that recently revisited the NINCDS-ADRDA criteria along with FDG-PET biomarker consistent with Alzheimer's disease.

Arms: arm 1: 20-22 subjects between the ages of 50-95 will receive riluzole arm 2: 20-22 subjects between 50-95 will receive placebo
Interventions: intervention 1: Riluzole intervention 2: Placebo
Intervention descriptions: intervention 1: 20-22 subjects between the ages of 60-85 will receive study drug. intervention 2: 20-22 subjects between the ages of 60-85 will receive placebo

Protocol documents:
Prot_SAP_000.pdf: 
 
Icahn School of Medicine at Mount Sinai                                                                                        Program for the Protection 
Mount Sinai Beth Israel                                                                                                                    of Human Subjects 
Mount Sinai Brooklyn                                                                                                                      Institutional Review Boards 
The Mount Sinai Hospital 
Mount Sinai Queens                                                                                                                           Mount Sinai Health System 
New York Eye and Ear                                                                                                                      One Gustave L. Levy Place,          
                          Infirmary                                                                                                                                             Box 1081 
 
            Mount Sinai St. Luke's 
                          Mount Sinai West 
 
 
NCT01703117 
IRB-17-02664 
Application 
 
Last approved on 6/18/2020 
 
1. Summary - Title 
Protocol Title 
Glutamatergic Dysfunction in Cognitive Aging: Riluzole in Mild Alzheimer's Disease 
Principal Investigator 
Ana Pereira 
Primary Department 
Neurology 
Application Initiated By 
Ana Pereira 
Lay Summary 
Cognitive aging is a major source of disability in an increasingly aging population (1, 2). The paucity of effective  
treatments for cognitive aging disorders, and most importantly in Alzheimer's disease instigates a need for further  
research into novel therapeutic possibilities. Alzheimer's disease is the most common neurodegenerative disorder  
and its prevalence steeply increases (3). Glutamate-mediated toxicity in neuropsychiatric disorders and  in 
particular in Alzheimer's disease has been shown to cause significant cerebral damage (4-6). Furthermore,  the 
release, propagation and toxicity of beta-amyloid and phosphorylated tau, neuropathological hallmarks of  
Alzheimer's disease, are also dependent on glutamatergic dysfunction. Bringing glutamatergic synapses to more  
homeostatic levels is a therapeutic opportunity for Alzheimer's disease treatment. Early effective therapeutic  
intervention in Alzheimer's disease is critical in order to prevent or at least slow down neuropathological 
progression  that will lead to widespread irreversible neuronal loss and significant cognitive dysfunction. Riluzole, 
a glutamate  modulator agent approved for ALS (7) has not yet been used in cognitive aging disorders, will be 
tested in mild Alzheimer's disease patients. Cognitive functional changes along with two in vivo  biomarkers, 
namely, Fluorodeoxyglucose (18F) positron emission  tomography (FDG- PET)  and Magnetic Resonance 
Spectroscopy (MRS) will be evaluated. 
 
IF Number 
IF2357604 
 
 
New York, NY 10029-6574
T 212-824-8200        
F 212-876-6789 
irb@mssm.edu 
icahn.mssm.edu/pphs 


 
2. Summary - Setup 
Funding Has Been Requested /  
Obtained 
Yes 
Application Type 
Request to Rely on Mount Sinai IRB 
Research Involves 
Prospective Study ONLY 
Consenting Participants 
Yes 
Requesting Waiver or Alteration  
of Informed Consent for Any  
Procedures 
No 
Humanitarian Use Device (HUD) 
Used Exclusively in the Course of 
Medical Practice 
No 
Use of an Investigational Device to 
No 
 Evaluate Its Safety or Effectiveness 
Banking Specimens for Future  
Research 
Yes
Cancer Related Research that 
Requires Approval from the  
Protocol Review and Monitoring  
Committee (PRMC). 
No 
   Is this Cancer Related Research?  Cancer Related Research is defined as research that  
has cancer endpoints or has a cancer population as part of or all of its targeted population.  
This includes protocols studying patients with cancer or those at risk for cancer. 
   
 
Clinical Trial 
Yes 
    
* A prospective biomedical or behavioral research study of human subjects that is designed 
to answer specific questions about biomedical or behavioral interventions  (drugs, 
treatments, devices, or new ways of using known drugs, treatments, or devices).    *  Used 
to determine whether new biomedical or behavioral interventions are safe,  efficacious, 
and effective.     
   
 
Drugs / Biologics  
Yes 
    
* Drugs / Biologics That Are Not a Part of Standard Practice  
* Controlled Substances  
* Drugs / Biologics Supplied by the Research Sponsor or Purchased with Study Funds  
   
 
   Ionizing Radiation for imaging or therapy, including X-Ray, Fluoroscopy, CT, Nuclear  
Medicine, PET andor Radiation Therapy: 
   
 
 
* Purely for standard of care: 
No 
* In frequency or intensity that  
exceeds what is necessary for  
standard of care: 
Yes
Hazardous Materials 
No 


IRB-17-02664 
Initial Application 
Ana Pereira 
Recombinant DNA  
* Viral Vectors  
* Plasmids  
* Bacterial Artificial Chromosomes  
* Toxic Chemicals, Potentially Toxic Medications, Carcinogens  
* Autologous Cell Lines  
   
 
Request Use of Clinical Research 
No 
 Unit Resources 
 
3. 
Summary - Background 
Objectives 
The objectives of the study is to investigate if an improved modulation of the glutamatergic synapse in Alzheimer's  
patients, which are vulnerable to degeneration in Alzheimer's disease, will impact brain function, evaluated through  
neuroimaging and neuropsychological measures.  
Aims 1 (primary): To measure cerebral levels of glucose metabolism using FDG PET and the neuronal viability 
marker NAA and glutamate using proton magnetic resonance spectroscopy (1H MRS) and in patients with probable 
mild AD at baseline and after 24 weeks of treatment with riluzole or with placebo. Hypothesis:  Treatment with 
riluzole for 24 weeks compared to placebo will alleviate glutamatergic and metabolic dysfunction and decrease 
excitotoxic neurodegeneration in mild AD as revealed by a slowing in the rate of temporal decline of FDG-PET 
glucose metabolism and cerebral glutamate and other 1H metabolites. Thus, at 24 weeks,  the placebo group will 
show lower  PET glucose metabolism and MRS metabolite levels than at baseline relative to the riluzole-treated 
group. 
Aim 2 (secondary): To correlate the neuroimaging outcome measures with neuropsychological measures at baseline  
and at 24 weeks. 
Hypothesis: A subset of cognitive measures (e.g. memory, executive function, functionality cognitive and AD score 
measures) will more strongly correlate with  the neuroimaging outcome measures to be further investigated in larger 
clinical studies/trials. 
Background 
Please, see attachment with extensive background, significance and graphs as well. 
Cognitive dysfunction is a growing health problem with the aging of the population. The common disorders of  
cognitive aging in the spectrum from normal cognitive aging, mild cognitive impairment and Alzheimer's disease  
(AD) will increasingly impair the life of millions of people worldwide (1, 2). Alzheimer's disease is a progressive  
neurodegenerative disorder that represents a major threat to public health (3). Thus, this scenario imposes the  
urgency for an effective medication that can ameliorate or slow down the onset of those cognitive aging symptoms in 
the  setting of the current era of an extremely scarce therapeutic armamentarium for those disorders. Glutamate is 
one of the most important neurotransmitters in the brain. 
Excitotoxicity from dysfunctional glutamatergic neural circuits has been implicated in various neurocognitive disorders  
as an important cause of neuronal damage, and especially in Alzheimer's disease (5, 6). Numerous studies have 
now shown that while the activation of the synaptic NMDA receptors (the major glutamatergic receptor) is  
neuroprotective and important for synaptic plasticity, activation of extrasynaptic NMDA receptors will lead to cell  
death molecular signaling -see review by Hardingham et al. 2010 (8). 
       Amyloid beta and phosphorylated tau are the neuropathological hallmarkers of AD. Studies have shown that  
oligomers of amyloid beta disrupt neuronal glutamate uptake (9) which will lead to elevated levels of glutamate  that 
inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NMDA  receptors 
(10). There is also evidence that dysfunctional glutamate levels increases tau phosphorylation (11),  tau gene 
expression (12) and tau propagation (Wu W. Karen Duff 2016). Riluzole (2-amino-6-trifluoromethoxy  benzothiazole) 
is a medication that has been shown to decrease presynaptic glutamate release (13), it facilitates astrocytic 


 
glutamate uptake (14) and increases oxidative metabolism with mitochondrial enhancing properties (15).        
Riluzole is a neuroprotective agent that has been safely used to treat amyotrophic lateral sclerosis (ALS), with  
evidence that it is effective in prolonging the median survival of patients with this condition (16). Recent clinical  
studies suggest riluzole also possesses anti-depressant and anxiolytic effects in patients with depression and anxiety  
(17, 18). As riluzole increases glutamate reuptake through the enhancement of glial excitatory amino-acid transporter  
functioning (19), riluzole may rapidly enhance glutamate-glutamine cycling, increasing the surviving promoting  
synaptic glutamatergic activity (17) while limiting the overflow of glutamate into the extrasynaptic space where it can  
stimulate extrasynaptic NMDA receptors that promote excitotoxicity and cell death. Riluzole, to our knowledge, has  
not been yet tested in cognitive aging disorders and in particular and of most interest in Alzheimer's disease.        
Synaptic density is the strongest pathological correlate of cognitive ability (20). Alzheimer's disease patients develop 
a robust synaptic degeneration (20). The hippocampal and cortical atrophy visible in AD brains demonstrate  the 
degeneration of brain areas predominated by large glutamatergic pyramidal neurons. Dysfunction of glutamatergic 
neural circuits and glutamate levels extra-synaptically could lead excitotoxicity, more release,  propagation and 
toxicity of beta-amyloid and tau, pathophysiological hallmark of AD and a cycle of toxicity in AD  that culminates in 
synaptic and neuronal loss. Importantly, as noted before, amyloid beta decreases glutamate uptake which will lead to 
more spillover of glutamate to extrasynaptic NMDA receptors that promote neuronal death signaling. On the other 
hand, dysfunctional glutamate increases tau expression and phosphorylation, which are also deleterious, enhancing 
a toxicity cycle. A medication such as riluzole that modulates the glutamatergic system by enhancing synaptic 
glutamatergic activity and inhibiting the activation of extrasynaptic NMDA receptor toxic signaling  may be beneficial 
to patients with Alzheimer's disease. 
       We hypothesize that the use of riluzole, a glutamate modulator agent, at the same dose approved by FDA that  
has been safely and effectively used for patients with ALS 50mg BID, in subjects with mild Alzheimer's disease  can 
decrease glutamatergic dysfunction, slow down decline of biomarkers of cerebral metabolism and slow down 
progression of cognitive disability. Notably, the PI has three preclinical publications showing that  (1) riluzole 
rescued age-related cognitive decline through clustering of dendritic spines, which increases neural communication, 
(2) that riluzole rescues age and AD  gene expression profiles (below) and (3) riluzole prevented hippocampal-
dependent spatial memory decline in an early-onset aggressive mouse model of AD (5XFAD), reversing many of the gene 
expression changes in immune pathways: 
-Pereira et al. Glutamatergic Regulation Prevents Hippocampal-Dependent Age-Related Cognitive Decline through  
Dendritic Spine Clustering. PNAS 2014 
-Pereira et al. Age and Alzheimer's disease gene expression profiles reversed by the riluzole. Mol. Psych2016 
  -Okamoto M…., Pereira AC. Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression 
in a transgenic mouse model of early-onset Alzheimer’s disease. Translational Psychiatry. 2018 
We will use imaging biomarkers as a primary outcome measure. Cerebral magnetic resonance spectroscopy (MRS)  
will be used as a biomarker of plasticity changes in the brain. N-acetylaspartate (NAA) is a neuronal viability marker  
that has been well studied -see review (23). It has been used in MRS studies in ALS,  depression, anxiety and 
several other neurologic and psychiatric disorders (17, 18). A decline in NAA  levels occurs in Alzheimer's disease 
(24). In Alzheimer's disease drug trials changes in ADASCognitive scores strongly correlate with parietal NAA 
changes during donepezil treatment (25). Glutamate levels can also be measured through MRS as a secondary 
outcome measure. Our focus of interest in the magnetic resonance spectroscopy analysis is the posterior cingulate 
cortex (primary) and exploratorily we will evaluate the hippocampus.  
Importantly, FDG-PET will be used as the main primary outcome measure biomarker as baseline hypometabolism in 
posterior cingulate, temporoparietal regions, hippocampus and prefrontal cortex has been validated in several 
studies in patients with Alzheimer's disease (26); it is a well established biomarker in AD (more validated than MRS 
for AD) that correlates with disease progression that we will evaluate for changes after riluzole  administration. FDG-
PET is the golden standard technique to evaluate for cerebral metabolism as it measures  regional cerebral glucose 
use. 18F-FDG is as a glucose analog that is taken up by the neuron and is a reflection of the distribution of glucose 
uptake. Synaptic and neuronal loss are tightly associated with a decrease in glucose metabolism, a primary energy 
source in the brain. FDG-PET metabolic changes will be evaluated pre-specified regions of interest  (posterior 
cingulate, precuneus, lateral temporal, inferior parietal, hippocampus and frontal cortex). Neuroimaging changes will 
be the primary outcome measure in this study.  
 
