Teriflunomide (Aubagio) Effects on Cognitive and Vocational Outcomes, as Related to Neurodegeneration in Multiple Sclerosis: A Prospective, Observational, Single-blinded Study.
Conditions: Multiple Sclerosis
Sponsor: State University of New York at Buffalo

 
University at Buffalo Institutional Review Board (UBIRB) 
Office of Research Compliance | Clinical and Translational Research Center Room 5018 
875 Ellicott St. | Buffalo, NY 14203 
UB Federalwide Assurance ID#: FWA00008824 
PROTOCOL TITLE: Teriflunomide (Aubagio®) Effects on Cognitive and 
Vocational Outcomes, as Related to Neurodegeneration in Multiple 
Sclerosis: A prospective, observational, single-blinded study. 
 
Page 1 of 43 
 
 
INSTRUCTIONS: Complete Research Protocol (HRP-503) 
 Depending on the nature of what you are doing, some sections may 
not be applicable to your research.  If so, you must provide the 
reason why the section is not applicable for the response.  For 
example, most behavioral studies would answer all questions in 
section 30 with words to the effect of “drugs and medical devices 
are not used in this study.” 
 When you write a protocol, keep an electronic copy. You will need 
to modify this copy when making changes. 
 Do not remove the italics instructions or headings. 
 If you are pasting information from other documents be sure to use 
the “Merge Formatting” paste option so that the formatting of the 
response boxes is not lost.  If information is presented outside of 
the response boxes, it will not be accepted.  
 If this study involves multiple participant groups who participate 
in different research procedures, consent processes, etc., be 
certain to provide information in each applicable section for each 
participant group and clearly label each participant group within 
a section or subsection.  
 
 
PROTOCOL TITLE: 
Include the full protocol title. 
Teriflunomide (Aubagio®) Effects on Cognitive and Vocational 
Outcomes, as Related to Neurodegeneration in Multiple Sclerosis: A 
prospective, observational, single-blinded study. 
PRINCIPAL INVESTIGATOR: 
Name 
Department 
Telephone Number 
Email Address 
Ralph HB Benedict 

 
Page 2 of 43 
Revised:October 10 2017 
Neurology 
716-323-0556 
Benedict@buffalo.edu 
VERSION NUMBER: 
Include the version number of this protocol. 
Version 7.  
DATE: 
Include the date of submission or revision. 
  April 6, 2020 
Grant Applicability: 
Describe whether or not this protocol is funded by a grant or contract and if so, 
what portions of the grant this study covers. 
Genzyme will financially support the work of the Investigator as it 
pertains to the conduct of this study. 
 

 
Page 3 of 43 
Revised:October 10 2017 
Table of Contents 
1.0 
Objectives .......................................................................................................... 4 
2.0 
Background ......................................................... Error! Bookmark not defined. 
3.0 
Inclusion and Exclusion Criteria .......................... Error! Bookmark not defined. 
4.0 
Study-Wide Number of Subjects (Multisite/Multicenter Only) ..Error! Bookmark 
not defined. 
5.0 
Study-Wide Recruitment Methods (Multisite/Multicenter Only)Error! Bookmark 
not defined. 
6.0 
Multi-Site Research (Multisite/Multicenter Only) . Error! Bookmark not defined. 
7.0 
Study Timelines .................................................. Error! Bookmark not defined. 
8.0 
Study Endpoints .................................................. Error! Bookmark not defined. 
9.0 
Procedures Involved ............................................ Error! Bookmark not defined. 
10.0 
Data and Specimen Banking ................................ Error! Bookmark not defined. 
11.0 
Data Management................................................ Error! Bookmark not defined. 
12.0 
Provisions to Monitor the Data and Ensure the Safety of Subjects ............... Error! 
Bookmark not defined. 
13.0 
Withdrawal of Subjects........................................ Error! Bookmark not defined. 
14.0 
Risks to Subjects ................................................. Error! Bookmark not defined. 
15.0 
Potential Benefits to Subjects ............................... Error! Bookmark not defined. 
16.0 
Vulnerable Populations ........................................ Error! Bookmark not defined. 
17.0 
Community-Based Participatory Research ............ Error! Bookmark not defined. 
18.0 
Sharing of Results with Subjects .......................... Error! Bookmark not defined. 
19.0 
Setting ................................................................ Error! Bookmark not defined. 
20.0 
Resources Available ............................................ Error! Bookmark not defined. 
21.0 
Prior Approvals ................................................... Error! Bookmark not defined. 
22.0 
Recruitment Methods........................................... Error! Bookmark not defined. 
23.0 
Local Number of Subjects.................................... Error! Bookmark not defined. 
24.0 
Confidentiality .................................................... Error! Bookmark not defined. 
25.0 
Provisions to Protect the Privacy Interests of Subjects.........Error! Bookmark not 
defined. 
26.0 
Compensation for Research-Related Injury........... Error! Bookmark not defined. 
27.0 
Economic Burden to Subjects .............................. Error! Bookmark not defined. 
28.0 
Consent Process .................................................. Error! Bookmark not defined. 
29.0 
Process to Document Consent in Writing.............. Error! Bookmark not defined. 
30.0 
Drugs or Devices ................................................. Error! Bookmark not defined. 
 

 
Page 4 of 43 
Revised:October 10 2017 
1.0 
Objectives 
1.1 Describe the purpose, specific aims, or objectives. 
This is a prospective, observational, single-blinded, longitudinal study of 
terinflunomide effects on cognitive performance in patients with multiple 
sclerosis (MS) over 24 months. The primary aim of this study is to 
determine the effect of teriflunomide (Aubagio®) on cognitive abilities in 
patients with relapsing-remitting multiple sclerosis (RRMS).  There are 
two secondary objectives, to [a] relate changes in cognition to vocational 
problems in employed participants, and [b] determine MRI correlates of 
change in cognition, more specifically gray-matter (GM) volume metrics, 
which we believe reflect neurodegeneration. 
1.2 State the hypotheses to be tested. 
Employed relapsing- remitting MS patients treated with teriflunomide 
(Aubagio®) are expected to follow a trajectory of cognitive performance 
and vocational stability over time, similar to that of healthy controls. 
2.0 
Background 
2.1 Describe the relevant prior experience and gaps in current 
knowledge. 
Cognitive Dysfunction in MS. Cognitive impairment constitutes a 
relevant clinical aspect of multiple sclerosis (MS).  Depending on the 
disease phase and type, 40-65% of MS patients develop various degrees of 
cognitive dysfunction [1, 2].  These changes may begin very early in the 
disease process [3, 4].  Difficulties with learning and memory and slowed 
information processing speed, along with higher order functions such as 
abstraction, problem solving, and behavioral inhibition impact continued 
employment, daily function, and overall quality of life in MS [5-9].   
Quantitative measurement of cognitive impairment in MS is frequently 
achieved through neuropsychological (NP) evaluation.  These evaluations 
are conducted by highly trained specialists, using a variety of 
psychometrically robust measures [10, 11].  These measures are validated 
through extensive study of their relationships to clinically relevant 
phenomena such as employment status, functional independence, and 
progression as detected by MRI.  Some examples of highly valid measures 
in MS are the Symbol Digit Modalities Test (SDMT) [12], Brief 
Visuospatial Memory Test- Revised (BVMT-R) [13], and Paced Auditory 
Serial Addition Test (PASAT) [14].  Relevance of these measures has 
been demonstrated by their relationship to deep gray matter and cortical 
atrophy [15, 16], as well as employment [11].   
Cognitive Impairment and GM Atrophy in MS.  MS is primarily a 
demyelinating disease of the central nervous system (CNS), but many 
patients also undergo progressive brain atrophy, especially in the gray 
matter (GM) [17-19].  GM atrophy plays a particularly prominent role in 

 
Page 5 of 43 
Revised:October 10 2017 
MS cognitive decline [20-22].  White matter (WM) demyelination is also 
correlated with cognitive impairment [23] but in several studies comparing 
multiple measures, central atrophy or GM volume indices accounted for 
most variance in predicting cognitive impairment [24-27]. 
The paired thalamic nuclei are GM structures on both sides of the third 
ventricle and are involved in a wide range of neurological functions 
including motor, sensory, integrative, and higher cortical functions  [28].  
Thalamic location, unique neurologic functions, widespread cortical and 
subcortical connections and vulnerability to MS pathology from the 
earliest clinical disease stages  [29-32] make it a critical structure for 
examining neurodegeneration [33, 34].  Given that progressive pathology 
of the thalamus has been shown in all different MS disease types [31, 32, 
35-37] and that thalamic volume loss is detected in pediatric MS patients 
[38, 39], measurement of thalamic atrophy may be a useful outcome in 
MS clinical trials for the following reasons: a) meaningful change over 
time - thalamic atrophy develops more rapidly than whole brain, GM or 
WM atrophy [40, 41]; b) clinically meaningful change - in recent studies, 
thalamic atrophy was the one of MRI outcomes most significantly 
associated with development of clinically definite MS, not being free of 
clinical disease and having disability progression [40, 41]; c) detectable 
early in the disease - thalamic pathology was detected in CIS patients from 
the first onset of disease [40-42] and in early pediatric patients [43] and d) 
not affected by water fluid shifts - by its location and size, the thalamus is 
potentially less affected by the pseudoatrophy effect than other global or 
tissue-specific brain volume measures [28, 44].  All of this makes the 
measurement of thalamic atrophy an ideal candidate in future clinical 
trials, as recently suggested [28, 41].  However, the role of teriflunomide 
in slowing down thalamic atrophy progression is unknown.  
MS studies focusing on deep GM and NP testing reveal robust correlation 
between thalamus volume and a range of cognitive tests.  In one study [45] 
regression models controlling for the influence of third ventricle width, a 
proposed proxy for thalamus atrophy, also retained cortical GM regions in 
predicting performance on tests of memory and executive function.  
Likewise, thalamus and putamen volumes were retained in regression 
models predicting cognition, after accounting for cortical volume [24].  
These studies lead us, and others [27, 30], to speculate that thalamus 
atrophy is an independent predictor of cognitive impairment, and is 
relevant in the progression of MS neurological disability in MS. The effect 
of teriflunomide on slowing down the progression of cognitive impairment 
in relapsing MS patients is unknown. 
2.2 Describe any relevant preliminary data.  
Cognition and Work Disability in MS.  MS is commonly diagnosed in 
the third or fourth decade of life, in the prime of career development, thus 
greatly reducing lifetime achievement [46, 47].  Within five years of 
diagnosis half of individuals with MS have exited the work force and 

