Conditions: Cognitive Deficits
Keywords: Healthy volunteers Topiramate Neurocognition Drug-induced cognitive deficits
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 60
Healthy volunteers: yes

Brief summary:
Cognitive impairment is a widely reported side effect of many commonly used drugs. Even a mild, untoward effect on an essential function such a linguistic behavior, a directly observable product of complex cognitive processes, is disruptive to daily life. Nevertheless, the mechanisms underlying a drug's impact on cognition are poorly understood. This lack of understanding impedes the ability to predict both the effects of drugs in development and the degree to which an individual is vulnerable to the cognitive impact of a particular agent. Topiramate (TPM, an antiepileptic drug) is, with increasing frequency, being prescribed for a range of conditions including migraine prophylaxis, obesity and pain. It is a prime example of a drug that causes speech and language problems severe enough in some patients to result in discontinuation of therapy. For reasons not well understood, TPM has a poorer cognitive profile than many of the older antiepileptic drugs. The investigators' rational for this study is that it will offer insight into the mechanisms underlying drug-induced cognitive deficits.

Detailed description:
The investigators' long-term goal is to enhance clinical strategies and inform drug development in order to maximize the benefits of individual drug therapy while minimizing adverse cognitive/language-related side effects. The investigators' objective in this application is to elucidate the relationship among drug exposure as measured by plasma drug levels, its neurophysiological effects, and consequent effects on the cognitive processes observable in everyday language use. Using topiramate (TPM) as a prototype, the investigators will apply the tools of clinical pharmacology, computational linguistics, neuroscience, and engineering to the design and execution of randomized, double blind, crossover studies using three (3) doses of TPM, one (1) dose of a comparator drug (lorazepam-LZP) and a placebo. In order to isolate the cognitive effects of TPM from those possibly arising from an underlying medical condition, subjects will be healthy adults. The investigators will capitalize on an innovative system for automated language and speech analysis (SALSA) developed in our laboratory, to quantify the effects of TPM administration on effective language use, a crucial component of normal day-to-day functioning.

Arms:
arm 1: Participant will receive 3 single-dose treatments with 2-week washout between each treatment. At each of 3 treatments, participants will receive 100mg torpiramate, 2mg lorazepam, or placebo. Treatment order is randomized. All participants in this arm will receive all 3 treatments. arm 2: Participant will receive 3 single-dose treatments with 2-week washout between each treatment. At each of 3 treatments, participants will receive 150mg torpiramate, 2mg lorazepam, or placebo. Treatment order is randomized. All participants in this arm will receive all 3 treatments. arm 3: Participant will receive 3 single-dose treatments with 2-week washout between each treatment. At each of 3 treatments, participants will receive 200mg torpiramate, 2mg lorazepam, or placebo. Treatment order is randomized. All participants in this arm will receive all 3 treatments.

Interventions: intervention 1: Lorazepam intervention 2: Placebo intervention 3: Topiramate 100mg intervention 4: Topiramate 150mg intervention 5: Topiramate 200mg
Intervention descriptions: intervention 1: Lorazepam: 2mg, po, 1x intervention 2: Non-active placebo, po, 1x intervention 3: Topiramate: 100 mg, po, 1x intervention 4: Topiramate: 150 mg, po, 1x intervention 5: Topiramate: 200 mg, po, 1x

Protocol document:
Prot_SAP_000.pdf: 
Marino, Susan E PI 
i 
University of Minnesota 
Protocol Design Template © 2007 
CHARACTERIZING AND PREDICTING DRUG EFFECTS ON 
COGNITION 
A  DOUBLE-BLIND, RANDOMIZED, CROSSOVER  STUDY OF 
THE EFFECT OF TOPIRAMATE AND LORAZEPAM ON 
LANGUAGE AND COGNITION (HEALTHY VOLUNTEERS)
Sponsor: 
Susan E Marino, PhD (PI) 
Center for Clinical and Cognitive Neuropharmacology 
Dept of Experimental and Clinical Pharmacology 
308 Harvard Street SE 7-115A WDH 
Minneapolis MN  55455 
612-624-2964
Funding Sponsor:  
National Institutes of Health/NINDS 
Study Product: 
Topiramate (TOPAMAX)/ Lorazepam (ATIVAN) 
Protocol Number: 
N/A 
IND/IDE Number: 
Exempt 
Date: 
07/15/2015 
Amended: 
Administrative 
Change: 
CONFIDENTIAL 
This document is confidential and the property of the University of Minnesota.  
No part of it may be transmitted, reproduced, published, or used by other persons 
without prior written authorization from the study sponsor. 


