Phase Two Randomized Controlled Crossover Trial of Atomoxetine to Treat Memory Impairment Due to Multiple Sclerosis
Phase: PHASE2
Conditions: Memory Disorders, Multiple Sclerosis
Sponsor: Icahn School of Medicine at Mount Sinai

Phase Two Randomized Controlled Crossover Trial of Atomoxetine to Treat Memory 
Impairment due to Multiple Sclerosis
PI: James Sumowski, PhD
NCT03091400
Document Date: Feb 8, 2017

IRB-16-01030
Amendment
James Sumowski
1. Modification
Summary of the Modification Request
We have a simple modification: changing the verbal memory test that we are using as our screening tool. We
 proposed using the California Verbal Learning Test, Second Edition (CVLT-II). We want to change this to the Rey
 Auditory Verbal Learning Test (RAVLT). Both are published validated memory instruments. (We have gone through
 the protocol and changed the CVLT-II to the RAVLT. This is the only change we made.)
Justification for the Modification
We believe the RAVLT will be more sensitive to memory deficits than the CVLT-II, as the normative data for the
 RAVLT is more appropriate for our sample (better matched for level of education).
This Modification Changes
 the Consent Document or
 Information that May Affect
 Subjects’ Willingness to Continue
 to Participate in the Research
No
Subjects Will Be Re-Consented or
 Provided with the New Information
No
Explanation Why Re-Consenting or Providing Subjects with the New Information is Not Necessary
This is a very minor change, which does not affect the consent form or patient burden (time or effort).
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Amendment
James Sumowski
2. Summary - Title
Protocol Title
Phase Two Randomized Controlled Crossover Trial of Atomoxetine to Treat Memory Impairment due to Multiple
 Sclerosis
Principal Investigator
James Sumowski
Primary Department
Neurology
Application Initiated By
James Sumowski
Lay Summary
Approximately half of persons with multiple sclerosis (MS) develop memory dysfunction, which makes it difficult to
 maintain gainful employment, manage a household, and lead a fully-engaged social life. There are currently no
 validated symptomatic treatments for memory deficits in persons with MS. We will perform a pilot fourteen-week
 double-blind cross-over phase-two randomized controlled trial (RCT) of atomoxetine (80mg qd) versus placebo to
 improve memory in MS patients with documented memory impairment. Atomoxetine is a non-stimulant selective
 norepinephrine reuptake inhibitor FDA-approved to treat cognitive-behavioral symptoms of attention deficit /
 hyperactivity disorder (ADHD; Strattera, Eli Lilly). Pre-clinical evidence suggests that atomoxetine may also improve
 memory by targeting brain mechanisms responsible for memory function (norepinephrine in the hippocampus).
 Twenty-four MS patients demonstrating objective memory impairment on neuropsychological screening tests will
 be randomly assigned to once-daily orally-administered atomoxetine or identically-encapsulated placebo for the
 first phase, followed by a two-week washout period, and then six weeks of the cross-over condition. The RCT
 will be performed at the Corinne Goldsmith Dickinson Center for MS at the Icahn School of Medicine at Mount
 Sinai. Baseline and follow-up evaluations will assess change on Primary Outcomes (objective memory function on
 neuropsychological tests and patient-reported memory change) and Secondary Outcomes (additional objective
 and self-reported memory measures; objective and self-reported cognitive efficiency measures; fatigue and mood).
 We predict that atomoxetine will lead to significantly greater improvements in Primary and Secondary memory
 outcomes relative to placebo. Consistent with the ADHD literature, there may be additional effects of atomoxetine
 versus placebo on Secondary cognitive efficiency outcomes. Results of this trial will inform decisions / planning for a
 possible phase 3 trial, which may ultimately support the use of non-stimulant, once-daily atomoxetine as a memory
 treatment option for MS patients.  
IF Number
IF1930708
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IRB-16-01030
Amendment
James Sumowski
3. Summary - Setup
Funding Has Been Requested /
 Obtained
Yes
Application Type
Request to Rely on Mount Sinai IRB
Research Involves
Prospective Study ONLY
Consenting Participants
Yes
Requesting Waiver or Alteration
 of Informed Consent for Any
 Procedures
No
Humanitarian Use Device (HUD)
 Used Exclusively in the Course of
 Medical Practice
No
Use of an Investigational Device to
 Evaluate Its Safety or Effectiveness
No
Banking Specimens for Future
 Research
No
Cancer Related Research that
 Requires Approval from the
 Protocol Review and Monitoring
 Committee (PRMC).
No
   Is this Cancer Related Research?  Cancer Related Research is defined as research that
 has cancer endpoints or has a cancer population as part of or all of its targeted population.
 This includes protocols studying patients with cancer or those at risk for cancer.
  
Clinical Trial
Yes
   
   * A prospective biomedical or behavioral research study of human subjects that is
 designed to answer specific questions about biomedical or behavioral interventions
 (drugs, treatments, devices, or new ways of using known drugs, treatments, or devices). 
   *  Used to determine whether new biomedical or behavioral interventions are safe,
 efficacious, and effective.    
  