 
Page 6 of 43 
Revised:October 10 2017 
within 15 years, two-thirds are unemployed [47].  Unemployment 
certainly impacts quality of life, both in terms of economic loss as well as 
lower self-esteem and risk of depression - work provides a sense of 
identity and has been found to improve long-term health [48] and quality 
of life [49]. 
Cognitive impairment is a chief driver of work disability in MS [50-52].  
The problem is linked to underlying white matter demyelination, as well 
as progressive gray matter atrophy [17-19].  While studies show that 
cognitive impairment leads to work disability [50-53], most research 
employed a dichotomized outcome, designating patients as either 
employed or disabled.  As noted in a recent topical review [54] this 
dichotomy misses more subtle work-related problems that impact patients 
prior to job loss. 
There is considerable interest in improving clinical outcome measures in 
MS research.  The PI, Dr. Benedict, is a board member of the NINDS 
Common Data Elements initiative [55], as well as the Multiple Sclerosis 
Outcome Assessments Consortium (MSOAC), a coalition of industry, 
academia, patient representatives, FDA, EMA, the Critical Path Institute, 
and the National MS Society [56].  He chaired the CDE cognition sub-
committee that proposed optimal cognitive function metrics for MS 
research.  The MSOAC will develop new standards for assessing 
outcomes in clinical trials of MS therapies.  Dr. Benedict is also co-chair 
of the panel for the Brief International Cognitive Assessment in MS [57].  
These initiatives highlight the relevance of cognition to patient care and 
outcomes in clinical trials, but as pointed out in a recent topical review, we 
lack understanding of when changes on NP outcomes become clinically 
meaningful [54].   
Toward this end, we are pursuing MS vocational disability research with 
two objectives, one clinical, one methodological.  First, our long-term goal 
is to track work-related problems more or less continuously so that 
transient problems can be identified by clinicians before patients lose work 
and incur other hardships.  Second, by monitoring work status with more 
fine-tuned outcomes, we hope to correlate such changes with increments 
of change on NP metrics.  Self-report surveys of work problems 
emphasizing self-appraisal have been developed [58].  Our approach is 
novel in that it is web-based, and emphasizes behaviorally-observed work 
events, not self-appraisal of capacity. 
To lay the groundwork for the project, we have developed a web-based 
vocational monitoring survey called the MS Vocational Monitoring 
Survey (MSVMS) using the Vovici survey platform.  The survey draws 
upon a variety of sources (e.g, the job accommodation network, National 
MS society, and current academic literature) for items that assess work 
events, vocational accommodations, and intervention strategies.  Formats 
have been tested to minimize typing and computer functions that might be 
difficult for individuals with MS, and focus groups of MS patients 

 
Page 7 of 43 
Revised:October 10 2017 
provided feedback on content and presentation.  Approximately 49% of 
participants have taken the survey a second time, and 20% have taken it a 
third time.  Feedback has been very positive, with some respondents 
expressing willingness to participate in subsequent phases of the research. 
At the time of this writing we have enrolled approximately 250 patients in 
the program.  In addition, we have just had a pilot study of 52 patients 
accepted for publication [59].  Participants were employed in a variety of 
professions/fields from the US, Canada, and UK. Many participants have 
reported work-related problems and/or receiving job accommodations, 
confirming the relevance of the proposed research.  The patients 
completed the vocational web survey and a clinical assessment.  Testing 
included the Timed 25 Foot Walk [T25FW] [60], Nine-Hole Peg Test 
[NHPT] [61], Beck Depression Inventory Fast Screen [BDIFS] [62] , 
California Verbal Learning Test, 2nd Edition [CVLT2] [63],  Brief Visual 
Memory Test Revised [BVMTR] [13], Symbol Digit Modalities Test 
[SDMT] [64], and the Paced Auditory Serial Addition Test [PASAT] [14].  
Thus, the exam spans the domains of ambulation, upper extremity motor 
function, cognition, and depression, not unlike the newer versions of the 
MSFC being proposed [65]. 
The mean number of hours worked per week was 36.7+8.3, range 08-60.  
Median annual salary was $45,000 USD.  Participants were employed in a 
wide range of fields and job titles; the most common, teachers, professors, 
administrators, mechanics, bank tellers, and one police officer.  No 
participant reported recent change in job title or requirements.  
Participants reported that they had held their current position for from 1 to 
38 years (median 6 years).  The majority (n=40) reported having disclosed 
to their employer having MS.  The web survey also includes the MS 
Neuropsychological Screening Questionnaire (MSNQ) [66], and the mean 
MSNQ for the sample was 20.7+10.5.   
Regarding negative work events, only 1 patient reported being formally 
disciplined by their employer.  However, 5 reported verbal reprimands and 
7 reported a decrease in scheduled work hours.  Two patients reported 
diminution of job responsibilities and 4 had undergone mandated 
additional retraining. 
Regarding accommodations, the majority of patients (n=34) did not report 
working extra hours at home in order to complete tasks or “catch-up,” but 
the range of extra unpaid hours for the remaining 16 patients was from 2 
to 20.  Nine patients had been allowed flexible work hours.  Among the 
more common specific accommodations were periodic rest breaks (n=4), 
additional time to complete tasks (n=4), and permission to work from 
home (n=8). 
Logistic regression models were undertaken to determine which clinical 
factors are most predictive of vocational status.  The model predicting 
negative work events [R2 = 0.54] included PASAT [B = -0.092, p = 0.026] 

 
Page 8 of 43 
Revised:October 10 2017 
and BDIFS [B = 0.814, p = 0.002], correctly classifying 81% of cases.  
The group means are presented in Figure 1.  Patients reporting negative 
work events were found to have lower performance on PASAT and higher 
scores on the BDIFS.  The effect size d for PASAT was 0.7 and for 
BDIFS was 1.4.  The model predicting accommodations included PASAT 
[p = 0.032] and T25FW [p = 0.022], correctly classifying 70% of cases 
[R2 = 0.30].  The model discriminating patients with decrease in scheduled 
work hours from normally scheduled counterparts retained [R2 = 0.30] 
PASAT [p = 0.05] and BDIFS [p = 0.05], correctly classifying 90% of 
cases.   
Figure 1.  Sub-sample Means for Stable Patients vs Patients Reporting 
Negative Work Events and Accommodations. 
MS patients were divided into two groups based on reports of negative 
work events and use of accommodations.  Patients reporting no such 
events are categorized as stable.   
Four domains of clinical status are assessed: ambulation = Timed 25 
Foot Walk, cognition = Paced Auditory Serial Addition Test, patient 
reported neuropsychological symptoms = MS Neuropsychological 
Screening Questionnaire, depression = Beck Depression Inventory Fast 
Screen. 
 
 
 

 
Page 9 of 43 
Revised:October 10 2017 
 
We believe that these preliminary results show that the proposed approach 
is feasible and valid. Now, we propose to combine this refined vocational 
status monitoring with an analysis of the effects of teriflunomide on 
cognition and MRI.  Ralph H. B. Benedict, PhD, Professor in the UB 
Neurology Department, will serve as the Principal Investigator and will be 
responsible for directing the project. 
2.3 Provide the scientific or scholarly background for, rationale for, and 
significance of the research based on the existing literature and how 
will it add to existing knowledge. 
The background clearly shows that MS cognitive dysfunction is common 
and is related to GM atrophy, and is a primary driver of work disability.  
However, we do not know how treatment with teriflunomide (Aubagio®) 
impacts GM atrophy and cognition, or how any hypothesized benefit 
would carry over to work capacity.  We will address these questions in a 
sample of 30 relapsing MS patients treated with teriflunomide.  The 
project will be carried out in conjunction with a concurrent study on MRI 
in teriflunomide treated patients (R Zivadinov, PI).  An information 
processing speed index and a memory composite index will be calculated 
from conventional, validated neuropsychological tests as recommended by 
consensus opinion publications.  Conventional clinical metrics for overall 
neurological disability will also be assessed.  For working participants, 
vocational status will be monitored using a newly developed on line 
survey called the MS Vocational Monitoring Survey (MSVMS).  Regional 
GM atrophy, as defined by measurement of thalamic and cortical atrophy, 
will serve as neurodegeneration outcomes.  We are not seeking funds to 
cover MRI acquisition or analysis, as this aspect of the study will be 
covered in Dr. Zivadinov’s proposal. 
 
2.4 Include complete specific citations/references.  
1. 
Rao SM, Leo GJ, Bernardin L, Unverzagt F: Cognitive 
dysfunction in multiple sclerosis. I. Frequency, patterns, and 
prediction. Neurology 1991, 41:685-691. 
2. 
Benedict RHB, Cookfair D, Gavett R, Gunther M, Munschauer F, 
Garg N, Weinstock-Guttman B: Validity of the Minimal Assessment of 
Cognitive Function in Multiple Sclerosis (MACFIMS). Journal of the 
International Neuropsychological Society 2006, 12:549-558. 
3. 
Feuillet L, Reuter F, Audoin B, Malikova I, Barrau K, Cherif AA, 
Pelletier J: Early cognitive impairment in patients with clinically 
isolated syndrome suggestive of multiple sclerosis. Mult Scler 2007, 
13(1):124-127. 
4. 
Glanz BI, Holland CM, Gauthier SA, Amunwa EL, Liptak Z, 
Houtchens MK, Sperling RA, Khoury SJ, Guttmann CR, Weiner HL: 

 
Page 10 of 43 
Revised:October 10 2017 
Cognitive dysfunction in patients with clinically isolated syndromes or 
newly diagnosed multiple sclerosis. Mult Scler 2007, 13(8):1004-1010. 
5. 
Simmons RD, Tribe KL, McDonald EA: Living with multiple 
sclerosis: longitudinal changes in employment and the importance of 
symptom management. Journal of Neurology 2010, 257(6):926-936. 
6. 
Benedict RHB, Zivadinov R: Risk factors for and management 
of cognitive dysfunction in multiple sclerosis. Nat Rev Neurol 2011, 
7(6):332-342. 
7. 
Patti F, Pozzilli C, Montanari E, Pappalardo A, Piazza L, Levi A, 
Onesti E, Pesci I: Effects of education level and employment status on 
HRQoL in early relapsing-remitting multiple sclerosis. Mult Scler 
2007, 13(6):783-791. 
8. 
Amato MP, Ponziani G, Rossi F, Liedl CL, Stefanile C, Rossi L: 
Quality of life in multiple sclerosis: the impact of depression, fatigue 
and disability. Multiple Sclerosis 2001, 7(5):340-344. 
9. 
Amato MP, Ponziani G, Siracusa G, Sorbi S: Cognitive 
dysfunction in early-onset multiple sclerosis: a reappraisal after 10 
years. Archives of Neurology 2001, 58(10):1602-1606. 
10. 
Benedict RH, Fischer JS, Archibald CJ, Arnett PA, Beatty WW, 
Bobholz J, et al.: Minimal Neuropsychological Assessment of MS 
Patients: A Consensus Approach. Clinical Neuropsychologist 2002, 
16:381-397. 
11. 
Benedict RH, Cookfair D, Gavett R, Gunther M, Munschauer F, 
Garg N, Weinstock-Guttman B: Validity of the minimal assessment of 
cognitive function in multiple sclerosis (MACFIMS). J Int 
Neuropsychol Soc 2006, 12(4):549-558. 
12. 
Smith A: Symbol digit modalities test: Manual. Los Angeles: 
Western Psychological Services; 1982. 
13. 
Benedict RHB: Brief Visuospatial Memory Test - Revised: 
Professional Manual. Odessa, Floriday: Psychological Assessment 
Resources, Inc.; 1997. 
14. 
Gronwall D: Paced auditory serial addition task: A measure of 
recovery from concussion. Perceptual and Motor Skills 1977, 44:367-
373. 
15. 
Benedict R, Ramasamy D, Munschauer FE, Weinstock-Guttman 
B, Zivadinov R: Memory impairment in multiple sclerosis: correlation 
with deep gray matter and mesial temporal atrophy. Multiple Sclerosis 
2008, 14:S252-S252. 
16. 
Benedict RHB, Bruce J, Dwyer MG, Weinstock-Guttman B, Tjoa 
C, Tavazzi E, Munschauer FE, Zivadinov R: Diffusion-weighted imaging 