Primary and Secondary Study Endpoints 


IRB-17-02664 
Initial Application 
Ana Pereira 
The primary outcome measures will be the glucose metabolic changes obtained through 18F-fluorodeoxyglucose  
positron emission tomography (FDG-PET) in regions of interest and the imaging biomarker N-acetylaspartate (NAA) 
obtained through magnetic resonance spectroscopy (1H MRS). 
The secondary outcome measures will be glutamate obtained through MRS, and the neurocognitive measures 
obtained through neuropsychological tests for correlation with neuroimaging biomarkers. 
 
Protocol Was Already Approved 
No  
by the Icahn School of Medicine at 
 Mount Sinai (ISMMS) Institutional 
 Review Board (IRB) Under a 
 Different Principal Investigator 
 
Protocol Was Previously Submitted Yes  
to an External(non-ISMMS) IRB 
External IRB Name 
Rockefeller University IRB for protocol 
Weill Cornell Medical Center IRB (for imaging portion of the study) 
 
Protocol Was Approved by the 
Yes 
 External IRB 
 
External IRB Approval Document 
RU IRB approval.pdf 
Page 5 of 50 
4. Research Personnel 
Name/Department 
Role/Status 
CC 
Access 
Obtaining  
Consent 
Phone 
Email 
Ana Pereira /  
Neurology 
PI /  
Yes 
SIGNAUTH Yes 
Tarah Gustafson /  
Neurology 
Admin (non-FCOI) /  
EDIT 
212-241-4264 
Emily Lampshire /  
Psychiatry 
Research Nurse /  
Yes 
EDIT 
Yes 
212-659-8301 
Florence Lau /  
Psychiatry 
Study Coordinator /  
READONL YYes 
Caroline Meuser/  
Psychiatry 
Study Coordinator /  Yes 
EDIT 
Yes 
Hillel Grossman /  
Psychiatry 
Co-Investigator /  
READONL YYes 
212-241-6500 
Julie Ciardullo / 
 Neurology 
Co-Investigator /  
READONL Y 
Gina Garcia Camilo /  
Psychiatry 
Admin (non-FCOI) /  Yes 
EDIT 
718-584-9000x 1710 
Judith Neugroschl /  
Psychiatry 
Co-Investigator /  
SIGNAUTH Yes 
212-241-8329 
Allison Ardolino /  
Psychiatry 
Study Coordinator /  
READONL YYes 
Amy Aloysi /  
Psychiatry 
Co-Investigator /  
READONL Y 
2126598751 


 
Jonathan 
 Greenberg / 
 Psychiatry 
Study Coordinator /  
READONL YYes 
(212) 
 659-5621 
Nelly Velasco /  
Psychiatry 
Study Coordinator /  
READONL YYes 
Martin Ljekocevic /  
Psychiatry 
Study Coordinator /  
READONL YYes 
Margaret Sewell /  
Psychiatry 
Faculty Member /  
READONL Y 
212-241-0188 
Clara Li / Psychiatry Faculty Member /  
READONL Y 
212-659-8786 
Michael Kinsella /  
Psychiatry 
Admin (non-FCOI) /  
Staff (non MD) 
Yes 
SIGNAUTH
212-659-8883 
Kelly Pun / Psychiatry Study Coordinator /  
READONL YYes 
Caroline Meuser /  
Psychiatry 
Study Coordinator /  Yes 
EDIT 
Yes 
Chloe Larson /  
Neurology 
Study Coordinator /  Yes 
EDIT 
Yes 
  


IRB-17-02664 
Initial Application 
Ana Pereira 
5. Sites 
Site Name 
Icahn School of Medicine at Mount Sinai 
Other External Site Name 
Contact Details 
Approved 
Approval Document 
Funded By Mount Sinai 
Other IRB 
 
Site Name 
Other External Site 
Other External Site Name Rockefeller University 
Contact Details 
Approved 
1 
Approval Document 
RU IRB approval.pdf 
Funded By Mount Sinai 
0 
Reviewed By 
Other IRB 
Other IRB 
Rockefeller University 
 
 


 
6. Subjects - Enrollment 
Site Name 
Icahn School of Medicine at Mount Sinai 
Subjects To Be Enrolled 
47 
Site Name 
Other External Site 
Subjects To Be Enrolled 
23 
Total Number of Subjects to be 
70 
 Enrolled Across All Listed Sites 
 Above (Auto Populated) 
As per IRB Modification Request – approved 6/18/19 – local enrollment increased from 26 to 47 at 
Mount Sinai and to 70 across both sites.  
 
 
 
 
 


IRB-17-02664 
Initial Application 
Ana Pereira 
7. Subjects - Setting and Resources 
Setting of Human Research 
Other 
Specify Other Setting of Human Research 
Neurology Research Office and ADRC 
Total Number of Subjects Needed 
26  To 
Complete Study 
Feasibility of Meeting Recruitment Goals 
Participants will be referred from Neurology clinic, Center for Cognitive Health, ADRC Dataware house,  clinicaltrial.gov, 
Alzheimer's Association and other related websites which will make recruitment goal feasible. The ADRC has a registry of 
subjects who have already been characterized and who have expressed interest in clinical trials.  This subject population is 
the most readily available cohort at the ADRC sites and the ADRC physicians are most efficient at recruiting from.  The 
ADRC at Mount Sinai evaluates a total of approximately 5-7 patients a month who have been diagnosed with mild to 
moderate AD.   Active recruitment to the ADRC comes from within Mount Sinai, from outside physicians and other health 
care professionals, and from efforts to inform the community at large.  This recruitment is accomplished through lectures, 
brochures, and institutional advertising including community and targeted advertising such as the NYC chapter of the 
Alzheimer 's disease Association newsletter. Special efforts are made to inform the geriatric community through public 
lectures, health fairs, articles in local papers and drug store magazines. These efforts are organized through the EIT Core, 
using a large roster of community Senior Centers, and senior organizations.  In addition, the MSHS neurological clinic will 
provide recruitment of participants to the study. 
Facilities To Be Used for Conducting Research 
 Neurology Research Clinic/Office and ADRC 
 
Multi-Center Study 
Yes 
Mount Sinai Principal Investigator 
Yes   
is Responsible for All Centers Management of 
Multi-Center Study 
Summary of recruitment:At both Rockefeller University and Mt Sinai sites, we screened a total of 94 
subjects, 44 did not pass screening, 50 were randomized and 42 completed the study. 
 
At the Mt Sinai site, a total of 31 subjects were screened, 7 did not pass screening, 24 were 
randomized and a total of 20 completed the study. At the Rockefeller University site, 63 participants 
were screened, 37 did not pass screening, 26 were randomized and 22 completed the study. 
 
 
Community-Based Participant 
No 
 Research Study 
 
  PI must attest to the following.  
   * Process is adequately described to ensure that all persons assisting with the trial are  
adequately informed about the protocol, the investigational product(s), and their trial related 
duties and functions. 
      
     
Page 9 of 50 


 
8. Subjects - Populations 
Inclusion Criteria 
1. Male or female; 50-95 years old with mild Alzheimer's disease determined after neurological and neuropsychological 
evaluation following the National Institute on Aging – Alzheimer's disease Association criteria (30) that recently revisited 
the NINCDS-ADRDA criteria ( 29). For mild Alzheimer's disease, Mini Mental State  Examination (MMSS) between 19 and 
27. 
2. Must be on donepezil or rivastigmine or galantamine at a consistent dose for at least 2 months. Patients will be 
considered for inclusion if they were previously unable to tolerate acetylcholinesterase inhibitors and as a result, are no 
longer on the medication for at least 2 months. 
3. Must be fluent in English 
4. The subject will appoint or have previously appointed a health care proxy specifically designated for research consent and 
that this be documented. 
Exclusion Criteria 
1. Severe Alzheimer's disease and other dementias as determined by neuropsychological testing and neurological 
evaluation. 
2. Previous riluzole treatment. 
3. MRI contra-indication (severe claustrophobia, metal implants, shunts, pacemaker, joint implants, metal valves). 
4. Currently taking medications that either have evidence of glutamatergic activity or has previous MRS evidence of effects 
on brain glutamate levels at the discretion of the PI such as lamotrigine, lithium, opiates, bupropion,  psychostimulants 
such as amphetamines and methylphenidates, tricyclic antidepressants, benzodiazepines and  any other drug that the 
investigators judge might interfere with the study. (subjects on those medications may  still be included in the study 
however only the values of NAA from MRS will be utilized and not the glutamate  measurements). 
5. Self-reported history or reported by LAR: study participant is a current user of the following illicit drugs: cocaine, MDMA 
("ecstasy"), heroin and other opioids (as verified by urine drug test) or has a history of drug or alcohol abuse  within the 
past 5 years. 
6. Serum creatinine >1.5 times the upper limit of normal. 
7. Abnormal liver function test (greater than 2 times the upper limit of normal for alanine aminotranferase (ALT) or aspartate 
aminotransferase (AST); or bilirubin >1.5 times the upper limit of normal. 
8. History of brain disease including Parkinson's Disease, severe brain trauma, seizures, history of stroke,clinically 
significant lacunar infarct in a region important for cognition or multiple lacunes or a cortical infarct or focal lesions of  
clinical significance, multiple sclerosis, mental retardation, normal pressure hydrocephalus, CNS tumor, Huntington's  
disease, subdural hematoma or other serious neurological disorder. 
9. Uncontrolled diabetes mellitus (Hba1c higher than 7) or chronically uncontrolled hypertension. 
10. Subject must not be taking Namenda® (memantine) for 6-weeks prior to study entrance.  
11. Currently taking any concomitant hepatotoxic drugs such as allopurinol, methyldopa and sulfasalazine. 
12. Any unstable serious co-existing medical condition(s) including but not limited to myocardial infarction, coronary artery 
disease requiring coronary bypass surgery, unstable angina, clinically evident congestive heart failure within 6  months 
prior to the screening visit. 
13. Current smoker or user of nicotine-containing products, such as chewing tobacco, nicotine patch or gum for the past 2 
months. 
14. Current untreated major depression defined by Geriatric Depression Scale > 20. (40) 
 