Drugs / Biologics 
Yes
   
   * Drugs / Biologics That Are Not a Part of Standard Practice 
   * Controlled Substances 
   * Drugs / Biologics Supplied by the Research Sponsor or Purchased with Study Funds 
  
   Ionizing Radiation for imaging or therapy, including X-Ray, Fluoroscopy, CT, Nuclear
 Medicine, PET andor Radiation Therapy:
  
* Purely for standard of care:
* In frequency or intensity that
 exceeds what is necessary for
 standard of care:
No
Hazardous Materials
No
   * Recombinant DNA 
   * Viral Vectors 

   * Plasmids 
   * Bacterial Artificial Chromosomes 
   * Toxic Chemicals, Potentially Toxic Medications, Carcinogens 
   * Autologous Cell Lines 
  
Request Use of Clinical Research
 Unit Resources
No
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IRB-16-01030
Amendment
James Sumowski
4. Summary - Background
Objectives
1. Investigate whether treatment with atomoxetine (versus placebo) improves (a) memory on objective cognitive tasks
 and (b) patient-reported memory in MS patients with documented memory impairment.
2. Investigate whether atomoxetine (versus placebo) also has beneficial effects on (a) cognitive efficiency on
 objective cognitive tasks, (b) patient-reported attention/organization, and (c) fatigue and mood.
Background
Memory Impairment in Multiple Sclerosis: Most persons with multiple sclerosis (MS) are diagnosed between ages
 20 and 40,[1] while they are striving to finish education, establish careers, and manage households. About half of
 MS patients will suffer memory decline,[2-4] which begins early in the disease[4,5] and negatively impacts quality
 of life (e.g., unemployment).[3,6] Despite the high prevalence and debilitating consequences of memory decline in
 MS patients, there are currently no validated symptomatic memory treatments.[7-9] We have reported preliminary
 support for levo-amphetamine (l-AMP) as an effective memory treatment in MS, with memory-impaired patients
 showing a 50% improvement on objective memory tasks relative to placebo,[10] with no effects on processing
 speed.[11] It is instructive that l-AMP, classified as a stimulant, improved memory rather than speed. Although both
 stimulants, l-AMP and dextro-amphetamine (d-AMP, prescribed for ADHD) have different mechanisms of action: d-
AMP works on dopaminergic targets in the frontal lobe (e.g., striatum) to increase attention, whereas l-AMP targets
 norepinephrine pathways, with a greater impact on hippocampal structure and memory in rodents.[12] Unfortunately,
 l-AMP is not FDA-approved for any indication, and there is no industry support to perform the necessary phase
 3 trials required for FDA approval. As such, l-AMP is not a viable option for treatment of MS memory impairment;
 however, the aforementioned preliminary data on l-AMP and memory provide critical guidance toward an even more
 promising non-stimulant option: atomoxetine.
Atomoxetine and Memory: Atomoxetine (Strattera, Eli Lilly) is a non-stimulant selective norepinephrine reuptake
 inhibitor FDA-approved for treatment of ADHD.[13] Neuropharmacologically, atomoxetine leads to increased
 norepinephrine in the cortex and hippocampus, without increases in dopamine within the striatum or nucleus
 accumbens,[14,15] which explains reduced risk of locomotor activation and addiction / abuse when using
 atomoxetine versus stimulant medication (e.g., methylphenidate, for review[16]). Clinical trials in ADHD have
 understandably focused on outcomes of inattention and hyperactivity; however, positive effects of atomoxetine on
 visual memory have also been reported,[17] consistent with (a) positive effects on memory in rodents,[18] (b) the
 importance of norepinephrine for memory generally,[19] and (c) human cerebral blood flow evidence showing that
 atomoxetine differentially increases mesial temporal blood flow relative to placebo and methylphenidate.[20] 
Atomoxetine as a Memory Treatment in MS: MS patients experience hippocampal atrophy beginning early in the
 disease,[21-23] histological studies document substantial hippocampal demyelination and synaptic loss,[24-26]
 and work from our group and others has linked MS memory deficits with hippocampal structure and function (e.g.,
[21,27-30]). Consistent with aforementioned roles of atomoxetine on hippocampal norepinephrine and memory,
 and preliminary effects of l-AMP on memory in MS[10]  (likely via norepinephrine[12]), there is adequate evidence
 to support a pilot clinical trial of norepinephrine reuptake inhibition with atomoxetine as a potential symptomatic
 treatment of memory impairment in MS. An important practical consideration supporting this proposal is that
 atomoxetine is already FDA-approved, so the path to clinical use for memory impairment in MS patients is more
 straightforward. Finally, there are important physiological, psychological, and regulatory barriers to stimulant
 medication use, which are circumvented by use of the non-stimulant atomoxetine. 
References:
1. Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain. 2006;129(Pt 3):606-616.
2. Thornton AE, Raz N. Memory impairment in multiple sclerosis: a quantitative review. Neuropsychology.
 1997;11(3):357-366.
3. Morrow SA, Drake A, Zivadinov R, Munschauer F, Weinstock-Guttman B, Benedict RH. Predicting loss of
 employment over three years in multiple sclerosis: clinically meaningful cognitive decline. Clin Neuropsychol.
 2010;24(7):1131-1145.
4. Deloire MS, Ruet A, Hamel D, Bonnet M, Dousset V, Brochet B. MRI predictors of cognitive outcome in early
 multiple sclerosis. Neurology. 2011;76(13):1161-1167.
5. Amato MP, Ponziani G, Pracucci G, Bracco L, Siracusa G, Amaducci L. Cognitive impairment in early-onset
 multiple sclerosis. Pattern, predictors, and impact on everyday life in a 4-year follow-up. Archives of neurology.
 1995;52(2):168-172.
6. Rao SM, Leo GJ, Ellington L, Nauertz T, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. II.
 Impact on employment and social functioning. Neurology. 1991;41(5):692-696.