 
Page 11 of 43 
Revised:October 10 2017 
predicts cognitive impairment in multiple sclerosis. Multiple Sclerosis 
2007, 13(6):722-730. 
17. 
Geurts JJ, Stys PK, Minagar A, Amor S, Zivadinov R: Gray 
matter pathology in (chronic) MS: modern views on an early 
observation. J Neurol Sci 2009, 282(1-2):12-20. 
18. 
Hulst HE, Geurts JJ: Gray matter imaging in multiple sclerosis: 
what have we learned? BMC Neurol 2011, 11:153. 
19. 
Zivadinov R, Pirko I: Advances in understanding gray matter 
pathology in multiple sclerosis: are we ready to redefine disease 
pathogenesis? BMC Neurol 2012, 12:9. 
20. 
Benedict R, Bruce J, Dwyer M, Abderlahman N, Zivadinov R: 
Neocortical atrophy, third ventricular width, and cognitive 
dysfunction in multiple sclerosis. Arch Neurol 2006, 63(9):1301-1306. 
21. 
Houtchens MK, Benedict RH, Killiany R, Sharma J, Jaisani Z, 
Singh B, Weinstock-Guttman B, Guttmann CR, Bakshi R: Thalamic 
atrophy and cognition in multiple sclerosis. Neurology 2007, 
69(12):1213-1223. 
22. 
Roosendaal SD, Bendfeldt K, Vrenken H, Polman CH, Borgwardt 
S, Radue EW, Kappos L, Pelletier D, Hauser SL, Matthews PM et al: 
Grey matter volume in a large cohort of MS patients: relation to MRI 
parameters and disability. Mult Scler 2011, 17(9):1098-1106. 
23. 
Sanfilipo MP, Benedict RH, Weinstock-Guttman B, Bakshi R: 
Gray and white matter brain atrophy and neuropsychological 
impairment in multiple sclerosis. Neurology 2006, 66(5):685-692. 
24. 
Batista S, Zivadinov R, Hoogs M, Bergsland N, Heininen-Brown 
M, Dwyer MG, Weinstock-Guttman B, Benedict RH: Basal ganglia, 
thalamus and neocortical atrophy predicting slowed cognitive 
processing in multiple sclerosis. J Neurol 2012, 259(1):139-146. 
25. 
Benedict RH, Ramasamy D, Munschauer F, Weinstock-Guttman 
B, Zivadinov R: Memory impairment in multiple sclerosis: correlation 
with deep grey matter and mesial temporal atrophy. J Neurol 
Neurosurg Psychiatry 2009, 80(2):201-206. 
26. 
Benedict RH, Zivadinov R: Risk factors for and management of 
cognitive dysfunction in multiple sclerosis. Nat Rev Neurol 2011, 
7(6):332-342. 
27. 
Filippi M, Rocca MA, Benedict RH, DeLuca J, Geurts JJ, 
Rombouts SA, Ron M, Comi G: The contribution of MRI in assessing 
cognitive impairment in multiple sclerosis. Neurology 2010, 
75(23):2121-2128. 
28. 
Minagar A, Barnett MH, Benedict RH, Pelletier D, Pirko I, 
Sahraian MA, Frohman E, Zivadinov R: The thalamus and multiple 

 
Page 12 of 43 
Revised:October 10 2017 
sclerosis: Modern views on pathologic, imaging, and clinical aspects. 
Neurology 2013, 80(2):210-219. 
29. 
Calabrese M, Rinaldi F, Mattisi I, Bernardi V, Favaretto A, Perini 
P, Gallo P: The predictive value of gray matter atrophy in clinically 
isolated syndromes. Neurology 2011, 77(3):257-263. 
30. 
Henry RG, Shieh M, Amirbekian B, Chung S, Okuda DT, Pelletier 
D: Connecting white matter injury and thalamic atrophy in clinically 
isolated syndromes. J Neurol Sci 2009, 282(1-2):61-66. 
31. 
Henry RG, Shieh M, Okuda DT, Evangelista A, Gorno-Tempini 
ML, Pelletier D: Regional Grey Matter Atrophy in Clinically Isolated 
Syndromes at Presentation. J Neurol Neurosurg Psychiatry 2008, 
79(11):1236-1244. 
32. 
Ramasamy DP, Benedict R, Cox JL, Fritz D, Abdelrahman N, 
Hussein S, Minagar A, Dwyer MG, Zivadinov R: Extent of cerebellum, 
subcortical and cortical atrophy in patients with MS A case-control 
study. J Neurol Sci 2009, 282(1-2):47-54. 
33. 
Cifelli A, Arridge M, Jezzard P, Esiri MM, Palace J, Matthews 
PM: Thalamic neurodegeneration in multiple sclerosis. Ann Neurol 
2002, 52(5):650-653. 
34. 
Gilmore CP, Donaldson I, Bo L, Owens T, Lowe J, Evangelou N: 
Regional variations in the extent and pattern of grey matter 
demyelination in multiple sclerosis: a comparison between the 
cerebral cortex, cerebellar cortex, deep grey matter nuclei and the 
spinal cord. J Neurol Neurosurg Psychiatry 2009, 80(2):182-187. 
35. 
Bergsland N, Horakova D, Dwyer MG, Dolezal O, Seidl ZK, 
Vaneckova M, Krasensky J, Havrdova E, Zivadinov R: Subcortical and 
Cortical Gray Matter Atrophy in a Large Sample of Patients with 
Clinically Isolated Syndrome and Early Relapsing-Remitting Multiple 
Sclerosis. AJNR Am J Neuroradiol 2012. 
36. 
Rocca MA, Mesaros S, Pagani E, Sormani MP, Comi G, Filippi M: 
Thalamic damage and long-term progression of disability in multiple 
sclerosis. Radiology 2010, 257(2):463-469. 
37. 
Mesaros S, Rocca MA, Pagani E, Sormani MP, Petrolini M, Comi 
G, Filippi M: Thalamic damage predicts the evolution of primary-
progressive multiple sclerosis at 5 years. AJNR Am J Neuroradiol 2011, 
32(6):1016-1020. 
38. 
Mesaros S, Rocca MA, Absinta M, Ghezzi A, Milani N, Moiola L, 
Veggiotti P, Comi G, Filippi M: Evidence of thalamic gray matter loss 
in pediatric multiple sclerosis. Neurology 2008, 70(13):1107-1112. 
39. 
Aubert-Broche B, Fonov V, Ghassemi R, Narayanan S, Arnold 
DL, Banwell B, Sled JG, Collins DL: Regional brain atrophy in 
children with multiple sclerosis. Neuroimage 2011, 58(2):409-415. 

 
Page 13 of 43 
Revised:October 10 2017 
40. 
Zivadinov R, Bergsland N, Dolezal O, Hussein S, Seidl Z, Dwyer 
M, Vaneckova M, Krasensky J, Potts J, Kalincik T et al: Evolution of 
cortical and thalamus atrophy and disability progression in early 
RRMS over 5 years. AJNR Am J Neuroradiol in press. 
41. 
Zivadinov R, Havrdová E, Bergsland N, Tyblova M, Hagemeier J, 
Seidl Z, Dwyer M, Vaneckova M, Krasensky J, Carl E et al: Thalamic 
atrophy is associated with development of clinically definite MS. 
Radiology in press. 
42. 
Hagemeier J, Weinstock-Guttman B, Bergsland N, Heininen-
Brown M, Carl E, Kennedy C, Magnano C, Hojnacki D, Dwyer MG, 
Zivadinov R: Iron Deposition on SWI-Filtered Phase in the 
Subcortical Deep Gray Matter of Patients with Clinically Isolated 
Syndrome May Precede Structure-Specific Atrophy. AJNR Am J 
Neuroradiol 2012, 33(8):1596-1601. 
43. 
Hagemeier J, Yeh EA, Brown MH, Bergsland N, Dwyer MG, Carl 
E, Weinstock-Guttman B, Zivadinov R: Iron content of the pulvinar 
nucleus of the thalamus is increased in adolescent multiple sclerosis. 
Mult Scler 2012. 
44. 
Zivadinov R, Reder A, Filippi M, Minagar A, Stüve O, Lassmann 
H, Racke M, Dwyer M, Frohman E, O. K: Mechanisms of action of 
disease-modifying agents and brain volume changes in multiple 
sclerosis. Neurology 2008, 71:136-144. 
45. 
Tekok-Kilic A, Benedict RH, Weinstock-Guttman B, Dwyer MG, 
Carone D, Srinivasaraghavan B, Yella V, Abdelrahman N, Munschauer F, 
Bakshi R et al: Independent contributions of cortical gray matter 
atrophy and ventricle enlargement for predicting neuropsychological 
impairment in multiple sclerosis. Neuroimage 2007, 36:1294-1130. 
46. 
Johnson KL, Amtmann D, Klasner ER, Kuehn CM, Yorkston KM: 
Medical, pyschological, social, and programmatic barriers to 
employment for people with multiple sclerosis. The Journal of 
Rehabilitation 2004, 70(1):38+. 
47. 
Uccelli MM, Specchia C, Battaglia MA, Miller DM: Factors that 
influence the employment status of people with multiple sclerosis: a 
multi-national study. Journal Of Neurology 2009, 256(12):1989-1996. 
48. 
Sweetland J, Riazi A, Cano SJ, Playford ED: Vocational 
rehabilitation services for people with multiple sclerosis: what 
patients want from clinicians and employers. Multiple Sclerosis Journal 
2007, 13(9):1183-1189. 
49. 
Rumrill PD, Jr, Roessler RT, Fitzgerald SM: Vocational 
rehabilitation-related predictors of quality of life among people with 
multiple sclerosis. Journal of Vocational Rehabilitation 2004, 20(3):155-
163. 