IRB-17-02664 
Initial Application 
Ana Pereira 
15. Participation in any investigational or marketed drug or device trial within 30 days prior to the screening visit. 
16. Significant neuropsychiatric illnesses such as bipolar disorder, schizophrenia, moderate- severe anxiety, vascular 
dementia, Creutzfeldt-Jakob dementia, HIV dementia, and dementia in other specified diseases. 
17. Subjects who have been on acetylcholinesterase inhibitor for longer than 5 years.  
18. Weight> 300 pounds. 
19. Lactose intolerance. 
20. Any medical or social condition that, in the opinion of the Investigator, might pose additional risk to the participant or 
confound the results of the study. 
21. Positive Hepatitis Serology (Hep. B antigen+ or Hep. C antibody+) 
 
Other Aspects that Could Increase Subjects Vulnerability 
Subjects are patients with mild Alzheimer's disease experiencing cognitive impairment . 
Safeguards to protect Subjects rights and welfare 
Subjects will undergo a capacity evaluation by a doctor to assess their understanding of the consent form and study  
procedures. There is also a possibility that participants may be socially or economically disadvantaged. It will be  
emphasized that their participation is completely voluntary, and clinical care is not dependent on participation. 
9. Subjects - Participation 
Duration of an Individual Subjects Participation in the Study 
8 months 
 
Procedures for Subjects to Request Withdrawal 
Subjects are free to withdraw from the study at any time without penalty. If a subject wishes to withdraw, they should  
contact the PI or study staff. 
Procedures for Investigator to Withdraw Subjects 
The Principal Investigator may withdraw subjects if they feel the subject's health is at risk, or subject fails to keep  
appointments and to follow protocol directions or if subject needs treatments not allowed during the course of the study or if 
the investigator terminates or cancels the research or if the willingness of participation has changed (i.e., a  subject revokes 
consent). 
 
Participants Will Be Recruited 
Yes 
Recruitment Method(s) 
Clinical Practice, Other Website, Physician 
 Referral, Research Match, Other 
Specify Other Recruitment Method 
ADRC Data warehouse, clinicaltrial.gov, Alzheimer's Association and other related websites, Neurology and Geriatric  clinic 
referrals at MSSM. 
How Participants Will Be Identified 
This subject population is the most readily available at the MSSM ADRC site. ADRC physicians have a record of efficiency 
at recruiting.  The ADRC at Mount Sinai evaluated a total of approximately 5-7 patients a month who have been diagnosed 
with mild to moderate AD.   Active recruitment to the ADRC comes from within Mount Sinai, from outside physicians and 
other health care professionals, and from efforts to inform the community at large.  This recruitment is accomplished 


 
through lectures, brochures, and institutional advertising including community and targeted advertising such as the NYC 
chapter of the Alzheimer 's disease Association newsletter. Special efforts are made to inform the geriatric community 
through public lectures, health fairs, articles in local papers and drug store magazines. These efforts are organized through 
the EIT Core, using a large roster of community Senior Centers, and senior organizations.  In addition, the Center for 
Cognitive Health Clinic, other Neurology clinic at MSSM will facilitate recruitment of participants to the study. 
 
How Research Will Be Introduced to Participants 
PI and staff will discuss research with participants at the time that potential participants are identified,  including purpose of the 
study, evaluations, neuroimaging, blood tests, potential risks and alternatives. 
How Participants Will Be Screened 
Subjects will be consented in a private office at the study site by the PI or approved PI delegate. Subjects will be given as 
much time as needed to ask questions and consider the research project. 
The standard Mount Sinai Program for the Protection of Human Subjects (PPHS) consent document will be used for this 
study, ADULT ICF template version for those that are deemed to have capacity and the Incapacitated Adult ICF  template 
version for those without capacity.  
Capacity to consent will be determined by an attending level physician. If it is determined that the subject does not have 
capacity to make the decision whether or not to participate in the research project, the subject's legally authorized 
representative (LAR) will undergo the informed consent process (using the Incapacitated Adult ICF template version). In 
such cases that it is determined that the subject does not have capacity to consent, verbal assent will be obtained from the 
subject as well and will be documented in the research chart and checked the box at the bottom of the incapacitated 
consent form. At the conclusion of screening procedures, including a neurological evaluation, the PI will review the entire 
forms and then respond to the Inclusion and Exclusion Criteria Checklists and determine eligibility. Subjects who sign 
consent but are deemed ineligible for the study or otherwise decline to participate after screening evaluation will be 
recorded in the research database as screen failures with a reason for  failure indicated. Data regarding screen failures 
including demographics, medical history and laboratory results will be retained in the database and available for analytic 
comparisons with active study cohort. 
Participants that pass screen and are considered eligible for the protocol will be enrolled in the study.  
 


IRB-17-02664 
Initial Application 
Ana Pereira 
10. Subjects - Risk and Benefits 
Risks to Subjects 
Risks Related to Treatment with Riluzole. Riluzole has been in the market for over 2 decades for ALS,  however,  potential 
new risks should be evaluated  for AD population. 
Experience in almost 800 ALS patients indicates that about 50% of riluzole-treated patients will experience at least  one 
ALT/SGPT level above the upper limit of normal, about 8% will have elevations > 3 X ULN, and about 2% of  patients will 
have elevations > 5 X ULN. Maximum increases in serum ALT usually occurred within 3 months after the  start of riluzole 
therapy and were usually transient when < 5 times ULN. In trials, if ALT levels were < 5 times ULN,  treatment continued and 
ALT levels usually returned to below 2 times ULN within 2 to 6 months. 
Among approximately 4000 patients given riluzole for ALS, there were three cases of marked neutropenia (absolute  
neutrophil count less than 500/mm3), all seen within the first 2 months of riluzole treatment. In one case, neutrophil  counts 
rose on continued treatment. In a second case, counts rose after therapy was stopped. A third case was  more complex, 
with marked anemia as well as neutropenia and the etiology of both is uncertain. Patients should  be warned to report any 
febrile illness to their physicians. The report of a febrile illness should prompt treating  physicians to check white blood cell 
counts. 
The most commonly observed AEs associated with the use of RILUTEK more frequently than placebo treated  patients 
were: asthenia, nausea, dizziness, decreased lung function, diarrhea, abdominal pain, pneumonia, vomiting,  vertigo, 
circumoral paresthesia, anorexia, and somnolence. Asthenia, nausea, dizziness, diarrhea, anorexia, vertigo,  somnolence, 
and circumoral paresthesia were dose related. Riluzole Adverse reactions(source Lexicomp) >10%: 
Gastrointestinal: Nausea (16%) Neuromuscular & skeletal: Weakness (19%) 1% to 10%: 
Cardiovascular: Hypertension (5%), peripheral edema (3%), tachycardia (3%) 
Central nervous system: Dizziness (4%), somnolence (2%), vertigo (2%), malaise (1%) 
Dermatologic: Pruritus (4%), eczema (2%), exfoliative dermatitis (1%) 
Gastrointestinal: Abdominal pain (5%), vomiting (4%), flatulence (3%), oral moniliasis (1%), stomatitis (1%), tooth caries 
(1%) 
Genitourinary: Urinary tract infection (3%), dysuria (1%) 
Hepatic: Liver function tests increased (8% >3 x ULN; 2% >5 x ULN) 
Neuromuscular & skeletal: Arthralgia (4%), paresthesia (circumoral; 2%), tremor (1%) Respiratory: Lung function  decreased 
(10%), cough increased (3%) 
<1%, postmarketing, and/or case reports (Limited to important or life-threatening): Alkaline phosphatase increased,  
amblyopia, anaphylactoid reaction, anaphylaxis, angioedema, aplastic anemia, arthrosis, asthma, ataxia, bone  necrosis, 
bradycardia, bundle branch block, cataract, cerebral hemorrhage, deafness, dementia, diabetes mellitus,  diabetes insipidus, 
edema, erythema multiforme, extrapyramidal syndrome, facial paralysis, gastrointestinal  hemorrhage, gastrointestinal ulcer, 
GGT increased, glaucoma, hallucination, heart failure, hematemesis, hematuria,  hemoptysis, hepatitis, hypercalcemia, 
hypokalemia, hypokinesia, hyponatremia, hypotension, hypersensitivity  pneumonitis, interstitial lung disease, jaundice, LDH 
increased, leukocytosis, leukopenia, lymphadenopathy, mania,  myoclonus, neutropenia, osteoporosis, pancreatitis, 
peripheral neuritis, pleural effusion, pseudomembranous colitis,  purpura, respiratory acidosis, seizure, subarachnoid 
hemorrhage, thrombosis, urinary retention, urticaria, uterine  hemorrhage, ventricular fibrillation, ventricular tachycardia 
Respiratory: Bronchitis, cough increased, dyspnea, pharyngitis, pneumonia, sore throat Miscellaneous: Diaphoresis,  fungal 
infection, flu symptoms, wandering 
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Abscess, angina, breast  fibroadenosis, 
cardiomegaly, cellulitis, cerebrovascular accident, cholecystitis, conjunctival hemorrhage,  conjunctivitis, deep vein 
thrombosis, diabetes mellitus, diverticulitis, eosinophilia, fibrocystic breast, gastrointestinal  ulcer, glaucoma, goiter, heart 
block, heart failure, hemolytic anemia, hepatitis, hyperglycemia, hypertonia,  hypokalemia, hypokinesia, hyponatremia, 
hypoxia, intracranial hemorrhage, jaundice, LFTs increased, MI,  neuroleptic malignant syndrome, pancreatitis, pleurisy, 
pulmonary collapse, pulmonary congestion, pyelonephritis,  renal failure, retinal hemorrhage, SVT, thrombocythemia, 
thrombocytopenia, tongue edema, transient ischemic  attack. 
Risk related to Brain Imaging: 
  