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This material is the property of the University of Minnesota.  Do not disclose or use except as authorized in writing by the study sponsor 
Revision # 
Version Date 
Summary of Changes 
Consent 
Revision/Date 
1 
08/07/2012 
Original to IRB 
n/a 
2 
06/28/2013 
#blood draws;compensation increase; 
transportation; #EEG sessions 
06/28/2013 
3 
08/07/2013 
Genetic testing; compensation 
08/07/2013 
4 
08/23/2013 
Add Postural Sway to test battery 
n/a 
5 
10/29/13 
Delete “into EDTA tubes” 
10/29/13 
6 
07/15/2015 
Addition of RTT to test battery;subject compensation 
07/15/2015 


 
 
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Table of Contents 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 4 
1.1 
BACKGROUND ................................................................................................................................ 4 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................ 4 
1.3 
PRECLINICAL DATA ........................................................................................................................ 4 
1.4 
CLINICAL DATA TO DATE................................................................................................................. 4 
1.5 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................ 5 
2 
STUDY OBJECTIVES ......................................................................................................................... 5 
3 
STUDY DESIGN ................................................................................................................................... 5 
3.1 
GENERAL DESIGN .......................................................................................................................... 5 
3.2 
PRIMARY STUDY ENDPOINTS .......................................................................................................... 7 
3.3 
SECONDARY STUDY ENDPOINTS ................................................... ERROR! BOOKMARK NOT DEFINED. 
3.4 
PRIMARY SAFETY ENDPOINTS ......................................................................................................... 8 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................... 8 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 8 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 8 
4.3 
SUBJECT RECRUITMENT AND SCREENING ....................................................................................... 8 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................. 9 
4.4.1 
When and How to Withdraw Subjects ..................................................................................... 9 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 9 
5 
STUDY DRUG ...................................................................................................................................... 9 
5.1 
DESCRIPTION ................................................................................................................................. 9 
5.2 
TREATMENT REGIMEN .................................................................................................................... 9 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ......................................................... 9 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ..................................................................... 9 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................... 9 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 10 
5.7 
PACKAGING ................................................................................................................................. 10 
5.8 
BLINDING OF STUDY DRUG ........................................................................................................... 10 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 10 
5.9.1 
Receipt of Drug Supplies ....................................................................................................... 10 
5.9.2 
Storage .................................................................................................................................. 10 
5.9.3 
Dispensing of Study Drug ...................................................................................................... 10 
5.9.4 
Return or Destruction of Study Drug ..................................................................................... 10 
6 
STUDY PROCEDURES ..................................................................................................................... 10 
6.1 
VISIT 1 ........................................................................................................................................ 10 
6.2 
VISIT 2 ........................................................................................................................................ 11 
6.3 
ETC. ............................................................................................ ERROR! BOOKMARK NOT DEFINED. 
7 
STATISTICAL PLAN ......................................................................................................................... 13 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 13 
7.2 
STATISTICAL METHODS ................................................................................................................ 14 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 15 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 15 
8.1 
DEFINITIONS ................................................................................................................................ 15 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 17 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS .................................................................................. 18 
8.3.1 
Study Sponsor Notification by Investigator ........................................................................... 18 
8.3.2 
EC/IRB Notification by Investigator ....................................................................................... 18 


 
 
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8.3.3 
FDA Notification by Sponsor ................................................................................................. 18 
8.4 
UNBLINDING PROCEDURES ........................................................................................................... 19 
8.5 
STOPPING RULES ......................................................................................................................... 19 
8.6 
MEDICAL MONITORING ................................................................................................................. 19 
8.6.1 
Internal Data and Safety Monitoring Board ............................. Error! Bookmark not defined. 
8.6.2 
Independent Data and Safety Monitoring Board ..................... Error! Bookmark not defined. 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 20 
9.1 
CONFIDENTIALITY ......................................................................................................................... 20 
9.2 
SOURCE DOCUMENTS .................................................................................................................. 20 
9.3 
CASE REPORT FORMS.................................................................................................................. 20 
9.4 
RECORDS RETENTION .................................................................................................................. 21 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 21 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 21 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 21 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 21 
12 
STUDY FINANCES ............................................................................................................................ 22 
12.1 
FUNDING SOURCE ........................................................................................................................ 22 
12.2 
CONFLICT OF INTEREST ................................................................................................................ 22 
12.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 22 
13 
PUBLICATION PLAN ........................................................................................................................ 23 
14 
REFERENCES ................................................................................................................................... 23 
15 
ATTACHMENTS ..................................................................... ERROR! BOOKMARK NOT DEFINED. 
 


 
 
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List of Abbreviations 
 
 
 
 
(e.g.) 
 
CFR  
Code of Federal Regulations 
 
ICH 
 
International Conference on Harmonisation 
 
CRF  
Case Report Form 
 
FDA  
Food and Drug Administration 
 
GCP  
Good Clinical Practice 
 
IRB 
 
Institutional Review Board 


Clinical Research Protocol Template 
 
Page 1 
Version 31Jan08 
Study Summary 
Title 
Characterizing and Predicting Drug Effects on Cognition 
 