 
Page 14 of 43 
Revised:October 10 2017 
50. 
Beatty WW, Blanco CR, Wilbanks SL, Paul RH: Demographic, 
clinical, and cognitive characteristics of multiple sclerosis patients 
who continue to work. Journal of Neurologic Rehabilitation 1995, 9:167-
173. 
51. 
Rao SM, Leo GJ, Ellington L, Nauertz T, Bernardin L, Unveragt F: 
Cognitive dysfunction in multiple sclerosis. II. Impact on employment 
and social functioning. Neurology 1991, 41:692-696. 
52. 
Benedict RHB, Wahlig E, Bakshi R, Fishman I, Munschauer F, 
Zivadinov R, Weinstock-Guttman B: Predicting quality of life in 
multiple sclerosis: Accounting for physical disability, fatigue, 
cognition, mood disorder, personality, and behavior change. Journal of 
the Neurological Sciences 2005:29-34. 
53. 
Strober LB, Christodoulou C, Benedict RH, Westervelt HJ, 
Melville P, Scherl WF, Weinstock-Guttman B, Rizvi S, Goodman AD, 
Krupp LB: Unemployment in multiple sclerosis: the contribution of 
personality and disease. Mult Scler 2012, 18(5):647-653. 
54. 
Benedict RH, Walton MK: Evaluating cognitive outcome 
measures for MS clinical trials: what is a clinically meaningful 
change? Mult Scler 2012. 
55. 
Benedict RHB, Krupp L, Francis G, Rao S, LaRocca N, Langdon 
D: NINDS Common Data Elements, Multiple Sclerosis, 
Neuropsychology/Cognition Recommendations. In. Edited by Group 
MCW. Washington: National Institute for Neurological Diseases and 
Stroke; 2012. 
56. 
Cohen JA, Reingold SC, Polman CH, Wolinsky JS, MS IACoCTi: 
Disability outcome measures in multiple sclerosis clinical trials: 
current status and future prospects. Lancet 2012, in press. 
57. 
Benedict R, Amato MP, Boringa J, Brochet B, Foley F, Fredrikson 
S, Hamalainen P, Hartung H, Krupp L, Penner I et al: Brief International 
Cognitive Assessment for MS (BICAMS): international standards for 
validation. BMC Neurol 2012, 12(1):55. 
58. 
Honan CA, Brown RF, Hine DW, Vowels L, Wollin JA, Simmons 
RD, Pollard JD: The multiple sclerosis work difficulties questionnaire. 
Mult Scler 2012, 18(6):871-880. 
59. 
Benedict RHB, Rodgers JD, Emmert N, Kininger R, Weinstock 
Guttman B: Negative Work Events and Accommodations in Employed 
Multiple Sclerosis Patients. Multiple Sclerosis Journal, in press. 
60. 
Schwid SR, Goodman AD, Mattson DH, Mihai C, Donohoe KM, 
Petrie MD, Scheid EA, Dudman JT, McDermott MP: The measurement 
of ambulatory impairment in multiple sclerosis. Neurology 1997, 
49(5):1419-1424. 

 
Page 15 of 43 
Revised:October 10 2017 
61. 
Mathiowetz V, Weber K, Kashman N, Volland G: Adult Norms 
for the Nine Hole Peg Test of Finger Dexterity. Occupational Therapy 
Journal of Research 1985, 5:24-38. 
62. 
Beck AT, Steer RA, Brown GK: BDI-Fast Screen for Medical 
Patients: Manual. San Antonio, TX: Psychological Corporation; 2000. 
63. 
Delis DC, Kramer JH, Kaplan E, Ober BA: California Verbal 
Learning Test: Adult version. San Antonio, TX: Psychological 
Corporation; 2000. 
64. 
Smith A: Symbol Digit Modalities Test (SDMT) manual 
(revised). Los Angeles: Western Psychological Services; 1982. 
65. 
Ontaneda D, LaRocca N, Coetzee T, Rudick R, Force NMT: 
Revisiting the multiple sclerosis functional composite: proceedings 
from the National Multiple Sclerosis Society (NMSS) Task Force on 
Clinical Disability Measures. Mult Scler 2012, 18(8):1074-1080. 
66. 
Benedict RHB, Cox D, Thompson LL, Foley FW, Weinstock-
Guttman B, Munschauer F: Reliable screening for neuropsychological 
impairment in MS. Multiple Sclerosis 2004, 10:675-678. 
67. 
Freeman JA, Hobart JC, Thompson AJ: Does adding MS-specific 
items to a generic measure (the SF-36) improve measurement? 
Neurology 2001, 57(1):68-74. 
68. 
Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD: The fatigue 
severity scale. Application to patients with multiple sclerosis and 
systemic lupus erythematosus. Archives of Neurology 1989, 
46(10):1121-1123. 
69. 
Delis DC, Kaplan E, Kramer JH: Delis-Kaplan Executive 
Function System. San Antonio, Texas: Psychological Corporation; 2001. 
70. 
Zivadinov R, Heininen-Brown M, Schirda CV, Poloni GU, 
Bergsland N, Magnano CR, Durfee J, Kennedy C, Carl E, Hagemeier J et 
al: Abnormal subcortical deep-gray matter susceptibility-weighted 
imaging filtered phase measurements in patients with multiple 
sclerosis: a case-control study. Neuroimage 2012, 59(1):331-339. 
71. 
Patenaude B, Smith SM, Kennedy DN, Jenkinson M: A Bayesian 
model of shape and appearance for subcortical brain segmentation. 
Neuroimage 2011, 56(3):907-922. 
72. 
Smith SM, Zhang Y, Jenkinson M, Chen J, Matthews PM, 
Federico A, De Stefano N: Accurate, robust, and automated 
longitudinal and cross-sectional brain change analysis. Neuroimage 
2002, 17(1):479-489. 
73. 
Zhang Y, Brady M, Smith S: Segmentation of brain MR images 
through a hidden Markov random field model and the expectation-

 
Page 16 of 43 
Revised:October 10 2017 
maximization algorithm. IEEE transactions on medical imaging 2001, 
20(1):45-57. 
74. 
Zivadinov R, Rudick RA, De Masi R, Nasuelli D, Ukmar M, 
Pozzi-Mucelli RS, Grop A, Cazzato G, Zorzon M: Effects of IV 
methylprednisolone on brain atrophy in relapsing-remitting MS. 
Neurology 2001, 57(7):1239-1247. 
75. 
Jenkinson M, Bannister P, Brady M, Smith S: Improved 
optimization for the robust and accurate linear registration and 
motion correction of brain images. Neuroimage 2002, 17(2):825-841. 
 
3.0 
Inclusion and Exclusion Criteria 
3.1 Describe the criteria that define who will be included or excluded in 
your final study sample.  
We will enroll 30 relapsing MS patients new to teriflunomide therapy.  
We will also sample 30 healthy control volunteers, matched on 
demographics with the treated group. 
We will include only MS subjects with a relapsing form of MS and who 
are enrolled in a research study that provides the Brain MRI metrics 
needed for GM atrophy analysis.  Specific entrance criteria are as follows:  
Inclusion criteria: 
 Patient diagnosed with MS according to McDonald criteria  
 Age 18-60 
 Have a relapsing disease course  
 Have EDSS scores 0-6.5  
 Have a disease duration <20 years 
 Treatment naïve to teriflunomide 
 Willing and able to comply with the study procedures for the duration of 
the trial 
 Have given written informed consent and signed Health Insurance 
Portability and Accountability Act (HIPAA) Authorization before any 
study-related activities are carried out 
 Normal kidney functioning (creatinine clearance >59) 
 None of the exclusion criteria 
Exclusion criteria: 
 
MS patients with hepatic impairment 
 
Nursing mothers or pregnant women who will need to undergo 12 months 
follow-up  

 
Page 17 of 43 
Revised:October 10 2017 
 
Women of childbearing potential not using reliable contraception 
 
Patients currently treated with teriflunomide  
 
A clinically significant infectious or neurological (for HC only) illness 
(e.g., cellulitis, abscess, pneumonia, septicemia) within 30 days prior to 
treatment assignment 
 
Unwillingness or inability to comply with the requirements of this 
protocol including the presence of any condition (physical, mental, or 
social) that is likely to affect the subject's ability to comply with the study 
protocol 
 
History of neurological disorder other than MS 
 
History of developmental learning disorder or other developmental 
anomaly 
 
History of major depressive disorder, or other psychiatric disorder that 
could impact cognitive capacity, preceding diagnosis of MS 
 
Current major depressive episode 
 
Other pathology related to MRI abnormalities 
Healthy Controls will be recruited if they are matched to the MS group on 
demographic variables, specifically age, achieved education level, gender 
and race.  Controls will have no history of any neurologic or psychiatric 
disorder that could significantly influence cognitive capacity, including, 
but not limited to traumatic brain injury, schizophrenia, major depressive 
disorder, systemic lupus erythematosus, treatment with chemotherapy, 
mild cognitive impairment, and cerebrovascular disease. 
3.2 Describe how individuals will be screened for eligibility. 
 Subjects will undergo eligibility screening conducted by trained members of the 
research team using the attached phone and in-person script, and health and social 
history form to determine whether the subject meet all of the eligibility criteria 
outlined above.  
 Please see attached.  
 
3.3 Indicate specifically whether you will include or exclude each of the 
following special populations: (You may not include members of 
these populations as subjects in your research unless you indicate 
this in your inclusion criteria.) 
 
Adults unable to consent 
 
Individuals who are not yet adults (infants, children, teenagers) 
 
Pregnant women 
 
Prisoners 

 
Page 18 of 43 
Revised:October 10 2017 
 
Inclusion criteria state subjects must be willing and able to comply with 
study procedures for the duration of the study.  
 
Individuals under the age of 18 will not be included 
 
Pregnant women will not be included 
 
Prisoners will not be included 
3.4 Indicate whether you will include non-English speaking individuals.  
Provide justification if you will exclude non-English speaking 
individuals.  
(In order to meet one of the primary ethical principles of equitable 
selection of subjects, non-English speaking individuals may not be 
routinely excluded from research.  In cases where the research is of 
therapeutic intent or is designed to investigate areas that would 
necessarily require certain populations who may not speak English, 
the researcher is required to make efforts to recruit and include non-
English speaking individuals.  However, there are studies in which it 
would be reasonable to limit subjects to those who speak English: 
e.g., pilot studies, small unfunded studies with validated instruments 
not available in other languages, numerous questionnaires, and 
some non-therapeutic studies which offer no direct benefit.)  
 
We will not be including non-English speaking individuals.  All 
neuropsychological measures are given in English and have not yet been 
translated. 
 
4.0 
Study-Wide Number of Subjects (Multisite/Multicenter Only) 
4.1 If this is a multicenter study, indicate the total number of subjects to 
be accrued across all sites. 
N/A 
5.0 
Study-Wide Recruitment Methods (Multisite/Multicenter Only) 
If this is a multicenter study and subjects will be recruited by methods not under 
the control of the local site (e.g., call centers, national advertisements) describe 
those methods.  Local recruitment methods are described later in the protocol. 
5.1 Describe when, where, and how potential subjects will be recruited. 
N/A 
5.2 Describe the methods that will be used to identify potential subjects. 
N/A 
5.3 Describe materials that will be used to recruit subjects. (Attach 
copies of these documents with the application. For advertisements, 
attach the final copy of printed advertisements. When advertisements 

 
Page 19 of 43 
Revised:October 10 2017 
are taped for broadcast, attach the final audio/video tape. You may 
submit the wording of the advertisement prior to taping to preclude 
re-taping because of inappropriate wording, provided the IRB 
reviews the final audio/video tape.) 
N/A 
6.0 
Multi-Site Research (Multisite/Multicenter Only) 
6.1 If this is a multi-site study where you are the lead investigator, 
describe the processes to ensure communication among sites, such 
as: 
 
All sites have the most current version of the protocol, consent 
document, and HIPAA authorization. 
 