-MRI/MRS: The MRS procedure is painless and not uncomfortable. It does, however, require the subject to lie still with the 
head and part of the body confined in a tunnel-like device for up to an hour which may cause anxiety. There is the potential 
risk that the MRI scanner attracts metal. Subjects with metal parts in their body will be excluded.  There is no evidence for 
long-term effects of MRI procedures on the body. The Food and Drug Administration (FDA) has set recommendations for 


 
exposure in MRI studies and this study satisfies those criteria. There are no contrast agents used for this study, proposing 
no risk to participants.  
MRI studies might involve unsuspected findings which might or might not be a sign of disease and might lead to further 
medical work-up. 
- 
PET Scan: Risks to the subject associated with the introduction of catheters into veins in the arm for administration 
of radiotracers during PET scans include the possibility of minor pain, soreness, light-headedness and/or bruising as  a 
result of the needle entering the skin and less commonly, the formation of a small clot or swelling of the vein and  bleeding 
into the tissues surrounding the puncture site.  A rare chance of infection also exists. The risks associated  with radiation 
exposure due to radioisotope administration are very small and the dosimetry calculations for the  studies that are proposed 
are within federal guidelines. The radiation dose to the body subjects will receive will be  approximately 10 mSv or 1/5th the 
annual exposure allowed for workers in radiology. For comparison purposes, the  dose from PET scan in this protocol is 
roughly 3-4 times the amount of radiation received annually from radiation  present in the natural environment. At this dose 
level, there are no known risks and this is not expected to cause any  pathological consequences. FDG-PET/CT scans 
included in this study are employed routinely in the care of patients  with medical conditions. 
- 
Risks due to venipuncture: Potential side effects associated with venipuncture include discomfort, pain, bleeding, 
phlebitis, infection, and/or hematoma at the insertion site, and syncope. 
- 
Risk due to neuropsychological testing: Subjects are at risk of boredom and embarrassment from being confronted 
by their deficits on neuropsychological testing 
Withdrawal criteria and procedures below: 
Study subjects whose liver enzymes are > 3 X ULN will have their liver enzymes monitored every one to two weeks until it 
returns to baseline.  
Study drug will be discontinued if ALT levels are equal of greater than 5 X ULN or if clinical jaundice develops. Judith 
Neugroschl, MD, will be monitoring laboratory safety values including liver enzymes and WBC so that the PI  an be 
maintained blinded. 
The study drug will be discontinued if there is evidence of marked neutropenia (absolute neutrophil count less than  
500/mm3). 
Cases of interstitial lung disease have been very rarely 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 will be performed, and in case of findings suggestive of interstitial lung disease or 
hypersensitivity pneumonitis (e.g., bilateral diffuse lung opacities), riluzole will be discontinued immediately. In the majority of 
the reported cases, symptoms resolved after drug discontinuation and symptomatic treatment. 
Description of Procedures Taken to Lessen the Probability or Magnitude of Risks  
-Safety will be assessed through monitoring of all adverse events that occur. Patients will be instructed about possible 
adverse effects.  
-Safety assessments will include monthly laboratory tests (hematology, chemistry) and monthly thorough neurologic  
evaluation. Full neuropsychological testing performed will take place at baseline, 3 months and 6 months. Since the 
Principal Investigator will be blind to placebo x experimental subjects, ADRC physician will be responsible  for checking 
results of all laboratory tests, including complete blood count, comprehensive metabolic panel and  particularly liver 
enzymes, which can be more commonly affected. 
-Medical records and routine laboratory data will be handled with HIPAA compliance and protected by internal rules and 
regulations. 
-To minimize risks associated with phlebotomy, blood drawing will be performed by experienced phlebotomists under  
aseptic conditions. Insertion of catheter for PET scan will be performed by experienced medical personnel at Weill Cornell 
Medicine. Should discomfort occurs, we will provide appropriate treatment. 
-Adverse events will be managed by the clinical trial team. They will assess and treat the event as appropriate,  including 
referral to an independent physician or department. 
-Safety monitoring will be conducted both internally and by an external data safety monitoring board [DSMB] which will 
review neuropsychological testing and adverse events as outlined by DSMB. 
-In addition, a summary will be produced for each of the following: serious adverse events; events leading to withdrawal from 
treatment; events judged by the investigator to be related to study drug; all events by severity.  


IRB-17-02664 
Initial Application 
Ana Pereira 
-MRI/MRS: Subjects with metal in the body will be excluded from the study due to potential risk that the MRI scanner  
attracts metal. The subject will be able to communicate with MRI operator throughout the procedure, in case of anxiety or 
claustrophobia, the subject will be able to stop it at any time. 
-All brain imaging in this study will be read and interpreted by Weill Cornell Medicine Department of Radiology the report will 
be provided to the Principal Investigator. In case of unsuspected incidental findings 
occur, the PI of the study, Dr. Pereira, a neurologist, will share the findings with the subject or a physician the subject may 
designate. 
Toxicity Management and Stopping Rules: 
-Study subjects whose liver enzymes are higher than 3 times upper normal limit will have their liver enzymes  
monitored weekly until it returns to baseline (based on data on ALS patients outlined above). If the liver enzyme  
levels do not decrease within 2 weeks of follow-up labs, the ADRC physician, who will check all laboratory results to  
maintain PI blind in the study, will communicate to DSMB and the medication will be stopped. 
-Study drug will be immediately discontinued if liver enzymes are equal or higher than five times the upper normal  
limit or if clinical jaundice develops. 
-The study drug will be discontinued if there is evidence of the rare side effect of marked neutropenia (absolute  
neutrophil could less than 500/mm3). 
-Cases of interstitial lung disease have been very rarely reported in patients treated with riluzole; upon further  
investigation, many of those cases were hypersensitivity pneumonitis. If respiratory symptoms develop such as  
dry cough and/or dyspnea, chest radiography will be performed, and in case of findings suggestive of interstitial  
lung disease or hypersensitivity pneumonitis (e.g., bilateral diffuse lung opacities), riluzole will be discontinued  
immediately. In the majority of reported cases, symptoms resolved after drug discontinuation and symptomatic  
treatment. 
Provisions for Research Related Harm / Injury 
If the participants are injured or made sick from taking part in this research study, medical care will be provided.  
Generally, this medical care will be billed to the subject's health care insurance. In some cases, the costs of this care  
may be paid by someone else. In the event of injury the PI is contacted. 
All forms of medical testing – whether routine or experimental – involve some risk of injury.  In spite of all safety  
measures, the participant might develop medical problems from participating in this study.  The participant must  
report any suspected illness or injury to the study doctor immediately.  If such problems take place, Mount Sinai  
Hospital will provide emergency medical treatment and will assist the participant in getting proper follow-up medical  
treatment.  The Dana Foundation and Alzheimer's Drug Discovery Foundation will not provide compensation for  
research-related injury.   
Incidental findings on MRI of clinical meaning or significance will be reviewed by the PI, a neurologist, with the  
participant and/or responsible caregiver. If the incidental findings warrant any further clinical attention then the PI will  
work with patient to find suitable resources (e.g.  a conversation with the patient's primary care doctor or a referral to  
a neurologist – this would depend upon the nature of the finding). 
Expected Direct Benefit to Subjects 
The subject may receive no benefit from participation.  
Subjects may personally benefit from the access to the medical expertise of the doctors conducting this research  
study, and the medical care they deliver. 
If riluzole is shown to have benefit to patients with Alzheimer's disease, some participants could benefit from this  
study. However, we do not know if riluzole is of benefit and this study will start to answer this question. 
Benefit to Society 
Benefits to society include the possibility that the study medication may show to be effective in treating patients with  
Alzheimer's disease. This study will generate further knowledge of glutamatergic dysregulation and the neurobiology  
of Alzheimer's disease that will be informative for future studies. 


 
 
Provisions to Protect the Privacy Interests of Subjects 
From the time participants are identified for recruitment until they complete study participation, every effort will be  
made to ensure their privacy. Phone calls made to subjects will be made in the privacy of the study coordinator or  
investigator's office.  
In order to ensure that subjects and their caregiver feel at ease with the research situation in terms of the questions  
being asked and the procedures being performed, the study staff will make every effort to explain the purpose of  
any testing conducted, what the test(s) will be like, how long testing will take, and what the day's schedule will be,  
including when the subject and caregiver may take breaks. After answering any questions, the subject (or study  
partner), as appropriate and feasible, will be asked to wait outside the test room in the designated waiting area. If  
the subject will comply only with the caregiver present, the caregiver will be instructed not to provide answers to any  
neuropsychological testing, and to sit in an area of the room where the subject will not easily turn to him or her for  
feedback. 
It is acceptable and appropriate for the members of the research team to approach the prospective participants about  
research, because they have completed their IRB trainings, including GCP, human subject protection and HIPAA  
trainings, and have an adequate knowledge of the study protocol. 
Economic Impact on Subjects 
There are no costs to participating in this study. Clinical and neurological assessments, neuroimaging,  
neuropsychological testing and blood tests are free of charges to participants and the subjects' other medical care at  
Mount Sinai or elsewhere is not contingent upon participation in the study. 
 


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IRB-17-02664 
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11. Subjects - Adults Without Capacity 
There is Anticipated Direct Benefit 
No  
to the Subjects 
 
Assent is Required of 
None of the Subjects 
   
  PI must attest that all of the following are true.   
* The proposed plan for the assessment of the capacity to consent is adequate.   * The 
objectives of the trial cannot be met by means of study of subjects who can give  consent 
personally.  
* The foreseeable risks to the subjects are low.   
* The negative impact on the subject’s well-being is minimized and low.  
* The trial is not prohibited by law.  
* Subjects have a disease or condition for which the procedures involved in the research 
are intended.  
* Subjects will be particularly closely monitored.  
* Subjects will be withdrawn if they appear to be unduly distressed.  
* The proposed plan for the assessment of the capacity to consent is adequate (and 
complies with institutional policy GPP-312).  
* The assessment of the capacity to consent will be performed by a qualified attending 
physician with appropriate training, licensing and certification, with special attention paid  
to qualifications re: assessing incapacity due to mental illness, mental retardation or  
developmental disability.  
* The proposed plan for the assessment of capacity includes the assessment of the cause 
and extent of the incapacity and likelihood that the subject will regain capacity.  
* The PI has indicated that he/she will document this determination with the above details of 
the assessment appropriately (eg. In the medical record when applicable and in research  
record).  
* The consent document includes a signature line for a legally authorized representative.  
   
  
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Ana Pereira 
 
12. Procedures - Narrative 
Description of the Study Design 
A double-blinded, randomized, placebo-controlled study will be performed. Forty-eight individuals with a diagnosis  
of mild Alzheimer's disease between 50-95 years old will complete the study. There will be two cohorts of 50-74  
and 75-95 years old that will be age-matched. All forty-eight individuals must be on donepezil or rivastigmine  or 
galantamine at a consistent dose for at least 2 months. Patients will be considered for inclusion if they were  
previously unable to tolerate acetylcholinesterase inhibitors and as a result, are no longer on the medication for at  
least 2 months. 