7. He D, Zhang Y, Dong S, Wang D, Gao X, Zhou H. Pharmacological treatment for memory disorder in multiple
 sclerosis. The Cochrane database of systematic reviews. 2013;12:CD008876.
8. Rosti-Otajarvi EM, Hamalainen PI. Neuropsychological rehabilitation for multiple sclerosis. The Cochrane database
 of systematic reviews. 2014;2:CD009131.
9. das Nair R, Martin KJ, Lincoln NB. Memory rehabilitation for people with multiple sclerosis. Cochrane Database
 Syst Rev. 2016;3:CD008754.
10. Sumowski JF, Chiaravalloti N, Erlanger D, Kaushik T, Benedict RH, DeLuca J. L-amphetamine improves memory
 in MS patients with objective memory impairment. Mult Scler. 2011;17(9):1141-1145.
11. Morrow SA, Kaushik T, Zarevics P, et al. The effects of L-amphetamine sulfate on cognition in MS patients:
 results of a randomized controlled trial. J Neurol. 2009;256(7):1095-1102.
12. Wiig KA, Whitlock JR, Epstein MH, Carpenter RL, Bear MF. The levo enantiomer of amphetamine increases
 memory consolidation and gene expression in the hippocampus without producing locomotor stimulation. Neurobiol
 Learn Mem. 2009;92(1):106-113.
13. Savill NC, Buitelaar JK, Anand E, et al. The efficacy of atomoxetine for the treatment of children and adolescents
 with attention-deficit/hyperactivity disorder: a comprehensive review of over a decade of clinical research. CNS
 Drugs. 2015;29(2):131-151.
14. Bymaster FP, Katner JS, Nelson DL, et al. Atomoxetine increases extracellular levels of norepinephrine and
 dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder.
 Neuropsychopharmacology. 2002;27(5):699-711.
15. Swanson CJ, Perry KW, Koch-Krueger S, Katner J, Svensson KA, Bymaster FP. Effect of the attention deficit/
hyperactivity disorder drug atomoxetine on extracellular concentrations of norepinephrine and dopamine in several
 brain regions of the rat. Neuropharmacology. 2006;50(6):755-760.
16. Upadhyaya HP, Desaiah D, Schuh KJ, et al. A review of the abuse potential assessment of atomoxetine:
 a nonstimulant medication for attention-deficit/hyperactivity disorder. Psychopharmacology (Berl).
 2013;226(2):189-200.
17. Shang CY, Gau SS. Improving visual memory, attention, and school function with atomoxetine in boys with
 attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2012;22(5):353-363.
18. Tzavara ET, Bymaster FP, Overshiner CD, et al. Procholinergic and memory enhancing properties of the
 selective norepinephrine uptake inhibitor atomoxetine. Mol Psychiatry. 2006;11(2):187-195.
19. Murchison CF, Zhang XY, Zhang WP, Ouyang M, Lee A, Thomas SA. A distinct role for norepinephrine in
 memory retrieval. Cell. 2004;117(1):131-143.
20. Marquand AF, O'Daly OG, De Simoni S, et al. Dissociable effects of methylphenidate, atomoxetine and placebo
 on regional cerebral blood flow in healthy volunteers at rest: a multi-class pattern recognition approach. Neuroimage.
 2012;60(2):1015-1024.
21. Sicotte NL, Kern KC, Giesser BS, et al. Regional hippocampal atrophy in multiple sclerosis. Brain. 2008;131(Pt
 4):1134-1141.
22. Audoin B, Zaaraoui W, Reuter F, et al. Atrophy mainly affects the limbic system and the deep grey matter at the
 first stage of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2010;81(6):690-695.
23. Anderson VM, Fisniku LK, Khaleeli Z, et al. Hippocampal atrophy in relapsing-remitting and primary progressive
 MS: a comparative study. Mult Scler. 2010;16(9):1083-1090.
24. Dutta R, Chang A, Doud MK, et al. Demyelination causes synaptic alterations in hippocampi from multiple
 sclerosis patients. Ann Neurol. 2011;69(3):445-454.
25. Dutta R, Chomyk AM, Chang A, et al. Hippocampal demyelination and memory dysfunction are associated with
 increased levels of the neuronal microRNA miR-124 and reduced AMPA receptors. Ann Neurol. 2013;73(5):637-645.
26. Geurts JJ, Bo L, Roosendaal SD, et al. Extensive hippocampal demyelination in multiple sclerosis. J Neuropathol
 Exp Neurol. 2007;66(9):819-827.
27. Schoonheim MM, Popescu V, Rueda Lopes FC, et al. Subcortical atrophy and cognition: sex effects in multiple
 sclerosis. Neurology. 2012;79(17):1754-1761.
28. Leavitt VM, Paxton J, Sumowski JF. Default network connectivity is linked to memory status in multiple sclerosis.
 J Int Neuropsychol Soc. 2014;20(9):937-944.
29. Sumowski JF, Wylie GR, Leavitt VM, Chiaravalloti ND, DeLuca J. Default network activity is a sensitive and
 specific biomarker of memory in multiple sclerosis. Mult Scler. 2013;19(2):199-208.
30. Muhlert N, Atzori M, De Vita E, et al. Memory in multiple sclerosis is linked to glutamate concentration in grey
 matter regions. J Neurol Neurosurg Psychiatry. 2014;85(8):833-839.
Primary and Secondary Study Endpoints
PRIMARY ENDPOINTS:
1. Memory will be assessed as a mean normative z-score across verbal and spatial memory tasks: (a) Selective
 Reminding Test (SRT) Total Learning, (b) SRT Delayed Recall, (c) Brief Visuospatial Memory Test, Revised (BVMT-
R) Total Learning, (d) BVMT-R Delayed Recall. Memory will be measured at three points: Baseline (day prior to
 phase one [treatment or placebo]), Treatment Follow-Up (last day of atomoxetine), and Placebo Follow-up (last day
 of placebo). (These will be known as phase one and phase two follow-ups initially, as treatment or placebo will only
 be revealed after the study is complete.) Alternate forms of the tests will be used. 