All required approvals have been obtained at each site 
(including approval by the site’s IRB of record). 
 
All modifications have been communicated to sites, and 
approved (including approval by the site’s IRB of record) 
before the modification is implemented. 
 
All engaged participating sites will safeguard data as required 
by local information security policies. 
 
All local site investigators conduct the study appropriately. 
 
All non-compliance with the study protocol or applicable 
requirements will reported in accordance with local policy. 
N/A 
6.2 Describe the method for communicating to engaged participating 
sites: 
 
Problems. 
 
Interim results. 
 
The closure of a study 
N/A 
7.0 
Study Timelines 
7.1 Describe the duration of an individual subject’s participation in the 
study. 
This is a prospective, observational, single-blinded, longitudinal study of 
teriflunomide effects on cognitive performance and vocational status. 
Neuropsychological and MS outcome measures will be assessed at 
baseline (0 months), 12 months and 24 months. For those who are 
working, vocational status will be assessed every three months. The 
duration of participation in this study will be 2 years (24 months).  
7.2 Describe the duration anticipated to enroll all study subjects. 
Enrollment of all study subjects is expected to take 4 years (48 months).  

 
Page 20 of 43 
Revised:October 10 2017 
7.3 Describe the estimated date for the investigators to complete this 
study (complete primary analyses) 
Completion of this study, including primary analyses is expected to be in 5 
years.  
8.0 
Study Endpoints 
8.1 Describe the primary and secondary study endpoints. 
Primary Endpoints 
 Information Processing Speed Index, mean z score based on previously 
published normative data. 
 Memory Index, representing a mean z score including the CVLT2 and 
BVMTR, using previously published normative data. 
 Executive Function Index, the mean z score obtained from the DKEFS 
Sorting Test, using previously published normative data. 
 Frequencies of employed/unemployed status, negative work events and 
accommodations obtained from the Vocational Monitoring Survey. 
Secondary Endpoints 
Secondary endpoints will include other clinical metrics and MS outcome 
measure such as: EDSS, BDIFS, FSS, T25FW, 9HPT, MSNQ, and SF-36.     
California Verbal 
Learning Test, 
second edition 
(CVLT-II) 
 
 
 
New Learning & 
Memory 
 
(D. C.  Delis, 
Kramer, Kaplan, & 
Ober, 2000) 
 
Patients listen to a 
list of words and are 
asked to recall them 
at different times 
(immediate and 
delayed recall) and 
recognize them at 
time of delayed 
recall. 
Brief Visuospatial 
Memory Test-
Revised (BVMTR) 
 
New Learning & 
Memory 
 
(R.H. Benedict, 
1997) 
 
Patients recall 
abstract visual 
displays at different 
times (immediate 
and delayed recall) 
and recognize them 
at time of delayed 
recall. 
Paced Auditory 
Serial Addition Test 
(PASAT) 
 
  
 
Processing Speed 
& Working 
Memory 
 
(Gronwall, 1977) 
 
Two 60-part trials 
are presented in 3-s 
and 2-s intervals 
wherein patients 
must continue to add 
consecutive integers 

 
Page 21 of 43 
Revised:October 10 2017 
to the preceding 
integer. 
Symbol Digit 
Modalities Test 
(SDMT) 
 
 
Processing Speed 
& Working 
Memory 
 
(Smith, 1982) 
 
Patients state 
numbers that 
correspond to 
matching symbols as 
they progress 
through multiple 
rows for 90-s. 
Delis-Kaplan 
Executive Function 
System Sorting Test 
(DKEFS) 
Executive 
Function 
 
(D. C. Delis, 
Kaplan, & Kramer, 
2001) 
 
Patient repeatedly 
sort cards into two 
groups and describe 
their reasoning for 
the sorts. 
 
8.2 Describe any primary or secondary safety endpoints. 
N/A 
9.0 
Procedures Involved 
9.1 Describe and explain the study design. 
This is a prospective, observational, single-blinded, longitudinal study of 
teriflunomide effects on cognitive performance and vocational status. 
Neuropsychological, MRI (through another study) and MS outcome 
measures will be assessed at baseline (0 months), 12 months and 24 
months. Vocational status will be assessed every three months. The 
duration of participation in this study will be 2 years (24 months).  
 
 
Table 1.  Proposed Assessments
EDSS
x
x
x
SDMT
x
x
x
PASAT
x
x
x
CVLT2
x
x
x
BVMTR
x
x
x
DKEFS
x
x
x
MSFC
x
x
x
BDIFS
x
x
x
FSS
x
x
x
SF36
x
x
x
MSNQ
x
x
x
Vocational Monitoring
x
x
x
x
x
x
x
x
x
MRI
x
x
x
0
3
6
9
12
15
18
21
24
Month

 
Page 22 of 43 
Revised:October 10 2017 
 
Abbreviations: 
EDSS = Expanded Disability Status Scale 
SDMT = Symbol Digit Modalities Test 
PASAT = Paced Auditory Serial Addition Test 
CVLT2 = California Verbal Learning Test Second Edition 
DKEFS = Delis Kaplan Executive Function System 
MSFC = MS Functional Composite 
BDIFS = Beck Depression Inventory Fast Screen 
FSS = Fatigue Severity Scale 
SF36 = Short Form 36 
MSNQ = MS Neuropsychological Screening Questionnaire 
 
 
9.2 Provide a description of all research procedures being performed 
and when they are performed, including procedures being performed 
to monitor subjects for safety or minimize risks. 
Please see table above for a summary of the study procedures. During 
routine clinic visits, patients for whom terifunomide has been prescribed 
by a treating clinician will be referred to the study team for screening. 
Suitable candidates will be asked to provide informed consent prior to the 
Baseline (Month 0) study assessment.  As shown below, all measures will 
be applied at this baseline assessment.  The full evaluation will be 
repeated at one- and two-years.  At each time point, subjects will be 
directed to the web-based survey.   
 Participants will complete approximately 75 minutes of clinical testing, as 
follows: The Expanded Disability Status Scale (EDSS) will be 
administered at baseline by a board certified clinical neurologist or study 
nurse for MS patients.  
The clinical status of each patient will be further assessed using validated 
tools for motor function, mood, fatigue and cognitive capacity.  Motor 
function tests will be the Timed 25 Foot Walk (T25FW) and the Nine-
Hole Peg Test (NHPT).  The Beck Depression Inventory Fast Screen for 
Medical Patients (BDIFS) will be used to measure the degree of 
depression.  The Short Form 36  and the Fatigue Severity Scale (FSS) will 
be administered for QoL and fatigue respectively. 
We will employ gold-standard measures of cognitive function as in our 
previous studies.  The NP tests will include the California Verbal Learning 
Test, 2nd Edition [CVLT2],  Sorting Test from the Delis-Kaplan Executive 

 
Page 23 of 43 
Revised:October 10 2017 
Function System (DKEFS), Brief Visual Memory Test Revised 
[BVMTR], Symbol Digit Modalities Test [SDMT], and the Paced 
Auditory Serial Addition Test [PASAT].  The MS Neuropsychological 
Screening Questionnaire [MSNQ] will again be administered for patient 
reported neuropsychological symptoms.  Alternate test forms will be 
applied as in our prior work with this battery in order to mitigate 
learning/practice effects. 
Note that MRI procedures and costs will be funded by another research 
study. Healthy controls undergo the same study procedures, with the 
exception of clinical assessment prior to screening.  
9.3 Describe procedures performed to lessen the probability or 
magnitude of risks. 
Safety and Dosing Regimen: 
This is an observational study following patients starting treatment with 
teriflunomide. Clinical and physical assessments will occur at baseline, 12 
months and 24 months.  We will evaluate occurrence of relapses and all 
patients will be monitored as per teriflunomide PI recommendations. All 
serious adverse events will be reported to Genzyme and local IRB within 
required timelines.  The study protocol will be approved by the local 
Health Sciences Institutional Review Board at the University at Buffalo. 
All relapsing MS patients who fulfill inclusion criteria will start 
teriflunomide at a dose of 14mg orally once daily and followed as per 
teriflunomide and clinician recommendations. The drug is not provided by 
the study. 
Treatment for relapses or other conditions will be used at the discretion of 
the treating physician as deemed necessary for the management of the 
subject. All patients will be treated with 3-5g of methylprednisolone for 
the relapse and MRI will be performed (through a separate study) at least 
30 days after steroid administration. 
Symptomatic therapy, such as treatment for spasticity, depression, or 
fatigue is not restricted but should be optimized as early as possible before 
the first dose of teriflunomide in an attempt to maintain consistent 
treatment for the duration of the study. Again, this is at the treating 
clinician’s discretion and any such treatments are not covered by the 
study.  
All patients will start the treatment at baseline, with teriflunomide 
adjustments in patients showing lack of treatment effect during the study. 
This will be made according to patient/physician decisions.  
ALL decisions are to be made by the treating clinician. This study is 
observational. No drug is provided, no intervention is involved, and no 
clinical decisions are made by anyone other than the patient’s treating 
clinician. 

 
Page 24 of 43 
Revised:October 10 2017 
 
9.4 Describe all drugs and devices used in the research and the purpose 
of their use, and their regulatory approval status. 
Teriflunomide (Aubagio) is an oral disease-modifying drug used to treat 
relapsing forms of Multiple Sclerosis.  This study will seek to determine 
the effects of teriflunomide on cognitive tests assessing information 
processing speed, memory, and executive function as well as determining 
if teriflunomide is protective for work disability in MS. 
This drug is not provided as part of the study.  
 
9.5 Describe the source records that will be used to collect data about 
subjects. (Attach all surveys, scripts, and data collection forms.) 
Source records include: 
 Expanded Disability Status Scale (EDSS) 
 Symbol Digit Modalities Test (SDMT) 
 Paced Auditory Serial Addition Test (PASAT) 
 California Verbal Learning Test Second Edition (CVLT2) 
 Brief Visuospatial Memory Test- Revised (BVMT-R) 
 Delis Kaplan Executive Function System (DKEFS) 
 MS Functional Composite (MSFC) 
 Beck Depression Inventory Fast Screen (BDIFS) 
 Fatigue Severity Scale (FSS) 
 Short Form 36 (SF36) 
 MS Neuropsychological Screening Questionnaire (MSNQ) 
 Vocational Accommodations and Multiple Sclerosis Survey 
Distribution of test forms is discouraged as per copyright regulations.   
The script used to introduce the study to subjects is attached.  
9.6 What data will be collected including long-term follow-up. 
The above mentioned data will be collected at month 0, 12 and 24 with the 
exception of the vocational and multiple sclerosis survey for which data 
will be collected every 3 months. 
9.7 For HUD uses provide a description of the device, a summary of 
how you propose to use the device, including a description of any 
screening procedures, the HUD procedure, and any patient follow-
up visits, tests or procedures. 