 
Twenty-four mild Alzheimer's disease patients will receive riluzole and another 24 will receive a placebo. All patients  
will have a neurological evaluation and neuropsychological tests performed to confirm that they meet criteria for  
probable Alzheimer's disease set out by the National Institute on Aging – Alzheimer's disease Association (29) that  
recently revisited the NINCDS-ADRDA criteria (30) and to have mild Alzheimer's disease. See full inclusion and  
exclusion criteria. (see below, protocol was later amended for sample size that at least 40 subjects would have 
completed the study). 
Patients will be imaged at baseline, after 3 months and 6 months of the riluzole/placebo administration with magnetic  
resonance spectroscopy measures for NAA, glutamate in posterior cingulate and for exploratory analysis the 
hippocampus. FDG-PET will be obtained at baseline and after 6 months. Neuropsychological testing will be 
performed at baseline, after 3 and 6 months of the study drug administration as per neuropsychological testing panel 
described below. 
Riluzole will be administered at a dose of 50mg once a day for the first 5 days of treatment to see whether it is well  
tolerated. This will be followed by twice a day dosing for the remainder of the study. Patients will be advised to take 
study article 1hr before or 2hrs after meals to avoid decreased absorption. This dose is FDA approved and has been 
safely used in ALS patients for several years. Because there was not much background information whether 
combination treatment with acetylcholenesterase inhibitors and riluzole, both neurologically active agents,  might 
interact an impact neuropsychological function, the DSMB reviewed on an ongoing basis the results of mental  status 
and neuropsychiatric testing in real time obtained at the first 4 visits (approximately 3 months) of 10 subjects evenly 
divided on drug and placebo.  
If a potential study subject presents for screening but is currently taking Namenda® (memantine), after informed  
consent is obtained, they will be asked to voluntarily washout this drug from their system for at least 6-weeks prior  
to participating in the study if they choose to participate in the study. The PI, Dr. Pereira, will discuss with the 
subject and their LAR the possible implications of stopping this medication and subject and their physician will make 
a decision on whether to stop Namenda or not. Of note, memantine is only FDA-approved for moderate-severe 
Alzheimer's disease as clinical trials have failed to demonstrate any benefit in the early stages of Alzheimer's 
disease that is aimed for this study population. 
Ana Pereira, MD PI on the study moved from Rockefeller to Mount Sinai, therefore, the study will also continue here  
at Mount Sinai once approved. All neuroimaging for this study is being conducted at Weill Cornell (for Rockefeller  
enrollees); we plan to continue to use this Neuroimaging center once the study is approved at Mount Sinai. The Weill  
Cornell site has IRB approval to conduct the neuroimaging for the study. Weill Cornell has submitted an amendment  
to their IRB to accept Mount Sinai enrollees once the study is approved at Mount Sinai 
Description of Procedures Being Performed 
All Neuroimaging will be performed at Citigroup Biomedical Imaging Center at Weill Cornell Medicine where the  
imaging portion of the protocol has an IRB approval. 
FDG PET Methods 
 
For each FDG PET scan, 5 mCi of florodeoxyglucose will be administered followed by a 40 minute uptake period during 
which the participant was in a resting state with eyes and ears open, without activity or audiovisual distraction. Images 
will be acquired on a Siemens Biograph 64mCT scanner as a series of 4 frames of 5 minutes each. In some initial cases, 
a full dynamic scan will performed and late timeframes extracted for processing and analysis.  
 
All PET images are inspected for motion or artifact. Using SPM12 (Wellcome Trust), motion correction are performed 
and frames averaged into a static image. Each 6 month scan are coregistered to the baseline FDG scan, which is co-
registered to the participant’s T1-weighted MRI scan. MRI scans are segmented into gray, white, and CSF tissue and 
spatially transformed to a template in MNI space, and the spatial transformations applied to the PET scans. Regions of 
interest  atlases are thresholded with a smoothed gray participant-specific segment and average intensities within each 
region of interest are measured. A reference region for calculation of Standardized Uptake Value Ratios (SUVRs) is 
defined based upon preserved voxels in the AD Progression Classifier, most pronounced in the paracentral region. 
Longitudinal changes in SUVRs using this reference will be compared to SUVRs referenced to (separately) centrum 
semiovale white matter, cerebellum, pons, and whole brain.  While these regions tend to be more variable due to 


IRB-17-02664 
Initial Application 
Ana Pereira 
technical factors (cerebellum, pons), progressive hypometabolism effects (whole brain), or potentially affected by riluzole 
(cerebellum), consistency in results could help to confirm the robustness of findings. Images will also be evaluated 
(scored) using the FDG AD Progression classifier. 
FGD-PET analysis will be performed by ADM diagnostics, in collaboration with Dawn Matthews.  
Rockefeller University/PI contracted with ADMdx to analyze the FDG-PET images. PET scans will be deidentified and 
coded and sent via mail service to ADMdx. 
 
MRI and 1H MRS methods  
All MRS neuroimaging studies will be conducted on a multinuclear 3.0T GE SIGNA HDx or Discovery MR750 system. 
Each enrolled subject will undergo high resolution axial T1-, T2- and spin density-weighted scans. These images will be 
used to prescribe the voxels of interest for the 1H MRS scans. A T1-weighted volumetric scan will be acquired using a 
spoiled gradient-recalled echo sequence (SPGR, TR 12.21 ms, TE 5.18 ms, flip angle = 7, voxels 0.94 x 0.94 x 1.5mm) 
on the GE HDx system or a magnetization-prepared rapid gradient-echo sequence (MPRAGE, TR 8.34 ms, TE 1.7 ms, 
flip angle = 7, voxels 0.94 x 0.94 x 1.5mm) on the GE Discovery MR750, along with an axial fast Fluid-Attenuated 
Inversion Recovery (FLAIR) scan for brain tissue segmentation and use in PET image co-registration and region of 
interest definition, and to rule out exclusionary focal brain lesions.  
 
In vivo brain levels of glutamate, NAA, tCr and other major metabolites will be obtained using 1H MRS and a 2x2x2-cm3 
Posterior Cingulate Cortex (PC) voxel of interest  with TE 30 ms, 129 constant-time increments (t1) of 0.8ms, and TR 
1500 ms and a receive-only 8-channel phased-array head coil. The distinguishing feature of CT-PRESS is that it enables 
MRS measurement of glutamate uncontaminated by glutamine  
1H MRS Data Processing and Quantification 
The areas of the individual spectral peaks, which are proportional to their respective concentrations, are obtained by 
frequency-domain fitting each resonance to a Gauss-Lorentz (i.e., pseudo-Voigt) lineshape function using the 
Levenberg-Marquardt nonlinear least-squares algorithm as implemented in 1H MRS data processing software written in 
IDL] for CT-PRESS and J-edited spectra, respectively. The levels of NAA, glutamate, GABA, Glx and other metabolites 
are  expressed semi-quantitatively as ratios of peak areas relative to that of the unsuppressed water signal (W) from the 
same voxels.  
 
 
Neuropsychological tests will be performed at MSSM, by neuropsychologists from ADRC and Neurology Department: 
-Mini-Mental State Exam (31) 
-Clinical Dementia Rating (32) 
-Attention/Psychomotor Speed: WAIS-IV Digit Span forward (33); Trail Making Test Part A (34) 
-Memory: Logical Memory subtest (older adult version only)- WMS IV (37)(33) and Benton Visual Retention Test V 
 (38) 
-Language: Letter and Category Fluency (36) 
-Executive Function/Working Memory: Trail Making Test B (34); WAIS-IV Digit Span Backwards (33) -
Visuospatial: Clock Drawing Test (35) 
-Premorbid ability: National Adult Reading Test-Revised (39) 
-Behavior/Mood: Neuropsychiatric Inventory (46) 
-Alzheimer's disease Assessment Scale - Cognitive Subscale (42, 43) 
-ADCS-Activities of Daily Living (ADL) Inventory (41) 
Screening  Visits Screen Visit #1 (3 hours) 
Consent process 
Medical History and Neurologic Evaluation 
Baseline Laboratory (CBC, comprehensive metabolic, LFT, Hba1c, Cytokines (2 Tubes). 
***Subjects will not begin washout of medication until they are informed by the PI, Dr. Pereira of any laboratory  
result(s) that may exclude them from continuation in the study). 


 
Screening Visit #2 (approx. 2 hours) 
After all labs are reviewed and if the subject is considered eligible, he/she will receive a call to have their baseline  
MRS and PET scan at Citigroup Biomedical Imaging Center at Weill Cornell Medicine. 
After MRI is read and reviewed for eligibility, Study Visit #1 will be scheduled. 
STUDY VISITS 
Study Visit #1 (within 4 weeks after Screening visit #2) 
Neuropsychological testing 
Randomization to study drug (riluzole) or placebo. First dose to be taken the following morning. 
Riluzole (Rilutek) tablets should be taken at least an hour before, or two hours after, a meal to avoid a food-related  
decrease in bioavailability. Study participant and caregiver will be taught how to self-administer the study drug and  
how to complete the study drug diary. 
Labs:  Cytokines (if not previously obtained at screening vs. 1). 
(If the study participant is not randomized to study drug the day of neuropsychological testing, the study subject will  
be brought back for study visit #1-A) 
Study Visit 1-A 
Randomization to study drug (riluzole) or placebo (If not done during study visit #1). First dose to be taken the  
following morning. 
Riluzole (Rilutek) tablets should be taken at least an hour before, or two hours after, a meal to avoid a food-related  
decrease in bioavailability. Study participant and caregiver will be taught how to self-administer the study drug and  
how to complete the study drug diary. 
Labs:  Cytokines (if not previously obtained at screening vs. 1). 
**Once the study medication has begun, the PI, Dr. Pereira is blinded to ALL laboratory results. Dr. Judith Neugroschl   
will monitor laboratory safety values including liver enzymes and WBC and conduct a clinical evaluation so the PI  
can maintain study blind. 
Study Visit #2 (1 hour)(30 days after study visit #1 or #1A)(+/- 7 days) 
Targeted mental status exam as required, adverse event (A/E) assessment, vital sign (VS), weight (Wt). 
Labs: CBC, Comprehensive metabolic, liver function test (LFT's), genetic testing for APOE collect 
returned bottle of study medication 
calculate study drug accountability based on diary and returned tablets 
dispense a new bottle of study drug 
dispense a new diary 
Study Visit #3 (1 hour) (60 days after study visit #1)(+/- 7days) clinical assessment -
Targeted mental status exam as required, A/E assessment, VS, Wt. 
Labs: CBC, Comprehensive metabolic, LFT's, genetic testing for APOE (if not obtained at study visit #2). 
collect returned bottle of study medication 
calculate study drug accountability based on diary and returned tablets 
dispense a new bottle of study drug dispense a new diary 
Study visit #4 (2-3 hours) (90 days after study visit #1) (+/- 7days) clinical assessment - 
Targeted mental status exam as required, A/E assessment, VS, Wt. 
Neuropsychological testing (to be done prior to lab tests to avoid stress) 
Labs: CBC, Comprehensive metabolic, LFTs, (Labs to be drawn after neuropsychological testing). 
collect returned bottle of study medication 
calculate study drug accountability based on diary and returned tablets 
dispense a new bottle of study drug 
dispense a new diary 
Imaging: MRS  (to be done within two weeks of visit) 