2. Patient-Reported Memory Change: Patients will endorse global memory change over the past month as: much
 improved (3), improved (2), slightly improved (1), unchanged (0), slightly worse (-1), worse (-2), much worse (-3).
 This will occur twice: at the phase one and phase two follow-ups.
SECONDARY ENDPOINTS:
1. At the same three time points above (baseline, phase one follow-up, phase two follow-up), we will administer two
 additional memory tasks: 
(a) CANTAB Paired Associate Learning (PAL, Total Errors Adjusted); (b) NIH Toolbox Picture Sequence Memory
 Test (PSMT; raw score).
2. Patient-Reported Memory Change: The Perceived Deficits Questionnaire (PDQ) will be administrated at the same
 three time points. Retrospective Memory and Prospective Memory subscales will be derived at each time point.
3. At the same three time points, we will measure performance on four cognitive efficiency tasks assessing
 processing speed (Symbol Digit Modalities Test, Oral Version: Total Correct), sustained attention/continuous
 performance (CANTAB Rapid Visual Information Processing: RVP A'), reading comprehension speed (Woodcock
 Johnson Reading Fluency), and working memory (WAIS-IV Digit Span: total raw score). 
4. Patient Reported Outcomes of (a) cognitive efficiency assessed with Attention and Planning/Organization
 subscales of the PDQ; (b) fatigue assessed with the Fatigue Severity Scale; (c) mood assessed with the Beck
 Depression Inventory Fast Screen, and (d) suicidal ideation with the Columbia Suicide Severity Rating Scale.
Protocol Was Already Approved
 by the Icahn School of Medicine at
 Mount Sinai (ISMMS) Institutional
 Review Board (IRB) Under a
 Different Principal Investigator
No
Protocol Was Previously Submitted
 to an External(non-ISMMS) IRB
No
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5. Research Personnel
Name/Department
Role/Status
Contact
Access
Signature
 Authority
Phone
Email
James Sumowski /
 Neurology
Principal
 Investigator / 
Signature
 Authority
Christina Lewis / 
ARC / 
Edit
 Access
Ilana Katz Sand / 
CI / 
Edit
 Access
Gabrielle Pelle / 
ARC / 
Edit
 Access
 
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James Sumowski
6. Sites
Site Name
Icahn School of Medicine at Mount Sinai
Other External Site Name
Contact Details
Approved
Approval Document
Funded By Mount Sinai
Other IRB
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James Sumowski
7. Subjects - Enrollment
Site Name
Icahn School of Medicine at Mount Sinai
Subjects To Be Enrolled
30
Total Number of Subjects to be
 Enrolled Across All Listed Sites
 Above (Auto Populated)
30
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James Sumowski
8. Subjects - Populations
Inclusion Criteria
1. Diagnosis of Multiple Sclerosis based on the Revised McDonald criteria (Polman. Ann Neurol 2011; 69: 292-302)
2. Age 21 - 60 years.
3. Memory Impairment on validated neuropsychological memory screening tests, as follows:
a) performance #16th percentile on both Rey Auditory Verbal Learning Test (RAVLT) Total Learning and WMS-IV
 Visual Reproduction (Immediate); and
b) mean normative performance is at least 1.0 standard deviation below expectations based on premorbid IQ (WTAR
 provides estimates of expected memory function).
4. Patient self-report of memory decline from previously higher level of functioning.
Exclusion Criteria
1. Current stimulant medication usage.
2. Previous diagnosis or treatment for ADHD or any neurologic condition other than multiple sclerosis (e.g., traumatic
 brain injury, epilepsy)
3. clinical relapse of MS within 60 days of screening,
4. change in disease-modifying therapy within 90 days of screening,
5. below average estimated premorbid intelligence (WTAR score #16th percentile),
6. severe cognitive impairment indicated by a Mini Mental Status Examination (MMSE) < 24/30,
7. contraindications for atomoxetine use: (a) self-reported history of suicidal ideation within the last twelve months
 (Columbia Suicide Severity Rating Scale), (b) diagnosis of bipolar illness, (c) moderate or severe current depressive
 symptomatology (Beck Depression Inventory Fast Screen # 9), (d) diagnosis of hepatic disease, (e) narrow angle
 glaucoma, (f) pheochromocytoma, (g) monoamine oxidase inhibitor within 14 days of study drug start, (h) taking
 strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine), (i) diagnosis of heart disease, (j) pregnant or
 planning pregnancy during the study period, (k) breastfeeding, (l) hypersensitivity to atomoxetine or component
 of formulation. Note that in the case where a potential subject is receiving medication for care that interacts with
 atomoxetine, her / his clinical regiment will not change to allow for study entry.
Enrollment Restrictions Based
 Upon Gender, Pregnancy,
 Childbearing Potential, or Race
Yes
Justify Restriction(s)
We are excluded women who are pregnant or planning to become pregnant during the study period. Pregnancy risk
 associated with atomoxetine is category C (risk cannot be ruled out). 
Age Range(s)
18 to 64 Years
Targeted Population(s)
Adults - Patients 
Other Aspects that Could Increase Subjects Vulnerability
None.
Safeguards to protect Subjects rights and welfare
We are employing inclusion / exclusion criteria which minimize risk to patients from atomoxetine, and we will monitor
 side effects. We will also emphasize the voluntary nature of this study, and that there is no penalty for withdrawal.
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9. Subjects - Participation
Duration of an Individual Subjects Participation in the Study
Once consented and screened, the baseline will be completed and the rest of the study will take fourteen weeks: six-
week phase one, two-week washout, six-week phase two.
Duration Anticipated to Enroll All Study Subjects
One year
Estimated Date for the Investigators
 to Complete This Study
Within one year
Procedures for Subjects to Request Withdrawal
Subjects who desire to discontinue participation in this study will contact the study coordinator via telephone or email
 to withdraw. 
The information collected prior to subject withdrawal may be used if deemed necessary to complete the study. As an
 FDA regulated study, the data cannot be destroyed. Data will not be distributed to anyone.
Procedures for Investigator to Withdraw Subjects
The investigator will withdraw subjects who fail to complete the baseline or follow-up evaluation, or who report serious
 side effects of the study medication as determined by Co-I Ilana Katz Sand, M.D. (attending MS neurologist). 
The information collected prior to subject withdrawal may be used if deemed necessary to complete the study,
 unless the subject informs us in writing that they withdraw the data collected and the samples collected.  Previously
 collected data can only be withdrawn if it has not yet been de-identified and distributed.
Participants Will Be Recruited
Yes
Recruitment Method(s)
Clinical Practice
How Participants Will Be Identified
Patients meeting inclusion criteria for age and MS diagnosis will be as asked by their treating physician, nurse
 practitioner, or neuropsychologist if they would be interested in hearing more about the study.  If the patient is
 interested in participating and reports subjective difficulty with memory, a member of the research team will either
 speak with them in person, or they will be asked if they want to be contacted by a member of the research team at
 another time, or they will be given contact information for a member of the research team.  If the patient is interested
 and would prefer to be contacted, the clinician will provide us with the name and best way to contact them. We also
 have a list of patients who have asked us to contact them if we have any enrolling research studies.  We will contact
 those patients at their preferred contact.  
Who Will Initially Approach
 Potential Participants
Member of Primary Care Team, Treating
 Physician
How Research Will Be Introduced to Participants
Patients will be asked by their physician, nurse practitioner, or neuropsychologist if they are interested in learning
 about a placebo-controlled RCT of a drug aiming to improve disease-related memory decline. Patients will be told
 that atomoxetine is a non-stimulant drug FDA-approved to treat ADHD, but that the use of atomoxetine to treat
 memory deficits is not an approved use of the drug. Patients will be told that it is a cross-over design, and that they
 will receive atomoxetine during one phase, and placebo during the other, but that he/she will not be blinded to phase.
 If they are interested, patients will be referred to the study personnel as noted above.
How Participants Will Be Screened
Inclusion and exclusion criteria will be reviewed with patients via telephone or in-person screening with study
 personnel.  Patients who report memory difficulties and meet demographic eligibility criteria will be invited to the
 MS Center for a brief twenty-minute in-person screening. After informed consent, the screening will include two
 memory screening tests (RAVLT, WMS-IV Visual Reproduction), a word-reading estimate of premorbid IQ (WTAR),
 a depression screening tool (BDI-FS), and an assessment of suicidal ideation with the past six months (Columbia
 Suicide Severity Rating Scale). Demographic (e.g., age) and medical (e.g., last relapse) will be reviewed with the
 patient and/or their medical record. All current medications will be recorded, and Co-I Ilana Katz Sand, M.D. will
 review for possible interactions with atomoxetine.