 
Page 25 of 43 
Revised:October 10 2017 
N/A 
10.0 Data and Specimen Banking 
10.1 If data or specimens will be banked for future use, describe where 
the data/specimens will be stored, how long they will be stored, how 
the data/specimens will be accessed, and who will have access to the 
data/specimens.  
Online survey responses will be stored online in a password-protected 
database. Neuropsychological testing data and clinical outcome measures 
will be stored in a locked cabinet until it has been entered into the 
database, after which it will be scanned into a pdf document and stored in 
a password protected online data storing system and the physical copies 
shredded. Digital files on the online server will only be able to be accessed 
bia encrypted lab computers with a security key.  MRI data (from a 
separate study) will be kept in a password-protected database managed by 
co-investigator Dr. Zivadinov. 
10.2 List the data to be stored or associated with each specimen. 
Online survey data, Neuropsychological testing data, clinical outcome 
measures, and MRI data (from the separate study). 
10.3 Describe the procedures to release data or specimens, including: the 
process to request a release, approvals required for release, who 
can obtain data or specimens, and the data to be provided with 
specimens. 
Identifiable data will not be released to any outside sources.  
11.0 Data Management 
11.1 Describe the data analysis plan, including any statistical 
procedures. 
Statistical Plan: 
Statistical analyses will be performed using SPSS 22.0 (IBM Inc., 
Armonk, NY, USA). Data will be analyzed on an intention-to-treat (ITT) 
basis. A p-value ≤ 0.05 will be used to determine significance.  
We will compare the teriflunomide treated patients and controls on 
demographics, using the chi square test, Student’s t-test and Mann-
Whitney U test, as appropriate.  Next the same approach will be pursued 
regarding the NP measures, controlling for demographics if necessary. 
Within-group changes will be analyzed using repeated measures ANOVAs 
and ANCOVAs controlling for candidate covariates as may be found to be 
important via detailed analysis of correlation coefficients.  Such 
incorporation of covariates will be approached conservatively due to the 
small sample size.   

 
Page 26 of 43 
Revised:October 10 2017 
Cross-sectional analyses will investigate the degree to which MS patients 
are abnormal on vocational monitoring outcomes.  Again, as above, the 
effects of teriflunomide in MS will be measured using repeated measures 
ANOVAs and ANCOVAs controlling for candidate covariates as may be 
found to be important via detailed analysis of correlation coefficients.   
Within-patient changes from baseline MRI measures and statistical 
differences within groups will be calculated using the paired t-test or 
Wilcoxon-rank sum tests. Model assumptions of linearity, normality and 
homoschedasticity will be verified.  Each of the MRI parameters will be 
examined and appropriate transformations will be applied, if necessary.  
Other group-wise comparisons will be made between MS patients and HC 
or MS patients who had MRI (new T2 and CE lesions) or both clinical 
(relapse) and MRI activity. 
This is an exploratory study on the effects of teriflunomide on work status 
and cognition in MS and no previous data are available for the repeated 
measures analyses.  For the cross-sectional analysis, we are powered to 
detect large effects.  Because of this limitation in the sample size, we will 
emphasize the within-group analysis of the teriflunomide patient outcomes 
where we will have power to detect moderate effects. 
11.2 Provide a power analysis. 
 N/A 
11.3 Describe the steps that will be taken secure the data (e.g., training, 
authorization of access, password protection, encryption, physical 
controls, certificates of confidentiality, and separation of identifiers 
and data) during storage, use, and transmission. 
Physical data protection:  NP testing data will be maintained in locked 
filing cabinets within a locked room (4085) within UBMD Neurology at 
the Conventus Center, 1001 Main Street, Buffalo, NY 14203 until it has 
been entered into the database, at which time it will be scanned into a pdf 
document and stored in a password protected online data storing system 
and the physical copies shredded  The NP testing database will be kept 
without identifying information on an encrypted computer and matched to 
online survey information using the assigned code number.   
 
Online security:  In order to maintain security of the information 
collected online, the researchers will use 
https://www.benedictneurocog.com and host the online survey.  The 
website domain was purchased by the principal investigator of the study. 
Security will be maintained by enabling Secure Socket Layers (SSL) 
through the website, protecting the information passed between the survey 
and the researchers.  This is the same security feature used for online 
marketing to protect sensitive information such as credit card information.   
 

 
Page 27 of 43 
Revised:October 10 2017 
Offline data protection:  Once retrieved from the 
www.benedictneurocog.com/ website the survey data will be separated 
from the contact and identifying information and maintained on separate 
encrypted computers.  In addition, the survey responses will be purged 
from www.benedictneurocog.com/ servers in order to minimize any risk 
of online security being broken.  Only a code number assigned by the 
researchers will be maintained as a link between the identifying 
information and the research responses. Other digital files (NP database 
and pdfs) on the online server will only be able to be accessed via 
encrypted lab computers with a security key. 
 
 
Email security:  All email correspondence will be conducted through the 
University at Buffalo email address mscogsur@buffalo.edu devoted 
specifically to the online survey project.  This will ensure correspondence 
is maintained on a secure email server and is not mixed with personal 
correspondence. 
11.4 Describe any procedures that will be used for quality control of 
collected data. 
Scoring and data entry will be completed and checked by trained staff 
members.  
11.5 Describe how data and specimens will be handled study-wide: 
Neuropsychological testing data will be kept in a locked room and in a 
locked cabinet. After data scoring and entry, neuropsychological testing 
files will be de-identified by blacking out identification information, 
scanned into the online server, and the physical copies shredded. 
Databases with identifiable information will not be kept on personal 
computers and only stored online in a password protected website. 
11.6 What information will be included in that data or associated with the 
specimens? 
Data points related to information processing speed, memory, executive 
functioning, depression, fatigue, disability and vocational status. 
11.7 Where and how data or specimens will be stored? 
Online survey data will be stored in an online password protected file 
sharing system. Neuropsychological testing data will be kept in a locked 
room and in a locked cabinet;after they have been entered, they will be 
scanned into pdf files and uploaded to a secure, password protected server 
only able to be accessed by designated lab computers with a security key. 
Physical files will then be shredded after they have been uploaded to this 
server. 
11.8 How long the data or specimens will be stored?  

 
Page 28 of 43 
Revised:October 10 2017 
Electronic copies of data are maintained indefinitely. Physical copies of 
data are maintained until they have been entered into the database, after 
which they will be scanned into a pdf document and are then shredded. 
The digital pdf of the physical data will be maintained indefinitely on an 
encrypted server in password protected folders. 
11.9 Who will have access to the data or specimens? 
Trained staff under Dr. Ralph Benedict (Primary Investigator) directly 
involved in the conduct of this study will have access to data.  
11.10 Who is responsible for receipt or transmission of the data or 
specimens? 
N/A 
11.11 How data and specimens will be transported? 
N/A 
12.0 Provisions to Monitor the Data and Ensure the Safety of Subjects 
12.1 Describe the plan to periodically evaluate the data collected 
regarding both harms and benefits to determine whether subjects 
remain safe.   
Participation in this study involves no more than minimal risk to 
participants.  
In order to maintain patient quality of care, those participants reporting a 
raw score drop of more than 6 points in the online MSNQ (1/2 standard 
deviation) between one or more data points will be referred to the PI (a 
board certified neuropsychologist) for consultation with the potential of a 
recommendation to consult their neurologist if there are signs that the 
decline in MSNQ is the result of a current exacerbation. 
Patients will also be assessed for general safety and asked about adverse 
events and medication changes during screening for Neuropsychological 
evaluations at month 0, 12, and 24. Any potential study-related issues 
and/or adverse events impacting a patient’s health or well-being will be 
communicated to his or her clinician.  
12.2 Describe what data are reviewed, including safety data, untoward 
events, and efficacy data. 
See 12.1 
12.3 Describe how the safety information will be collected (e.g., with case 
report forms, at study visits, by telephone calls with participants). 
Safety information will be collected at each study visit and via the online 
survey. 
12.4 Describe the frequency of data collection, including when safety 
data collection starts.  

 
Page 29 of 43 
Revised:October 10 2017 
Data for the vocational online survey will be collected for each patient at 
three-month intervals by sending a reminder email to take the survey from 
home. 
Neuropsychological testing data will be collected at month 0, month 12, 
and month 24. 
 
12.5 Describe who will review the data. 
Designated, trained staff under Dr. Ralph Benedict (Primary Investigator) 
will review survey and neuropsychological data.  
12.6 Describe the frequency or periodicity of review of cumulative data. 
Review of online survey data will occur within one week of receipt of the 
survey response. Neuropsychological data will be reviewed at the initial 
scoring of neuropsychological tests conducted at each study visit and 
additionally if the need arises. 
12.7 Describe the statistical tests for analyzing the safety data to 
determine whether harm is occurring. 
N/A 
12.8 Describe any conditions that trigger an immediate suspension of the 
research. 
N/A 
13.0 Withdrawal of Subjects 
13.1 Describe anticipated circumstances under which subjects will be 
withdrawn from the research without their consent. 
Circumstances that could possibly lead to the withdrawal of a subject 
without his or her consent would be if continuation of treatment with 
teriflunomide were no longer in the patient’s best interest, based on his/her 
treating clinician’s judgment. The treating clinician may remove subjects 
from the study at any time should he/she feel it is no longer in the 
subject’s best interest. Healthy controls can be withdrawn from the study 
if they no longer wish to participate or if they are non-compliant with the 
study procedures.  
13.2 Describe any procedures for orderly termination. 
N/A 
13.3 Describe procedures that will be followed when subjects withdraw 
from the research, including partial withdrawal from procedures 
with continued data collection.  
Participation in this study is voluntary. Patients being treated with the 
study medication may refuse to participate without penalty and such 
refusal will not prejudice future treatment at theUBMD Neurology . If a 

 
Page 30 of 43 
Revised:October 10 2017 
subject chooses to withdraw from the study, the data collected up to the 
time of withdrawal will continue to be used, but the subject will no longer 
be contacted and no further data will be collected. Healthy controls 
withdrawing from the study will not be penalized in any way.  
14.0 Risks to Subjects 
14.1 List the reasonably foreseeable risks, discomforts, hazards, or 
inconveniences to the subjects related the subjects’ participation in 
the research. Include as may be useful for the IRB’s consideration, a 
description of the probability, magnitude, duration, and reversibility 
of the risks. Consider physical, psychological, social, legal, and 
economic risks. 
There are no identified risks to the subjects in this study.  If participants 
should feel discomfort or choose not to answer a question they are free to 
discontinue the neuropsychological evaluation and/or surveys.  
14.2 If applicable, indicate which procedures may have risks to the 
subjects that are currently unforeseeable. 
N/A 
14.3 If applicable, indicate which procedures may have risks to an 
embryo or fetus should the subject be or become pregnant. 
N/A 
14.4 If applicable, describe risks to others who are not subjects. 
N/A 
15.0 Potential Benefits to Subjects 
15.1 Describe the potential benefits that individual subjects may 
experience from taking part in the research. Include as may be 
useful for the IRB’s consideration, the probability, magnitude, and 
duration of the potential benefits.  
There are no direct benefits to the participants in this study.  The potential 
benefits to society are increased knowledge about the effects of 
teriflunomide on cognitive function and vocational status. 
15.2 Indicate if there is no direct benefit. Do not include benefits to 
society or others. 
There are no direct benefits to the participants in this study. 
16.0 Vulnerable Populations 
16.1 If the research involves individuals who are vulnerable to coercion 
or undue influence, describe additional safeguards included to 
protect their rights and welfare. 