IRB-17-02664 
Initial Application 
Ana Pereira 
Study Visit #5 (1 hour)(120 days after study visit #1) (+/- 7 days) clinical assessment - 
Targeted mental status exam as required, A/E assessment, VS, Wt. Labs: CBC, 
Comprehensive metabolic, LFT's collect returned bottle of study medication 
calculate study drug accountability based on diary and returned tablets 
dispense a new bottle of study drug dispense a new diary 
Study Visit #6 (1hour) (150 days after study visit #1)(+/- 7 days) clinical assessment -
Targeted mental status exam as required, A/E assessment, VS, Wt. Labs: CBC, 
Comprehensive metabolic, LFT's collect returned bottle of study medication 
dispense a new diary 
calculate study drug accountability based on diary and returned tablets 
dispense a new bottle of study drug 
Study Visit #7 (2-3 hours) (180 days after study visit #1; (+/- 7days) clinical 
assessment - Targeted mental status exam as required, A/E assessment, VS, Wt. 
Labs: CBC, Comprehensive metabolic, LFT's, Cytokines (2 tubes) 
collect returned bottle of study medication 
calculate study drug accountability based on diary and returned tablets 
Neuropsychological testing 
Imaging: MRS and FDG-PET (to be done within two weeks of visit). 
Unscheduled Study Visits: 
Study subjects may be asked to return to our research clinic for additional bloodwork to be taken in the event of  
abnormal or missing labs. 
Study subjects whose liver enzymes are > 3 times the ULN, will have their liver enzymes monitored every one to two  
weeks until it returns to baseline. If the liver enzyme levels do not decrease within 2 weeks of follow-up labs, Dr.  
Judith Neugroschl, who will check all laboratory results to maintain PI blind in the study, will communicate to DSMB  
and the medication will be stopped. Study drug will be immediately discontinued if liver enzymes are equal or higher  
than five times the upper normal limit or if clinical jaundice develops. 
Changes to study participants medications should be avoided. Any changes to medications, the participant and their  
caregiver will be instructed to notify Dr. Pereira of those changes. 
Description of the Source Records that Will Be Used to Collect Data About Subjects  
Medical records, neurological examination, mini-mental state exam will be evaluated on screening visit to determine  
eligibility, followed by neuroimaging and neuropsychological testing. 
Description of Data that Will Be Collected Including Long-Term Follow-Up 
Neuroimaging data for FDG-PET and MRS will be used for quantitative analysis for research purposes as well as  
neuropsychological data. 
 
Research Requires HIV Testing 
No 
13. Procedures - Genetic Testing 
 
Genetic Testing Will Be Performed 
Yes 
Guidance and Policies > Future Use Data Sharing and Genetic Research 
   
Genetic Testing Will Be Performed 
No  
for Clinical Purposes 
   
  Genetic test is being done for research purposes only and the following must be present  
in the consent form:  
* a statement that the sample will be used for future Genetic Tests;  


 
* the time period during which the tissue will be stored, or if no time limit is specified, a 
statement that the tissue will be stored for as long as deemed useful for research  
purposes;  
* a description of the policies and procedures to protect patient confidentiality;  
* a statement of the right to withdraw, at any time, consent to future use of the tissue, and 
the name of the organization that should be contacted to withdraw consent;  
* a statement allowing individuals to consent to future contact for any or all purposes, 
including the following: (i) research purposes; (ii) provision of general information about  
research findings; and (iii) information about test on their sample that may benefit them or  
their family members in relation to their choices regarding preventive or clinical care , and  
* a statement explaining the benefits and risks of consenting to future contact.  
     
  
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Initial Application 
Ana Pereira 
 
14. Procedures - Details 
 
Surveys or Interviews 
Yes 
 
Type of Instruments Being Used 
Standardized 
Names of Standardized Instruments 
Standardized neuropsychological testing, MRI/MRS and FDG-PET will be performed as described under "Description  
of Procedures Being Performed". 
Neuropsychological tests are standardized instruments routinely used in the ADRC to test cognition (memory and  
thinking abilities).  
 
 
Audio / Photo / Video Recording 
No 
Deception 
No 
Results of the Study Will Be Shared Yes  
with Subjects or Others How the Results 
Will Be Shared 
During participation in the study subjects will have access to their medical records and any study information that is  
part of that record. MRI structural imaging reading by a radiologist will also be made available to participants. 
Research results (genetic testing and cognitive testing) will not be shared with the participant and are considered for  
research purposes only. 
When the Results Will Be Shared 
The final results of the study may be shared with the participant after the publication.  
At subject's request. 
 


IRB-17-02664 
Initial Application 
Ana Pereira 
15. Consent - Obtaining Consent 
 
Consent Process 
Adult Consent, Legally Authorized 
 Representative (LAR) Permission 
Where and When Consent Will Be Obtained 
Neurology Office and ADRC prior to initiation of any research procedures 
Waiting Period for Obtaining Consent 
The investigator or investigator's representative will explain the study and review the consent document with the  
potential subject and study partner.  The subjects and study partners will also have the opportunity to read the  
consent document on their own.  Ample time will be given for the participant and study partner to ask any questions  
pertaining to the study. 
 
SOP HRP-090 Informed Consent 
Yes 
 Process for Research Is Being 
 Used 
PPHS Worksheets, Checklists and SOPs 
   
Process to Document Consent in 
Will Use Standard Template  
Writing 
Non-English Speaking Participants 
No  
Will Be Enrolled 
Justification for Not Enrolling Non-English Speaking Participants 
To maintain standardization of neuropsychological testing previously performed and previous recruitment at  
Rockefeller University. 


IRB-17-02664 
Initial Application 
Ana Pereira 
16. Consent - Legally Authorized Representative 
Process to Determine Whether an Individual is Capable of Consent 
To ensure that the protocol is consistent with the hospital policy regarding research involving incapacitated adults, 
the study team will comply with Mount Sinai Hospital Policies regarding Incapacity, Policy A3-113 and A3-113.9 
revised  6/12. An attending level physician will be determining whether a potential participant does NOT have 
capacity and authorize a surrogate as appropriate. If participant is found to lack capacity, their legal representative 
will decide how to proceed. If either the subject or legal representative objects to participation then they will not be 
enrolled in the study. If the subject and the legal representative wish to proceed, the legal representative will sign the 
consent form for an incapacitated adult and a verbal assent will be obtained from the subject as well and will be 
documented in the research chart and checked the box at the bottom of the incapacitated consent form. If at any 
point during the course of the study the investigator feels that the subject has lost capacity, a capacity assessment 
will be done. For this capacity assessment, the subject will be asked to reiterate in their own words the purpose of 
the research, what they will need to do as participants in the study, and what the potential risks, benefits, and 
alternatives are. If the patient is found to have the capacity to understand and sign the consent form, the subject will 
sign the consent form. If the subject is found to lack the capacity to understand their participation in the study, the 
subject's LAR will decide how to proceed. 
Prioritized List of Individuals from whom Permission will be Obtained 
This study adheres to the HRP-013 SOP regarding legally authorized representatives. The hierarchy of who is able 
to be considered a legal representative is as follows: i) Court appointed guardian who is specifically given 
authorization to consent to participation in research. ii) A court appointed guardian who is specifically given 
authorization to consent to health care. iii) A previously designated health care proxy iv) Spouse, partner or 
significant other. 
Process for Assent of the Subjects 
Verbal assent will be obtained for incapacitated subjects. 
If the subject is determined to not have capacity at the time of the consent process then the Incapacitated ICF will be  
used.  
  For research conducted in New York State, review “SOP HRP-013 Legally Authorized  
Representatives, Children, and Guardians” to be aware of which individuals in the state  
meet the DHHS and FDA definition of “legally authorized representative." 
  For research conducted outside of New York State, obtain consultation from Mount Sinai  
legal counsel as to the definition of “legally authorized representative” in the jurisdiction(s)  
where you are performing your research.  After receiving consultation with Legal, provide  
an explanation in this section about which individuals are authorized under applicable  law 
to consent on behalf of a prospective subject to their participation in the procedure(s)  
involved in this Human Research. 
      
  
Page 29 of 50 
17. Consent - Documents 
Consent Documents 
Type 
revised consent Adult 
Name 
Consent form Adult  
Upload 
Consent form Adult_30JAN2018.doc 
Type 
revised consent Incapacitated Adult 
Name 
Consent form Incapacitated Adult 


IRB-17-02664 
Initial Application 
Ana Pereira 
Upload 
Consent Templates 
 Process to Determine Whether an 
Individual is Capable of Consent 
To ensure that the protocol is 
consistent with the hospital policy 
regarding research involving 
incapacitated adults, the study team 
will comply with Mount Sinai Hospital 
Policies regarding Incapacity, Policy 
A3-113 and A3-113.9 revised  6/12. 
An attending level physician will be 
determining whether a potential 
participant does NOT have capacity 
and  authorize a surrogate as 
appropriate. If participant is found to 
lack capacity, their legal 
representative will decide how to 
proceed. If either the subject or legal 
representative objects to participation 
then they will not be enrolled in the  
study. If the subject and the legal 
representative wish to proceed, the 
legal representative will sign the 
consent form for an incapacitated 
adult and a verbal assent will be 
obtained from the subject as well and 
will be documented in the research 
chart and checked the box at the 
bottom of the incapacitated consent 
form. If at any point during the course  
of the study the investigator feels that 
the subject has lost capacity, a 
capacity assessment will be done. For 
this capacity assessment, the subject 
will be asked to reiterate in their own 
words the purpose of the research, 
what they will need to do as 
participants in the study, and what the 
potential risks, benefits, and 
alternatives are. If the patient is found 
to have the capacity to understand 
and sign the consent form, the subject 
will sign the consent form. If the  
subject is found to lack the capacity to 
understand their participation in the 
study, the subject's LAR will decide 
how to proceed. 
Prioritized List of Individuals from 
whom Permission will be Obtained 
This study adheres to the HRP-013 
SOP regarding legally authorized 
representatives. The hierarchy of who 
Consent form Incapacitated  
Adult_30JAN2018.docx 


IRB-17-02664 
Initial Application 
Ana Pereira 
is able to be considered a legal 
representative is as follows: i) Court 
appointed guardian who is specifically 
given authorization to consent to 
participation in research. ii) A court 
appointed guardian who is specifically 
given authorization to  onsent to 
health care. iii) A previously 
designated health care proxy iv) 
Spouse, partner or significant other. 
Process for Assent of the Subjects 
Verbal assent will be obtained for 
incapacitated subjects. 
If the subject is determined to not 
have capacity at the time of the 
consent process then the 
Incapacitated ICF will be used.  
 For research conducted in 
New York State, review “SOP 
HRP-013 Legally Authorized  
Representatives, Children, and 
Guardians” to be aware of 
which individuals in the state  
meet the DHHS and FDA 
definition of “legally 
authorized representative." 
 For research conducted 
outside of New York State, 
obtain consultation from 
Mount Sinai legal counsel as 
to the definition of “legally 
authorized representative” in 
the jurisdiction(s)  where you 
are performing your research.  
After receiving consultation 
with Legal, provide an 
explanation in this section 
about which individuals are 
authorized under applicable  
law to consent on behalf of a 
prospective subject to their 
participation in the 
procedure(s)  involved in this 
Human Research. 
     