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10. Procedures - Narrative
Description of the Study Design
This is a double-blind randomized placebo-controlled cross-over design whereby each of 24 enrolled MS patients
 (meeting inclusion criteria / screening) will complete the following:
1. Baseline Evaluation (neuropsychological, psychological, self-report, and motor assessment; about 1 hour).
2. Phase One Drug: Six weeks of treatment with atomoxetine or placebo (randomly assigned)
3. Phase One Evaluation: baseline evaluation repeated on the last day of phase one.
4. Two week washout period
5. Phase Two Drug: Six weeks of opposite condition as phase one (i.e., if atomoxetine in phase one, then placebo in
 phase two)
6. Phase Two Evaluation: baseline evaluation repeated on the last day of phase one.
Description of Procedures Being Performed
After informed consent, subjects will engage in a 30-minute screening consisting of memory tests (Rey Auditory
 Verbal Learning Test, Visual Reproduction of the Wechsler Memory Scale, Fourth Edition), word-reading test
 (Weschler Test of Adult Reading), depressive symptoms (Beck Depression Inventory, Fast Screen), and assessment
 of suicidal ideation within the past twelve months (Columbia Suicide Severity Rating Scale). 
Patients who meet all inclusion criteria will advance to the fourteen week crossover trial.
1. Baseline Evaluation: 
a. Memory Tests: Selective Reminding Test, Brief Visuospatial Memory Test, Revised, CANTAB Paired Associate
 Learning, NIH Toolbox Picture Sequence Memory Test (PSMT)
b. Cognitive Efficiency Tests: Symbol Digit Modalities Test, CANTAB Rapid Visual Information Processing, Woodcock
 Johnson Reading Fluency, WAIS-IV Digit Span
c. Questionnaires: Perceived Deficits Questionnaire (self-report of cognitive/memory deficits), Beck Depression
 Inventory, Fast Screen (mood), Fatigue Severity Scale (fatigue), Columbia Suicide Severity Rating Scale (suicidal
 ideation)
d. Motor Tasks: 25-foot walk, Nine Hole Peg Test
2. Phase One Drug:
Patients will receive atomoxetine or identically encapsulated placebo from the research pharmacy. They will receive
 two containers: one containing seven 40mg capsules, and one containing enough 80mg capsules for the remaining
 five weeks. Subjects will be instructed to take the 40mg dose once per day (in the morning) for the first seven
 days, and then switch to the 80mg dose once per day (in the morning) for the remainder of Phase One. Subjects
 will be encouraged to set an alert in their smartphones to remind them to take the capsule at the same time each
 day. Subjects will also be provided with information about atomoxetine (Strattera) provided by the pharmaceutical
 company (Eli Lilly). Patients will be instructed not to take more than one capsule per day. If they miss a dose,
 they should keep it in the container. All remaining capsules will be returned to the investigator at the end of the six
 weeks (when the subject returns for the first follow-up). Patients will also be instructed to contact the study team
 immediately if they experience any side effects.
3. Phase One Evaluation: The baseline evaluation will be repeated on the last day of Phase One. Alternate forms
 will be used as appropriate. In addition, patients will be asked to guess which type of capsule they were tasking, and
 also complete an additional questionnaire: 
Patient-Reported Memory Change: Patients will endorse global memory change over the past month as: much
 improved (3), somewhat improved (2), mildly improved (1), unchanged (0), mildly worse (-1), somewhat worse (-2),
 much worse (-3). 
4. Two week washout period.
Patients will go two weeks without taking any study capsule.
5. Phase Two Drug
The same procedures as Phase One will be followed, except that patients will receive the opposite capsules as
 Phase One.
6. Phase Two Evaluation
The same procedures as the Phase One Evaluation will be repeated. 
Description of the Source Records that Will Be Used to Collect Data About Subjects 