 
Page 31 of 43 
Revised:October 10 2017 
 
If the research involves pregnant women, review 
“CHECKLIST: Pregnant Women (HRP-412)” to ensure that 
you have provided sufficient information. 
 
If the research involves neonates of uncertain viability or non-
viable neonates, review “CHECKLIST: Neonates (HRP-413)” 
or “HRP-414 – CHECKLIST: Neonates of Uncertain Viability 
(HRP-414)” to ensure that you have provided sufficient 
information. 
 
If the research involves prisoners, review “CHECKLIST: 
Prisoners (HRP-415)” to ensure that you have provided 
sufficient information. 
 
If the research involves persons who have not attained the 
legal age for consent to treatments or procedures involved in 
the research (“children”), review the “CHECKLIST: Children 
(HRP-416)” to ensure that you have provided sufficient 
information. 
 
If the research involves cognitively impaired adults, review 
“CHECKLIST: Cognitively Impaired Adults (HRP-417)” to 
ensure that you have provided sufficient information. 
 
Consider if other specifically targeted populations such as 
students, employees of a specific firm or 
educationally/economically disadvantaged persons are 
vulnerable to coercion or undue influence.  The checklists 
listed above for other populations should be used as a guide to 
ensure that you have provided sufficient information.  
N/A 
17.0 Community-Based Participatory Research 
17.1 Describe involvement of the community in the design and conduct of 
the research. 
N/A 
Note: “Community-based Participatory Research” is a collaborative 
approach to research that equitably involves all partners in the 
research process and recognizes the unique strengths that each 
brings. Community-based Participatory Research begins with a 
research topic of importance to the community, has the aim of 
combining knowledge with action and achieving social change to 
improve health outcomes and eliminate health disparities. 
18.0 Sharing of Results with Subjects 
18.1 Describe whether or not results (study results or individual subject 
results, such as results of investigational diagnostic tests, genetic 
tests, or incidental findings) will be shared with subjects or others 
(e.g., the subject’s primary care physicians) and if so, describe how 
it will be shared. 

 
Page 32 of 43 
Revised:October 10 2017 
Participants and/or clinicians requesting interpretation of 
neuropsychological testing will be referred for clinical consultation and 
evaluation with Dr. Ralph Benedict.  If a patient reports adverse side 
effects of teriflunomide during a study visit, the PI and/or research 
personnel will notify the patient’s neurologist.  
19.0 Setting 
19.1 Describe the sites or locations where your research team will 
conduct the research.  
All research will be conducted at through the UBMD Department of 
Neurology located on the fourth floor of the Conventus Building at 1001 
Main St, Buffalo, NY 14203. Subjects may complete the online survey 
from their homes.  
19.2 Identify where your research team will identify and recruit potential 
subjects. 
All identification of potential subjects will be conducted at the UBMD 
Department of Neurology located on the fourth floor of the Conventus 
Building at 1001 Main St, Buffalo, NY 14203, based on clinical referral. 
Healthy controls will be identified  from the community and around the 
medical campus via word of mouth. Participants will be also recruited via 
flyers posted in various locations on and around the Buffalo Medical 
Campus and community.  Community locations will include grocery 
stores, coffee shops, libraries, and shopping malls.  We will seek 
permission from individual sites in the community, as applicable, prior to 
posting of flyers.   
We may utilize the services of The CTSI Community Engagement Team 
(CET) to assist in subject recruitment. Outreach also occurs from the CTSI 
Community Recruitment Liaison via email or postal mail with the IRB 
approved flyer for the study. 
The CET also hosts a standing table at Conventus on the 4th floor of 
UBMD where the IRB approved flyer may be spotlighted, if deemed 
appropriate for this recruitment strategy, as well. 
 
Please find attached flyer. 
19.3 Identify where research procedures will be performed. 
All research will be conducted at the UBMD Department of Neurology 
located on the fourth floor of the Conventus Building at 1001 Main St, 
Buffalo, NY 14203. Subjects may complete the online survey from their 
homes.  
19.4 Describe the composition and involvement of any community 
advisory board. 

 
Page 33 of 43 
Revised:October 10 2017 
N/A 
19.5 For research conducted outside of the organization and its affiliates 
describe: 
 Site-specific regulations or customs affecting the research for 
research outside the organization. 
 Local scientific and ethical review structure outside the 
organization. 
N/A 
20.0 Resources Available 
20.1 Describe the qualifications (e.g., training, experience, oversight) of 
you and your staff as required to perform their role. When 
applicable describe their knowledge of the local study sites, culture, 
and society. Provide enough information to convince the IRB that 
you have qualified staff for the proposed research. Note- If you 
specify a person by name, a change to that person will require prior 
approval by the IRB. If you specify people by role (e.g., coordinator, 
research assistant, co-investigator, or pharmacist), a change to that 
person will not usually require prior approval by the IRB, provided 
that person meets the qualifications described to fulfill their roles. 
This study will be conducted and supervised by qualified investigators. 
Dr. Ralph H B Benedict is the senior investigator and a board certified 
neuropsychologist.  He holds the rank of professor in the Department of 
Neurology at the University at Buffalo, State University of New York.  He 
is the lead neuropsychologist for the Jacobs MS Center, directed by 
Bianca Weinstock-Guttman, MD, who is also a contributor to this project.   
All research staff involved in this research project must pass rigorous 
training on administering neuropsychological tests, patient interaction 
protocol and consent process protocol. Study coordinator is responsible for 
tracking referrals, recruitment, screening, consenting and monitoring 
patient progress over the course of their enrollment.  All research staff has 
completed GRP training. 
The PI will be responsible for coordinating the database, conducting 
statistical analyses, coordinating recruitment efforts and presenting the 
data.  
Describe other resources available to conduct the research: For example, 
as appropriate: 
20.2 Justify the feasibility of recruiting the required number of suitable 
subjects within the agreed recruitment period. For example, how 
many potential subjects do you have access to? What percentage of 
those potential subjects do you need to recruit? 

 
Page 34 of 43 
Revised:October 10 2017 
On average 120 MS patients per week are seen at through the UBMD 
Department of Neurology located on the fourth floor of the Conventus 
Building at 1001 Main St, Buffalo, NY 14203 .  Approximately 5-10 
patients are prescribed teriflunomide per month.  We aim to recruit all 
patients who are prescribed teriflunomide meet screening criteria, and 
agree to participate.  
20.3 Describe the time that you will devote to conducting and completing 
the research. 
One full time research coordinator and two part time research coordinators 
will devote half of their time to conducting and completing the research. 
20.4 Describe your facilities. 
Our research is conducted through the UBMD Department of Neurology 
located on the fourth floor of the Conventus Building at 1001 Main St, 
Buffalo, NY 14203 . All neuropsychological testing will be conducted in 
private rooms. 
 
20.5 Describe the availability of medical or psychological resources that 
subjects might need as a result of an anticipated consequences of the 
human research. 
There are no anticipated consequences associated with this observational 
study. However, relapses or other conditions that may occur at some point 
during the study will be identified and treated by the clinician and at 
his/her discretion. No treatment or clinical care will be covered by the 
study.   
20.6 Describe your process to ensure that all persons assisting with the 
research are adequately informed about the protocol, the research 
procedures, and their duties and functions. 
All new staff will undergo research orientation and will not be cleared for 
research work until approved by the PI and research coordinator.  All new 
staff must complete GRP and CITI training. 
 
21.0 Prior Approvals 
21.1 Describe any approvals that will be obtained prior to commencing 
the research. (E.g., school, external site. funding agency, laboratory, 
radiation safety, or biosafety approval.) 
N/A 
22.0 Recruitment Methods 
22.1 Describe when, where, and how potential subjects will be recruited. 

 
Page 35 of 43 
Revised:October 10 2017 
Subjects will be patients from the UBMD Department of 
Neurology/Jacobs MS Center in Buffalo, NY.  Patients newly prescribed 
teriflunomide by their neurologists will be referred to research staff and 
then offered the opportunity to participate in the study.  Research staff will 
then screen patients to determine eligibility for the study. Willing and 
eligible patients will provide informed consent prior to any research 
procedures.  
 Healthy controls may be recruited from family and friends of 
participating MS subjects, from the surrounding medical 
campus/community via word of mouth or via flyers. We may also utilize 
the services of The CTSI Community Engagement Team (CET) to assist 
in subject recruitment. The CET hosts the Buffalo Research Registry 
(BRR) that can connect us to community members who have completed a 
health profile and have agreed to be contacted about potential research 
opportunities that they may be an interested in based on their self-reported 
information. The CET also goes out and tables at many events in the 
community throughout the year and if and when it is appropriate they may 
have this studies IRB approved flyer spotlighted at the table. They attend 
events such as Good for the Neighborhood hosted by Independent Health 
Foundation, UB on the Green, Juneteenth, Elmwood Arts Festival and 
many others. Outreach occurs from the CTSI Community Recruitment 
Liaison via email or postal mail with the IRB approved flyer for the study. 
Then the BRR member can contact the coordinator (info provided on the 
IRB approved flyer) if they are interested. One week after outreach has 
been completed the Community Recruitment Liaison will give the 
matched BRR members contact info (name, phone, address and email) to 
the study coordinator so that they may conduct follow up to gauge interest 
in participation. 
The CET also hosts a standing table at Conventus on the 4th floor of 
UBMD where the IRB approved flyer may be spotlighted, if deemed 
appropriate for this recruitment strategy, as well. 
22.2 Describe the source of subjects. 
Refer to 22.1 
22.3 Describe the methods that will be used to identify potential subjects. 
Refer to 22.1 
22.4 Describe materials that will be used to recruit subjects. (Attach 
copies of these documents with the application. For advertisements, 
attach the final copy of printed advertisements. When advertisements 
are taped for broadcast, attach the final audio/video tape. You may 
submit the wording of the advertisement prior to taping to preclude 
re-taping because of inappropriate wording, provided the IRB 
reviews the final audio/video tape.) 
Please find attached flyer under recruitment materials. 

 
Page 36 of 43 
Revised:October 10 2017 
22.5 Describe the amount and timing of any payments to subjects. 
Subjects will receive a check for $125 after each neuropsychological 
assessment at months 0, 12, and 24.   
23.0 Local Number of Subjects 
23.1 Indicate the total number of subjects to be accrued locally. 
All 30 MS patients and 30 healthy controls will be accrued locally. 
23.2 If applicable, distinguish between the number of subjects who are 
expected to be enrolled and screened, and the number of subjects 
needed to complete the research procedures (i.e., numbers of 
subjects excluding screen failures.) 
Subjects who agree to participate and pass screening requirements will be 
enrolled in the study.  Thirty MS patients and 30 normal controls will be 
enrolled. 
 