 


IRB-17-02664 
Initial Application 
Ana Pereira 
18. Data - Collection 
Health Related Information Will Be 
Yes 
 Viewed, Recorded, or Generated 
Description of Health Information That Will Be Viewed, Recorded, or Generated 
Mini Mental State Exam scores, neuropsychological testing and neuroimaging as described in detail under  
"Description of Procedures Being Performed" 
Non-Health Related Information Will No 
 Be Viewed or Recorded 
HIV / AIDS Related Information Will  
Be Viewed or Recorded 
No 
Data That Will Be Viewed, 
Recorded, or Generated Contains 
ANY of the Following Directly 
Identifiable Information 
Yes 
Will Be Viewed 
Name, Social Security Number, Medical 
Record Number, Address by street location, 
Telephone number, Email Address 
Will Be Recorded 
Name, Social Security Number, Medical 
Record Number, Address by street 
location,  Telephone number, All Elements 
of Dates  for Dates Directly Related to an 
Individual  (i.e., Birth Date, Admission Date, 
Discharge 
Date), Email Address 
Data Collection Sheet 
DATA AND SAFETY MONITORING 
PLAN_Mount Sinai and Rockefeller 
University.docx 
         
         
     
Data Collection Source(s) 
Participant, Medical Chart (Paper or 
 Electronic), Data Warehouse, External Site, 
 Other Research Study, Clinical Database 
Page 31 of 50 
19. Data - HIPAA 
Obtaining HIPAA Authorization 
Yes 
How PHI Will Be Protected from Improper Use or Disclosure 
PERSONALLY IDENTIFIABLE INFORMATION WILL NEVER BE KEPT WITH HEALTH INFORMATION. ONLY 
 THE STUDY TEAM WILL HAVE ACCESS TO AN ENCRYPTED SPREADSHEET THAT LINKS A PARTICIPANT'S  
PERSONAL INFORMATION AND THEIR STUDY ID (DE-IDENTIFIER). ALL RESEARCH DATA WILL BE 
DEIDENTIFIED. 
PHI Will Be Destroyed at the 
Yes 
 Earliest Opportunity Consistent  
with the Research 
When and How PHI Will Be Destroyed  


IRB-17-02664 
Initial Application 
Ana Pereira 
DE-IDENTIFIED RESEARCH DATA WILL BE KEPT LOCALLY FOR 7 YEARS FOLLOWING THE COMPLETION 
OF THE LAST SUBJECT IN THE TRIAL. NO PHI IS BEING STORED. PERSONALLY IDENTIFIABLE 
INFORMATION  WILL BE DESTROYED ONCE IT IS NO LONGER NEEDED (I.E. WE NO LONGER HAVE A NEED 
TO CONTACT  THAT PATIENT AS A PART OF STUDY PARTICIPATION). PAPER RECORDS WILL BE 
DESTROYED  FOLLOWING ISMMS GUIDELINES USING SENSITIVE DOCUMENT SHREDDING BINS. 
PHI Will Be Shared 
No 
  PI must attest to the following. 
  * I assure that the protected health information (PHI) will not be disclosed to any other  
person or entity not listed on this form except where required by law or for the authorized  
oversight of this research project. If at any time I want to reuse this PHI for other purposes  
or disclose it to other individuals or entities I will seek approval from the IRB.  
   
  
Page 32 of 50 
20. Data - Storage 
Location Where Data Will Be Stored 
Data will be stored in a secure location during the course of the study and doubled locked at room A20-02a at  
Annenberg building. Only investigators in this protocol will have access to the data files. 
How will the data be stored? 
With a Code That Can Be Linked to the 
Identity of the Participant 
Research Personnel Responsible  
for: 
Ana Pereira 
Accessing Data 
Yes 
Receipt or Transmission of Data 
Yes 
Holding Code That Can Be Linked  
to Identity of Participants 
Yes 
Research Personnel Responsible  
for: 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked 
to Identity of Participants 
Tarah Gustafson 
Research Personnel Responsible  
for: 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked 
to Identity of Participants 
Emily Lampshire, Caroline Meuser 
Research Personnel Responsible  
for: 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked 
to Identity of Participants 
Florence Lau 


IRB-17-02664 
Initial Application 
Ana Pereira 
Research Personnel Responsible  
for: 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked 
to Identity of Participants 
Caroline Meuser 
Research Personnel Responsible  
for: 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked 
to Identity of Participants 
Hillel Grossman 
Research Personnel Responsible  
for: 
Julie Ciardullo 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked  
to Identity of Participants 


 
Research Personnel Responsible  
for: 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked 
to Identity of Participants 
Gina Garcia Camilo 
Research Personnel Responsible  
for: 
Judith Neugroschl 
Accessing Data 
Yes 
Receipt or Transmission of Data 
Yes 
Holding Code That Can Be Linked  
to Identity of Participants 
Yes 
Research Personnel Responsible  
for: 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked 
to Identity of Participants 
Allison Ardolino 
Research Personnel Responsible  
for: 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked 
to Identity of Participants 
Amy Aloysi 
Research Personnel Responsible  
for: 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked 
to Identity of Participants 
Jonathan Greenberg
Research Personnel Responsible  
for: 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked 
to Identity of Participants 
Nelly Velasco 
Research Personnel Responsible  
for: 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked 
to Identity of Participants 
Martin Ljekocevic 
Research Personnel Responsible  
for: 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked 
to Identity of Participants 
Margaret Sewell 
Research Personnel Responsible  
for: 
Clara Li 


 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked  
to Identity of Participants 
Research Personnel Responsible  
for: 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked 
to Identity of Participants 
Michael Kinsella 
Research Personnel Responsible  
for: 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked 
to Identity of Participants 
Kelly Pun 
Research Personnel Responsible  
for: 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked 
to Identity of Participants 
Caroline Meuser
Research Personnel Responsible  
for: 
Chloe Larson 
Accessing Data 
Receipt or Transmission of Data 
Holding Code That Can Be Linked  
to Identity of Participants 
Duration Data Will Be Stored 
15 years 
Steps That Will Be Taken to Secure the Data During Storage, Use, and Transmission 
Data will be stored in a secure location during the course of the study and doubled locked at room A20-02a at  
Annenberg building.  
Imaging conducted at Citigroup Bio-imaging at Weill Cornell Medicine will be coded as below and kept secure and  
double locked on CDs at Dr. Dikoma's Shungu office (PI at Weill Cornell Medicine for Neuroimaging portion of the  
study)  
APE-XXX-101a; APE-XXX-102a, etc., will be used for the first MRS scan. APE-XXX-201a; APE-XXX-202a, etc., will  
be used for the first PET scan. 
If a subject undergoes a second scan (e.g., a second PET scan), they will be coded : APE-XXX-201b, APEXXX-
202b, etc. 
After completion of the study the data source will be stored in a secure location for a period of 15 years.  
 
Power Analysis/Data Analysis Plan (Including Any Statistical Procedures) 
In a previous study (Alexander, 2002- ref  45) using longitudinal FDG-PET to evaluate cerebral metabolic decline  in 
similar subjects, it was concluded that "24 patients with Alzheimer's disease per active treatment and placebo  group 
would be needed to detect a 33% treatment response with p # 0.05 (two- tailed) and 80% power". A previous study of 
memantine, which affects the glutamatergic system through a different mechanism, suggested that significant 
treatment-related differences in glucose metabolism measured using FDG PET in posterior cingulate and precuneus 
could be detected in Alzheimer’s disease patients at 80% power, 2-tailed t-test, significance at P<0.05 (uncorrected 
for multiple comparisons), with as few as 16 participants per arm (Wang T, Huang Q et a. J Clin Psychopharmaco 


 
2013). Our primary outcomes will be FDG-PET and NAA results. In (Adalsteinsson, 2000 - ref 24), the observed 
mean change of  NAA concentration over a year was #12%, with a standard deviation (SD) of 15%, compared to no 
change among  the healthy controls with an SD of 8%. Hence, we expect a change of #6% over 6 months with an SD 
of 10%  among controls. If riluzole were able to slow down disease progression, we would expect an SD of 8%. 
Given that the consequences of type I errors in this pilot study are substantially lower than in a later-stage 
confirmatory trial, we will accept a level of .20 (two- sided), resulting in a nominal sample size requirement of 21 per 
group. Subjects who are dropping out will be replaced.   
 
As per IRB Approved Continued Review (dated 11/25/2019), we re-visited power analysis and changed total 
completed subjects across sites to at least 40 (rather than 48 originally planned).  
 
Analysis plan by ADM dx for FDG PET added to protocol prior to unblinding and approved by IRB on  
06/18/2020: 
 
FDG-PET analysis plan from ADMdx prepared by Dawn Matthews 
Background 
In this exploratory Phase II clinical trial, FDG PET images, measuring cerebral glucose metabolism, have been 
acquired on patients with a clinical diagnosis of mild Alzheimer’s disease before and after 6 months of treatment with 
riluzole or placebo.  Volumetric MRI T1 weighted scans have also been acquired at these timepoints. 
 
Analysis Objectives  
The primary analysis objective is to compare the 6-month longitudinal change in regional cerebral glucose metabolism 
in patients treated with riluzole vs. those treated with placebo. 
 
Secondary objectives are to: 
• 
evaluate relationships between covariates of age, sex, and ApoE4 carrier status to changes in glucose 
metabolism, and compare longitudinal change in younger vs. older participants 
• 
characterize and stratify patients at baseline with regard to pre-treatment patterns and severity of 
hypometabolism; compare longitudinal change in placebo vs. treatment within these strata   
• 
compare longitudinal change in regional brain volume between patients treated with riluzole vs. placebo 
• 
correlate baseline glucose metabolism and changes in FDG PET and volumetric measures to clinical endpoints 
 
Image Quality Control and Processing 
Prior to unblinding, all scans will be quality controlled and processed.  Quality control of FDG PET scans includes 
verification that all brain anatomy was included in the scan, checks for adequate image signal (counts), qualitative 
and quantitative evaluation of inter-frame motion, review for potential emission-transmission scan misalignment 
(asymmetry), and checks for occipital or other artifact. Quality control of volumetric MRI scans includes verification 
that all brain anatomy was included in the scan, checks for adequate gray/white contrast and resolution, review for 
motion artifact, and examination for other image artifact that could impact processing.  
 