Paper source records will include demographic information, general medical history, and MS medical history
 information; however, there will be no PHI on any source forms. All data will be collected using paper
 neuropsychological record forms and/or score sheets. CANTAB tasks are performed on an iPad; however, no PHI
 will be entered into the iPad. Instead, CANTAB scores will be transferred to paper score sheets. All data will be
 entered into a RedCap database, which will include no PHI.
Description of Data that Will Be Collected Including Long-Term Follow-Up
This is documented above. 
Research Requires HIV Testing
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11. Procedures - Genetic Testing
Genetic Testing Will Be Performed
No
Guidance and Policies > Future Use Data Sharing and Genetic Research
  
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12. Procedures - Details
Surveys or Interviews
Yes
Type of Instruments Being Used
Standardized, Created By Research Team
Names of Standardized Instruments
NEUROPSYCHOLOGICAL INSTRUMENTS
Rey Auditory Verbal Learning Test
Visual Reproduction of the Wechsler Memory Scale
Brief Visuospatial Memory Test, Revised
Selective Reminding Test
CANTAB Paired Associate Learning
NIH Toolbox Picture Sequence Memory Test
Symbol Digit Modalities Test
CANTAB Rapid Visual Information Processing
Woodcock Johnson IV Reading Fluency
Wechsler Adult Intelligence Test, Third Edition: Digit Span
Wechsler Adult Reading Test
25-Foot Walk
Nine Hole Peg Test
QUESTIONNAIRES
Perceived Deficits Questionnaire
Beck Depression Inventory, Fast Screen
Fatigue Severity Scale 
Columbia Suicide Severity Rating Scale
Description of Instruments Created By Research Team
Patient-Reported Memory Change: Patients will endorse global memory change over the past month as: much
 improved (3), improved (2), slightly improved (1), unchanged (0), slightly worse (-1), worse (-2), much worse (-3). 
Audio / Photo / Video Recording
No
Deception
No
Results of the Study Will Be Shared
 with Subjects or Others
No
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IRB-16-01030
Amendment
James Sumowski
13. Procedures - Instruments
Instruments Created By Research Team
Type
Questionnaire
Name
Patient Reported Memory Change
Upload
MEMORY QUESTIONNAIRE.docx
Type
Questionnaire (Revised)
Name
Patient Reported Memory Change
Upload
Memory Questionnaire Revised.docx
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IRB-16-01030
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James Sumowski
14. Procedures - Compensation
Compensation for Participation
Yes
Type
Check
Amount Per Visit
10
# of Visits
1
Line Total
10
Justification
Time
Who Will Pay
Specify Who Will Pay
Comment
For completion of baseline evaluation
Type
Check
Amount Per Visit
20
# of Visits
1
Line Total
20
Justification
Time
Who Will Pay
Specify Who Will Pay
Comment
For completion of Phase One Follow-up
Type
Check
Amount Per Visit
20
# of Visits
1
Line Total
20
Justification
Time
Who Will Pay
Specify Who Will Pay
Comment
For completion of Phase Two Follow-up
Total Compensation
50
  
  PI must attest that all of the following are true. 
  * Credit for payment accrues as the study progresses. 
  * Payment is not contingent upon completing the entire study. 
  * The amount of payment and the proposed method and timing of disbursement is neither
 coercive nor presented undue influence. 
  * Any amount paid as a bonus for completion is reasonable and not so large as to unduly
 induce subjects to stay in the study when they would otherwise have withdrawn. 
  * All information concerning payment, including the amount and schedule of payments, is
 in the informed consent document. 
  * Compensation does not include a coupon good for a discount on the purchase price of
 the product once it has been approved. 
  
 

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IRB-16-01030
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James Sumowski
15. Consent - Obtaining Consent
Consent Process
Adult Consent
Where and When Consent Will Be Obtained
Consent will be obtained in the Corinne Goldsmith Dickinson Center for MS (MS Center) at Mount Sinai (FPA)
Waiting Period for Obtaining Consent
The study will be discussed with potential subjects prior to the day of the study, and persons will be given a copy
 of the consent form to review at home before deciding whether to participate. The study and consent form will be
 discussed with potential subjects again on the day they come in for the study, and they will have an opportunity to
 ask questions. Only then will the consent form be signed and the study begin.
SOP HRP-090 Informed Consent
 Process for Research Is Being
 Used
Yes
PPHS Worksheets, Checklists and SOPs
  
Process to Document Consent in
 Writing
Will Use Standard Template
Non-English Speaking Participants
 Will Be Enrolled
No
Justification for Not Enrolling Non-English Speaking Participants
The neuropsychological assessment tools used for this trial are validated in English only.
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IRB-16-01030
Amendment
James Sumowski
16. Consent - Documents
Consent Documents
Type
Informed Consent Form
Name
ICF v1.0
Upload
Sumowski_ICF_revised_clean.doc
Consent Templates
  
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IRB-16-01030
Amendment
James Sumowski
17. Data - Collection
Health Related Information Will Be
 Viewed, Recorded, or Generated
Yes
Description of Health Information That Will Be Viewed, Recorded, or Generated
Medical History: information required to determine study eligibility (see inclusion criteria), such as a history of
 depression or other mood disorder, ADHD, or neurologic disease other than MS. We will also document current
 medications.
MS History: Medical information directly related to MS, including the type of MS (e.g, relapsing, progressive), last
 clinical relapse of MS, history of MS medication, current levels of MS disability (e.g., neurologic exam on record)
Performance on neuropsychological, psychological, and motor tasks described above.
Non-Health Related Information Will
 Be Viewed or Recorded
Yes
Description of Non-Health Information That Will Be Viewed or Recorded
Demographic information: age, sex, education, primary language, maternal education, occupation, race, ethnicity
 (required for reporting purposes for grant-funding agency)
Note that identifiable information checked below (e.g., name, MRN, address, etc.) will be used to maintain contact
 with the subject, to complete required forms for reimbursement, and/or confirm medical history. Identifiable
 information will also be kept separate from study data, as noted above.
HIV / AIDS Related Information Will
 Be Viewed or Recorded
No
Data That Will Be Viewed,
 Recorded, or Generated Contains
 ANY of the Following Directly
 Identifiable Information
Yes
Will Be Viewed
Name, Social Security Number, Medical
 Record Number, Address by street
 location, Telephone number, Geographical
 Subdivisions Smaller Than a State, All
 Elements of Dates for Dates Directly
 Related to an Individual (i.e., Birth Date,
 Admission Date, Discharge Date), Email
 Address
Will Be Recorded
Name, Social Security Number, Medical
 Record Number, Address by street
 location, Telephone number, Geographical
 Subdivisions Smaller Than a State, All
 Elements of Dates for Dates Directly
 Related to an Individual (i.e., Birth Date,
 Admission Date, Discharge Date), Email
 Address
Data Collection Sheet
        