24.0 Confidentiality 
Describe the local procedures for maintenance of confidentiality. 
24.1 Where and how data or specimens will be stored locally? 
Refer to 10.1 
24.2 How long the data or specimens will be stored locally? 
Data will be stored until completion of all study related activities 
24.3 Who will have access to the data or specimens locally? 
PI and research staff 
24.4 Who is responsible for receipt or transmission of the data or 
specimens locally?  
N/A 
24.5 How data and specimens will be transported locally? 
N/A 
25.0 Provisions to Protect the Privacy Interests of Subjects 
25.1 Describe the steps that will be taken to protect subjects’ privacy 
interests. “Privacy interest” refers to a person’s desire to place 
limits on whom they interact or whom they provide personal 
information. 
No information will be shared with outside sources. All data will be kept 
in a locked safe and/or stored in a password protected online data storing 
system. 

 
Page 37 of 43 
Revised:October 10 2017 
25.2 Describe what steps you will take to make the subjects feel at ease 
with the research situation in terms of the questions being asked and 
the procedures being performed. “At ease” does not refer to 
physical discomfort, but the sense of intrusiveness a subject might 
experience in response to questions, examinations, and procedures. 
All study participants will be adequately informed of the aims, methods, 
funding sources, anticipated benefits and potential risks of the study.  The 
subject will be informed of the right to abstain or withdraw from 
participation in the study at any time without reprisal.  After ensuring that 
the participant has understood the information, freely given informed 
consent will be obtained.   
25.3 Indicate how the research team is permitted to access any sources of 
information about the subjects. 
Only trained and authorized staff will be granted access to data. 
 
26.0 Compensation for Research-Related Injury 
26.1 If the research involves more than Minimal Risk to subjects, describe 
the available compensation in the event of research related injury. 
N/A 
26.2 Provide a copy of contract language, if any, relevant to 
compensation for research-related injury. 
N/A 
27.0 Economic Burden to Subjects 
27.1 Describe any costs that subjects may be responsible for because of 
participation in the research. 
N/A 
28.0 Consent Process 
28.1 Indicate whether you will be obtaining consent 
Yes 
28.2 Describe where the consent process take place 
The consent process will take place in a private testing room. 
28.3 Describe any waiting period available between informing the 
prospective subject and obtaining the consent. 
Patients are informed of study procedures when referred to research staff 
by their neurologists.  Consent from all subjects is obtained prior to any 
procedures. 
28.4 Describe any process to ensure ongoing consent. 

 
Page 38 of 43 
Revised:October 10 2017 
Subject understanding of study objectives, procedures, potential 
risks/benefits, etc. will be ensured prior to enrollment and at the beginning 
of each subsequent study visit. Assent will be obtained. At each online 
survey assessment patients will be ask to give online consent. 
28.5 Describe whether you will be following “SOP: Informed Consent 
Process for Research (HRP-090).” If not, describe: 
 
The role of the individuals listed in the application as being 
involved in the consent process. 
 
The time that will be devoted to the consent discussion. 
 
Steps that will be taken to minimize the possibility of coercion 
or undue influence. 
 
Steps that will be taken to ensure the subjects’ understanding. 
We will be following the SOP: Informed Consent Process for Research 
(HRP-090). 
Non-English Speaking Subjects  
28.6 Indicate what language(s) other than English are likely to be 
spoken/understood by your prospective study population or their 
legally authorized representatives. 
N/A 
28.7 If subjects who do not speak English will be enrolled, describe the 
process to ensure that the oral and written information provided to 
those subjects will be in that language. Indicate the language that 
will be used by those obtaining consent. 
N/A 
Waiver or Alteration of Consent Process (consent will not be obtained, 
required information will not be disclosed, or the research involves 
deception) 
28.8 Review the “CHECKLIST: Waiver or Alteration of Consent Process 
(HRP-410)” to ensure you have provided sufficient information for 
the IRB to make these determinations. Provide any additional 
information necessary here: 
N/A 
28.9 If the research involves a waiver the consent process for planned 
emergency research, please review the “CHECKLIST: Waiver of 
Consent for Emergency Research (HRP-419)” to ensure you have 
provided sufficient information for the IRB to make these 
determinations. Provide any additional information necessary here: 
N/A 
Subjects who are not yet adults (infants, children, teenagers) 

 
Page 39 of 43 
Revised:October 10 2017 
28.10Describe the criteria that will be used to determine whether a 
prospective subject has not attained the legal age for consent to 
treatments or procedures involved in the research under the 
applicable law of the jurisdiction in which the research will be 
conducted. (E.g., individuals under the age of 18 years.) For 
research conducted in NY state, review “SOP: Legally Authorized 
Representatives, Children, and Guardians (HRP-013)” to be aware 
of which individuals in the state meet the definition of “children.” 
N/A 
28.11For research conducted outside of NY state, provide information that 
describes which persons have not attained the legal age for consent 
to treatments or procedures involved the research, under the 
applicable law of the jurisdiction in which research will be 
conducted. One method of obtaining this information is to have a 
legal counsel or authority review your protocol along the definition 
of “children” in “SOP: Legally Authorized Representatives, 
Children, and Guardians (HRP-013).” 
N/A 
28.12Describe whether parental permission will be obtained from: 
 
Both parents unless one parent is deceased, unknown, 
incompetent, or not reasonably available, or when only one 
parent has legal responsibility for the care and custody of the 
child. 
 
One parent even if the other parent is alive, known, competent, 
reasonably available, and shares legal responsibility for the 
care and custody of the child. 
N/A 
28.13Describe whether permission will be obtained from individuals other 
than parents, and if so, who will be allowed to provide permission. 
Describe the process used to determine these individuals’ authority 
to consent to each child’s general medical care. 
N/A 
28.14Indicate whether assent will be obtained from all, some, or none of 
the children. If assent will be obtained from some children, indicate 
which children will be required to assent. 
N/A 
28.15When assent of children is obtained describe whether and how it will 
be documented. 
N/A 
Cognitively Impaired Adults 

 
Page 40 of 43 
Revised:October 10 2017 
28.16Describe the process to determine whether an individual is capable 
of consent. The IRB sometimes allows the person obtaining assent to 
document assent on the consent document and does not 
automatically require assent documents to be used. 
N/A 
Adults Unable to Consent 
When a person is not capable of consent due to cognitive impairment, a 
legally authorized representative should be used to provide consent and, 
where possible, assent of the individual should also be solicited. 
28.17List the individuals from whom permission will be obtained in order 
of priority. (e.g., durable power of attorney for health care, court 
appointed guardian for health care decisions, spouse, and adult 
child.)  For research conducted in NY state, review “SOP: Legally 
Authorized Representatives, Children, and Guardians (HRP-013)” 
to be aware of which individuals in the state meet the definition of 
“legally authorized representative.”  The list in the consent template 
signature section corresponds to the priority list for NYS.   
N/A 
28.18For research conducted outside of NY state, provide information that 
describes 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 research. One method of obtaining 
this information is to have a legal counsel or authority review your 
protocol along the definition of “legally authorized representative” 
in “SOP: Legally Authorized Representatives, Children, and 
Guardians (HRP-013).” 
N/A 
28.19Describe the process for assent of the subjects. Indicate whether: 
 
Assent will be required of all, some, or none of the subjects. If 
some, indicated, which subjects will be required to assent and 
which will not. 
 
If assent will not be obtained from some or all subjects, an 
explanation of why not. 
 
Describe whether assent of the subjects will be documented 
and the process to document assent. The IRB allows the person 
obtaining assent to document assent on the consent document 
and does not routinely require assent documents and does not 
routinely require subjects to sign assent documents. 
N/A 

 
Page 41 of 43 
Revised:October 10 2017 
28.20For HUD uses provide a description of how the patient will be 
informed of the potential risks and benefits of the HUD and any 
procedures associated with its use. 
N/A 
29.0 Process to Document Consent in Writing 
 
If your research presents no more than minimal risk of harm to subjects and 
involves no procedures for which written documentation of consent is normally 
required outside of the research context, the IRB will generally waive the 
requirement to obtain written documentation of consent. 
(If you will document consent in writing, attach a consent document. If you will 
obtain consent, but not document consent in writing, attach a consent script. 
Review “CHECKLIST: Waiver of Written Documentation of Consent (HRP-411)” 
to ensure that you have provided sufficient information. You may use 
“TEMPLATE CONSENT DOCUMENT (HRP-502)”to create the consent 
document or script.) 
29.1 Describe whether you will be following “SOP: Written 
Documentation of Consent (HRP-091).” If not, describe whether and 
how consent of the subject will be obtained including whether or not 
it will be documented in writing. 
We will be following the SOP: Written Documentation of Consent (HRP-
091). 
30.0 Drugs or Devices 
30.1 If the research involves drugs or device, describe your plans to store, 
handle, and administer those drugs or devices so that they will be 
used only on subjects and be used only by authorized investigators.  
N/A 
If the drug is investigational (has an IND) or the device has an IDE or a 
claim of abbreviated IDE (non-significant risk device), include the 
following information: 
30.2 Identify the holder of the IND/IDE/Abbreviated IDE. 
N/A 
30.3 Explain procedures followed to comply with FDA sponsor 
requirements for the following: 
N/A 
31.0 
Drugs or Devices 
☒ 
N/A:  This study does not involve drugs or devices.  This section does not 
apply. 

 
Page 42 of 43 
Revised:October 10 2017 
31.1 If the research involves drugs or devices, list and describe all drugs and 
devices used in the research, the purpose of their use, and their regulatory 
approval status.  
Response:  
 
31.2 Describe your plans to store, handle, and administer those drugs or devices 
so that they will be used only on subjects and be used only by authorized 
investigators. 
Response: 
 
If the drug is investigational (has an IND) or the device has an IDE or a claim 
of abbreviated IDE (non-significant risk device), include the following 
information: 
31.3 Identify the holder of the IND/IDE/Abbreviated IDE. 
Response:  
 
31.4 Explain procedures followed to comply with FDA sponsor requirements for 
the following:   
 
 
Applicable to: 
FDA Regulation 
IND Studies 
IDE studies 
Abbreviated 
IDE studies 
21 CFR 11 
X 
X 
 
21 CFR 54 
X 
X 
 
21 CFR 210 
X 
 
 
21 CFR 211 
X 
 
 
21 CFR 312 
X 
 
 
21 CFR 812 
 
X 
X 
21 CFR 820 
 
X 
 
Response:  
 
32.0 
Humanitarian Use Devices 
☒ 
N/A:  This study does not involve humanitarian use devices.  This does 
not apply. 
32.1 
For Humanitarian Use Device (HUD) uses provide a description of the 
device, a summary of how you propose to use the device, including a description 
of any screening procedures, the HUD procedure, and any patient follow-up 
visits, tests or procedures. 

 
Page 43 of 43 
Revised:October 10 2017 
Response:  
 
32.2 
 For HUD uses provide a description of how the patient will be informed 
of the potential risks and benefits of the HUD and any procedures associated with 
its use.