FDG PET scans will be motion corrected and the timeframes averaged to create a single scan per patient per visit. 
Six-month visit PET scans will be co-registered to their baseline PET scan, and PET scans will be co-registered to 
their corresponding volumetric MRI. FDG PET images will be smoothed to a uniform resolution consistent with 
images from the Alzheimer’s Disease Neuroimaging Initiative. 
 


 
Volumetric MRI scans will be processed using Freesurfer version 7.1, producing segments (binary masks) that define 
anatomical regions in the native space of the MRI scan.  
 
MRI scans will be spatially transformed to a common template and the transforms applied to the FDG PET scans.  FDG 
PET scans will be intensity normalized to whole brain.  
 
Quantitative Measurement 
Prior to unblinding 
The anatomical segments derived using Freesurfer will be smoothed and thresholded, and used to measure regional 
values on the FDG PET scans.   
 
FDG PET scans will also be evaluated using ADMdx’s Dementia Differentiation Classifier and AD Progression 
Classifier.  These classifiers compare the scans to previously developed patterns that allow quantitation of the degree 
to which a scan expresses an Alzheimer’s like disease pattern. The AD Progression scores can then be used in 
statistical analysis. 
 
These steps will produce a set of blinded values. 
 
Following unblinding 
Once group designations are available, the spatially normalized, intensity normalized images will be evaluated using 
ADMdx’s multivariate classification software.  This allows identification of patterns of glucose metabolism, or in the 
case of MRI, volumetric measures, that differentiate between classes.  Analyses will include the following: 
- 
Comparison of placebo and riluzole treatment groups at baseline 
- 
Two class analyses of placebo group at baseline and 6 months, and riluzole group at baseline and 6 months 
- 
Combined analyses of placebo and riluzole groups at baseline and 6 months 
- 
Subgroup analyses using age, baseline severity, and ApoE4 carrier status as stratification factors 
 
The outputs of the classifier analyses are numeric scores and metabolic patterns of hypometabolism and preservation 
or hypermetabolism relative to whole brain (for FDG) or a listing of brain volumes contributing to group differentiation 
with relative weights.  The numeric scores reflect pattern expression in each case.  
 
Region of interest values and classifier scores will be evaluated in comparison to clinical endpoints at baseline and with 
regard to longitudinal change. 
 
Patients who exceed the longitudinal time window by more than one month will be flagged and excluded from these 
group analyses, but will be then scored against the patterns derived. This will prevent them from influencing the 
patterns, but will still allow for evaluation. 
 
Statistical Analysis 
 
The FDG PET analysis primary endpoints are: 
 
• 
Regional SUVRs:  hippocampus, posterior cingulate, precuneus, lateral temporal, inferior parietal, and middle 
frontal 
 
Other endpoints: 
• 
AD Progression score 
• 
Classifier scores from the combined multivariate analysis of placebo and riluzole at baseline and after 6 months 
 
 
Endpoints will be evaluated using t-tests in JMP version 15.1 (SAS) with adjustment for baseline covariates if these are 
determined to differ between groups or to be significant in the analyses. Covariates evaluated will be age, sex, baseline 
endpoint measure, and ApoE4 status. A p-values of 0.05 will be considered significant. Because this is an exploratory 
study with a limited number of patients, correction for multiple comparisons, though evaluated, will not be used to 
determine significance. 


 
 
IRB-17-02664 
Initial Application 
Ana Pereira 
 
 
Data Monitoring Committee  
Description 
DATA AND SAFETY MONITORING 
PLAN_Mount Sinai and Rockefeller 
University.docx 
DMC Charter Available 
Yes 
Data Monitoring Committee Charter DATA AND SAFETY MONITORING 
PLAN_Mount Sinai and Rockefeller 
University.docx 
Will the Research Include Data  
Coordinating Center Activities? 
No 
IRB-17-02664 
Initial Application 
Ana Pereira 
 
21. Specimen Banking 
 
Where the Specimens Will Be Stored 
Blood samples in freezers at ADRC and Neurology Department will be stored with participants' codes. No identifiers  
will be associated with samples in freezers. 
Sources are stored in the research office room A20-02A at the Annenberg building under double lock with only  
access by PI and research coordinator specified for this study.  
Imaging conducted at Citigroup Bio-imaging at Weill Cornell Medicine will be coded as below and kept secure and  
double locked on CDs at Dr. Dikoma's Shungu office (PI at Weill Cornell Medicine for Neuroimaging portion of the  
study)  
APE-XXX-101a; APE-XXX-102a, etc., will be used for the first MRS scan. APE-XXX-201a; APE-XXX-202a, etc., will  
be used for the first PET scan. 
If a subject undergoes a second scan (e.g., a second PET scan), they will be coded : APE-XXX-201b, APEXXX-
202b, etc. 
Duration Specimens Will Be Stored 
15 years 
How Researchers Will Gain Access to Specimens 
through code identifiers 
APE-XXX-001; APE-XXX-002; etc. will be used for lab samples. 
APE-XXX-101a; APE-XXX-102a, etc., will be used for the first MRS scan. APE-XXX-201a; APE-XXX-202a, etc., will  
be used for the first PET scan. 
If a subject undergoes a second scan (e.g., a second PET scan), they will be coded : APE-XXX-201b, APEXXX-
202b, etc. 
All codes will not be linked to any subject identifiers. 
Information To Be Stored or Associated with Each Specimen 
Each specimen will be associated with a code as above. Stored samples will not be associated with identifiers. 
 
Specimens Will Be Released 
No 


IRB-17-02664 
Initial Application 
Ana Pereira 
 
Funding Source Name 
Alzheimers Drug Discovery Foundation 
Contact 
Niyati Thakker 
Funding Category 
Foundation 
Meditrack (https://contracts.tractmanager.com/Contracts/Login.aspx) 
Grant or Contract Title 
Alzheimer's Drug Discovery Foundation: Glutamatergic Dysfunction in Cognitive 
Aging:  Riluzole in Mild Alzheimer's Disease 
Grant or Contract  
20120703; GCO #18-0428  Number 
Funding Status 
Pending 
Project Initiated By 
Investigator 
Grant / Contract Principal Ana Pereira 
Investigator (PI) 
Department 
Neurology 
Department 
Phone 
Neurology 
Email 
Ana.Pereira@mssm.edu 
Protocol and Funding  
Proposal Match 
Identify Substantive 
Differences Between 
Protocol and Funding 
Proposal 
Yes 
Funding Source Name 
Dana (Charles A.) Foundation, Inc. 
Contact 
Edward Rover 
Funding Category 
Foundation 
Meditrack (https://contracts.tractmanager.com/Contracts/Login.aspx) 
Grant or Contract Title 
Dana Foundation grant : Understanding the susceptibility of Glutamatergic Neural  
Circuits to Alzheimer's Disease: Clinical and Basic Studies 
Grant or Contract  
Number 
GCO # 18-0664 
Funding Status 
Pending 
Project Initiated By 
Investigator 
Grant / Contract Principal Ana Pereira  
Investigator (PI) 
Department 
Neurology 
Department 
Neurology 
Phone 
Email 
Ana.Pereira@mssm.edu 
Protocol and Funding 
Yes 
Proposal Match 
Identify Substantive 
Differences Between 
Protocol and Funding 
Proposal 


 
22. Radiation Safety 
Study protocol involves any of the 
Yes  
following Radiological Procedures  
requiring use of Dosimetry Chart 
           
* Radiological procedures that are administered in addition to those that the participant 
would receive as part of standard care (radiation above and beyond standard of  care)  
* Radiological procedures that are administered solely for experimental or research 
purposes (would NOT be otherwise administered)  
* Standard of care radiological procedures that are being altered or performed differently 
for research  
* Use of radiological procedures that are the subject of the investigation (comparison 
studies)  
           
       
            Dosimetry Chart 
            Please fill out the chart and attach it below. 
         
Dosimetry Chart 
Copy of AP_Dos Wiz_1.22.2018.xlsx 
Study protocol involves any of the 
Yes  
following Radiological Procedures 
           
* Use of an investigational radiopharmaceutical, or use of an approved radiopharmaceutical 
for an investigational purpose  
* Use of investigational radiotherapy, or use of approved radiotherapy for an investigational 
purpose  
* Use of fluoroscopy  
* Radiation exposure to children or pregnant women  
* Radiation exposure to healthy subjects (ADULTS)  
* Use of an investigational radiologic device (such as an experimental scanner), or use of 
an approved device for an investigational purpose  
           
       
Study protocol involves any of
 No  the following Standard of Care  
Radiological Procedures (including  
projects where discrete Standard  of 
Care Imaging is acquired in  addition to 
Research Imaging) 
           
* CT imaging  
* Nuclear medicine  
* Radiography  
* Fluoroscopy  
* Radiation-based therapy  
* PET/CT  
           


 
 stored in a secure area and in such a way to restrict access to authorized personnel  
only as defined in the protocol. Additionally, all associated records will be stored in a  
restricted area and/or locked. 
Justification Why Any of  
the Above Distribution  
Criteria Cannot Be Met 
 
 
 


 
 
23. Attachments 
Type 
Name 
Version Status 
Filename 
Uploaded 
 Date 
Approval Document 
RU IRB approval.pdf 1 
approvedRU IRB approval.pdf 10/04/2017 
Approval Document 
WCMC IRB 
 approval.pdf 
1 
approvedWCMC IRB 
 approval.pdf 
10/04/2017 
Other - Other IRB  
Correspondance 
Rockefeller study  
application 
1 
approvedPDF_iRIS2Study 
 Application_.pdf 
10/23/2017 
External IRB 
 Approval Document 
RU IRB approval.pdf 1 
approvedRU IRB approval.pdf 10/23/2017 
Data Monitoring 
 Committee 
 Description 
DATA AND SAFETY 
 MONITORING 
 PLAN_Mount Sinai  
and Rockefeller  
University.docx 
1 
approvedDATA AND SAFETY 
 MONITORING 
 PLAN_Mount Sinai  
and Rockefeller  
University.docx 
10/23/2017 
Other - Other IRB  
Correspondance 
General Rational and 
 Graphs_Specific 
 Aims 
1 
approvedScan_20171026 
 (3).pdf 
10/26/2017 
FDA - FDA Approval  
of Drug or IND  
Determination 
IND exempt letter 
1 
approvedScan_20171026 
 (2).pdf 
10/26/2017 
FDA - Package Insert 
for Approved Drug 
Study medication  
insert 
1 
approvedRiluzole_Prescription  
Insert.pdf 
10/26/2017 
Data Collection Sheet DATA AND SAFETY 
 MONITORING 
 PLAN_Mount Sinai  
and Rockefeller  
University.docx 
1 
approvedDATA AND SAFETY 
 MONITORING 
 PLAN_Mount Sinai  
and Rockefeller  
University.docx 
10/27/2017 
Data Monitoring 
 Committee Charter 
DATA AND SAFETY 
 MONITORING 
 PLAN_Mount Sinai  
and Rockefeller  
University.docx 
1 
approvedDATA AND SAFETY 
 MONITORING 
 PLAN_Mount Sinai  
and Rockefeller  
University.docx 
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10/19/2018 
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