        A Data Collection Sheet is required if you are either performing a retrospective review,
 or your study meets the category of exempt 4 research, or your study meets the category
 of expedited 5 research. Please upload it here.
        
    
Data Collection Source(s)
Participant, Medical Chart (Paper or
 Electronic)

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James Sumowski
18. Data - HIPAA
Obtaining HIPAA Authorization
Yes
How PHI Will Be Protected from Improper Use or Disclosure
Study data will include no direct identifiers, and a unique number assigned to each patient. Study data will be kept in
 a locked filing cabinet in the PI's office, and kept separate from the subjects' signed consent forms (also in a locked
 cabinet). A list of subject-number pairings will also be in a locked filing cabinet, and only the PI and the study team
 will be assess to these cabinets. 
PHI Will Be Destroyed at the
 Earliest Opportunity Consistent
 with the Research
Yes
When and How PHI Will Be Destroyed 
PHI will be destroyed at the completion of the study by shredding documents with PHI, which are otherwise in locked
 filing cabinets.  The key linking the study data (in RedCap) to PHI (e.g., consent forms) will be destroyed at the end
 of the study, so that PHI (and patient identities) cannot be linked back to the study data. Only the de-identified study
 data will be needed for publication. Signed consent forms with HIPPA waivers (unlinked to data) will be kept for six
 years following completion of the study, and then destroyed via shredding.
PHI Will Be Shared
No
  PI must attest to the following.
  * I assure that the protected health information (PHI) will not be disclosed to any other
 person or entity not listed on this form except where required by law or for the authorized
 oversight of this research project. If at any time I want to reuse this PHI for other purposes
 or disclose it to other individuals or entities I will seek approval from the IRB. 
  
 
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Amendment
James Sumowski
19. Data - Storage
Location Where Data Will Be Stored
Data will be stored in a locked filing cabinet located in a locked closet, within a locked office (PI: JF Sumowski). Each
 lock has a separate key. 
How will the data be stored?
With a Code That Can Be Linked to the
 Identity of the Participant
Research Personnel Responsible
 for:
James Sumowski
Accessing Data
Yes
Receipt or Transmission of Data
Yes
Holding Code That Can Be Linked
 to Identity of Participants
Yes
Research Personnel Responsible
 for:
Christina Lewis
Accessing Data
Yes
Receipt or Transmission of Data
Yes
Holding Code That Can Be Linked
 to Identity of Participants
Yes
Research Personnel Responsible
 for:
Ilana Katz Sand
Accessing Data
Receipt or Transmission of Data
Holding Code That Can Be Linked
 to Identity of Participants
Research Personnel Responsible
 for:
Gabrielle Pelle
Accessing Data
Yes
Receipt or Transmission of Data
Yes
Holding Code That Can Be Linked
 to Identity of Participants
Yes
Duration Data Will Be Stored
Raw data will be stored for three years following completion of the study. Non-identifiable data in the form of a
 database (RedCap) will be kept indefinitely. 
Steps That Will Be Taken to Secure the Data During Storage, Use, and Transmission
Data will be stored in a locked filing cabinet located in a locked closet, within a locked office (PI: JF Sumowski).
 Each lock has a separate key. Only two persons have the key to the filing cabinet: JF Sumowski (PI) and the study
 research coordinators. Data files will be kept separate from identifiable data (PHI), with the exception of a password
 protected and encrypted Excel file linking subject names and subject numbers. This file will be located on a ISMMS
 network drive and only accessed from ISMMS computers. Only JF Sumowski and the coordinators will have the
 password. Raw data files may be retrieved by JF Sumowski or the research coordinator, and viewed on site in a
 private office space. Files will not be removed from Mount Sinai Hospital. Files will be immediately returned to their
 secure location within the filing cabinet. 
Power Analysis/Data Analysis Plan (Including Any Statistical Procedures)
JF Sumowski will lead statistical analyses, which will consist of dependent T-tests comparing differences in outcomes
 (e.g., memory composite score) between the drug and placebo phases of the cross-over trial.
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James Sumowski
20. Data - Safety Monitoring
More Than the Minimum Data
 Safety Monitoring Will Be Done
Yes
Principal Monitor
Ilana Katz Sand
Additional Monitors
Specific Items That Will Be Monitored for Safety
Suicidal ideation will be monitored with the Columbia Suicide Severity Rating Scale. Subjects who report suicidal
 ideation at any point in the study will be escorted to the psychiatric emergency department at Mount Sinai Hospital
 for further evaluation. 
Suicidal ideation and other adverse events reported by patients will be recorded. Co-I Ilana Katz Sand, M.D. will
 review all adverse events as they are reported, and judge severity. Dr. Katz Sand is not involved in data collection or
 processing, so she can be unblinded to identify whether adverse events occurred during atomoxetine or placebo. 
Frequency of Data Review
Suicidal ideation will be evaluated at baseline, first follow-up, and second follow-up for all subjects, and immediate
 action will be taken if suicidal ideation is present (as noted above).
Dr. Katz Sand will also be told immediately of any other serious adverse events, such as allergy to atomoxetine. She
 will have access to condition assignments in the case of adverse events.
Rules for Alteration of Study Design
After twelve subjects have been completed the trial, Dr. Katz Sand will evaluate whether serious adverse events are
 more likely during atomoxetine or placebo. If serious adverse events are 2:1 more likely during atomoxetine, the
 study will be halted. 
Selection Procedures to Minimize Toxicity
We are using the recommended dosage of atomoxetine based on prescribing information in the package insert. Also,
 we are excluding patients taking strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine), which minimizes
 risk of toxicity.
Grading System to Evaluate Adverse Events
Serious adverse events will include suicidal ideation and allergy to atomoxetine.
Other adverse events include constipation, upset stomach, difficulty sleeping, dry mouth, loss of appetite, irregular
 periods, decrease in sexual function, urinary hesitancy sweating, and dizziness.
Procedures to Assure Data Accuracy
All adverse events reported to the research team at any time in the study (including the three assessment phases)
 will be recorded for frequency and severity. Severity will be judged my our study physician, Ilana Katz Sand, M.D.
 These will be documented in a study RedCap database, and will be reported for each condition (atomoxetine,
 placebo) with the study results. Dr. Katz Sand will also be able to determine subject condition in the event of serious
 adverse events.
Suspension Reported to
Suspension would be reported the the IRB.
Anticipated Circumstances of Subject Withdrawal
Subjects would be withdrawn from the study if they experience any severe adverse events. Of course, subjects may
 choose to withdraw at any time without penalty.
Primary or Secondary Safety Endpoints
Primary safety outcome will be suicidal ideation.
Secondary safety endpoints include constipation, upset stomach, difficulty sleeping, dry mouth, loss of appetite,
 irregular periods, decrease in sexual function, urinary hesitancy sweating, dizziness, and allergy to atomoxetine.
Data Monitoring Committee
 Description
DMC.docx
DMC Charter Available
No

Will the Research Include Data
 Coordinating Center Activities?
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IRB-16-01030
Amendment
James Sumowski
21. Funding
Funding Source Name
National Multiple Sclerosis Society
Contact
Funding Category
Foundation
Meditrack (https://contracts.tractmanager.com/Contracts/Login.aspx)
Grant or Contract Title
Pilot Randomized Controlled Trial of Atomoxetine to Treat Memory Impairment in MS
 Patients
Grant or Contract 
 Number
PP-1606-24739
Funding Status
Funded
Project Initiated By
Investigator
Grant / Contract Principal
 Investigator (PI)
James Sumowski
Department
Neurology
Department
Neurology
Phone
Email
james.sumowski@mssm.edu
Protocol and Funding
 Proposal Match
No
Identify Substantive
 Differences Between
 Protocol and Funding
 Proposal
We changed the trial from a parallel design to a cross-over design to improve statistical
 power. As such, we lowered our sample size from 30 to 24. All other aspects (e.g.,
 hypotheses, doses, outcomes, etc.) are the same.
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Amendment
James Sumowski
22. Drugs / Biologics
Study Fund Account (or alternate
 departmental / fund account, if
 study is not yet established)
Select One:
  A fund number is required before the IDS will sign off on any forms or initiate any
 procedures. For those studies which an alternate departmental fund number is provided,
 IDS will delay billing by 6 months.
      Add all drugs and biological agents whose use is specifically prescribed in the
 research.  This includes approved drugs that are supplied or paid for by the company for
 this research, approved drugs that are not given under routine care guidelines, and all
 investigational drugs.  Approved drugs whose use is up to the discretion of an attending
 physician as part of medical care do not need to be added.  Contact the Investigational
 Drug Service (IDS) if unsure http://www.mssm.edu/ids .
 To be completed by Pharmacy staff upon review of the protocol:
 FYI: NO ACTION REQUIRED
 IDS FEE SCHEDULE
 Review:  ___
 Initiation:___
 Dispensation:___
 Maintenance:___
 Special Compounding:___
 Coordinating Center:___
 Close-Out:___
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James Sumowski
23. Financial Administration
  This information will help the Financial Administration of Clinical Trials Services (FACTS)
 office determine whether a Medicare Coverage Analysis (MCA) is needed for the research
 study. If you have any questions while completing this form, please contact the FACTS
 office at (212) 731-7067 or FACTS@mssm.edu.
Clinical Research Study Category
Investigator Initiated
 Payment Options: 
* Option 1:  No protocol-required services will be billed to patients or third-party payers.
 Does Not Need MCA 
* Option 2:  Protocol-required services (i.e., routine care services) will be billed to patients
 or third-party payers. Must Have MCA 
* Option 3:  Study is initiated and federally funded by a Government Sponsored
 Cooperative Group who will only pay for services that are solely conducted for research
 purposes and other protocol-required services (i.e., routine care services) will be billed to
 patients or third-party payers. Billing Grid Only Required, NO MCA 
* Option 4:  Study involves only data collection and has no protocol-required clinical
 services. Does Not Need MCA 
* Option 5:  Study is not described in any of the above options. Please describe the study
 and specify whether External Sponsor (i.e., industry, government, or philanthropic source)
 and/or patient/third party payer will pay for protocol required services. MCA MAY Be
 Required 
Payment Option
Option 1
 No MCA is needed per option selected above. 
 Payment Option 1: 
* Option 1A:  Department/collaborating departments will act as internal sponsor paying for
 all protocol-required services and no protocol-required services will be billed to patients or
 third party payers. 
* Option 1B:  Study involves protocol-required clinical services and an External Sponsor
 (i.e., industry, government, or philanthropic source) will pay for all protocol-required
 services. 
Payment Option 1
Option 1B
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IRB-16-01030
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James Sumowski
24. Attachments
Type
Name
Version Status
Filename
Uploaded
 Date
Other - Other IRB
 Correspondance
RAVLT
1
New
RAVLT.pdf
02/23/2017
Package Insert
 Document (DRUG
 NAME)
strattera-pi.pdf
1
New
strattera-pi.pdf
02/26/2017
Page 32 of 32