Short Title 
Drug Effects on Cognition 
Protocol Number 
 
Phase 
R01 
Methodology 
Parallel group, randomized, double-blind, cross-over design with 
placebo 
Study Duration 
Five (5) years 
Study Center(s) 
Single-center 
Objectives 
Our primary objective is to elucidate the relationship among drug 
exposure as measured by plasma drug levels, its 
neurophysiological effects measured by EEG, and consequent 
effects on the cognitive processes observable in everyday 
language use. Using topiramate (TPM) as a prototype, we apply 
the tools of clinical pharmacology, computational linguistics, 
neuroscience, and engineering to the design and execution of  
parallel group, randomized, double blind, crossover studies using 
three (3) single, low doses of TPM  and a placebo. In order to 
isolate the cognitive effects of TPM from those possibly arising 
from an underlying medical condition, subjects will be healthy 
adults. We will capitalize on an innovative system for automated 
language and speech analysis (SALSA) developed in our 
laboratory, to quantify the effects of TPM administration on 
effective language use, a crucial component of normal day-to-day 
functioning. 
Number of 
Subjects 
Three parallel groups of 24 (12 men; 12 women; total n=72; 
enrollment target = 84 to account for dropouts), 
Diagnosis and 
Main Inclusion 
Criteria 
Healthy volunteers native English-speaking (necessary for 
language analysis), ages 18-50 
Study Product, 
Dose, Route, 
Regimen 
Topiramate (TPM): 100mg, 150mg or 200mg, po, 1x;  Lorazepam 
(LZP): 2mg, po, 1x; 
Duration of 
administration 
Only one (1) dose of each drug will be administered during the 
study (3 parallel groups) 
Reference therapy 
Placebo (PLA) (non-active) 


 
 
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Statistical 
Methodology 
Neuropsychological and speech data will be analyzed on both the 
group and individual level.  For each individual neuropsychological 
and speech measure, the two baseline scores will be averaged to 
correct for any practice effects associated with repeated testing 
across the entire study. This average is then used in a change 
score, for each measure for each participant, associated with drug 
conditions, computed as (drug session score - average baseline 
score)/average baseline score.  Neuropsychological and speech 
change scores will each be summarized by drug group at each 
collection time (0.5, 2.5, 6 and either 24, 48, 72 or 96 hours post 
dose) with means and standard deviations. Change scores at 2.5 
hours post dose are our primary outcome; change scores at 0.5 
and 6 hours post dose will be used in exploratory analyses.  
Change scores will each be independently taken as the outcome 
in a repeated measures ANOVA with drug group (TPM, LZP, PLA) 
as the primary factor of interest. The Tukey-Kramer procedure will 
be used to adjust type I error rates for the multiple comparisons 
among the three drug groups. All ANOVAs will be adjusted for 
treatment order and session number, and include a random effect 
for participant to control for within-person correlation across the 
three sessions. Separate ANOVAs will examine the three TPM 
dose groups compared to each other. As exploratory work, we will 
also examine whether age or gender modify any of the drug 
effects. 
 
Each TPM dose will be used in a three-way crossover 
study with 24 participants. Detectable differences are based on 
pilot data estimates of within-person and between-person 
variability in each of the outcomes shown; in general, within-
person correlation was weak, well below 0.5. Our budget allows 
for recruiting 4 extra participants per dose study in case of 
dropout. 
 
Pharmacokinetic/Pharmacodynamic analyses: Separately for the 
three TPM doses and for LZP, neuropsychological and speech 
data change scores will each be used as the outcome in a linear 
regression with the three pharmacokinetic parameters (AUC, 
trough, maximum) as the primary predictors of interest. If AUC, 
trough, and maximum are highly collinear, we will consider them 
one at a time. With 24 participants per drug/dose combination, 
and two-sided p=0.05, we will have power 75% to detect a 
correlation of size ≥0.5, 90% power to detect a correlation of size 
≥0.6, and 98% to detect a correlation of size ≥0.7. All regressions 
will be adjusted for session number, age, and gender. We will also 
compare the R-square from the model with AUC as predictor to 
the R-square from the model with dose as predictor. Population 
pharmacokinetic modeling will be used to calculate individual 
measures of exposures. 


 
 
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1 Introduction 
 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 
312 or 812 and International Conference on Harmonization guidelines), applicable 
government regulations and Institutional research policies and procedures.  
1.1 Background 
Cognitive impairment is a widely reported side effect of many commonly used drugs. 
Even a mild, untoward effect on an essential function such as linguistic behavior, a 
directly observable product of complex cognitive processes, is disruptive to daily life.  
Nevertheless, the mechanisms underlying a drug’s impact on cognition are poorly 
understood.  This lack of understanding impedes our ability to predict both the effects of 
drugs in development and the degree to which an individual is vulnerable to the 
cognitive impact of a particular agent.  Topiramate (TPM), a second-generation 
antiepilepsy drug (AED) is, with increasing frequency, being prescribed for a range of 
conditions including migraine prophylaxis, obesity, and pain.  Moreover, it is a prime 
example of a drug that causes speech and language problems severe enough in some 
patients to result in discontinuation of therapy.  However, unlike many newer AEDs, and 
for reasons not well understood, TPM has a poorer cognitive profile than many of the 
older AEDs.   While the number and magnitude of adverse cognitive side effects have 
been attributed, in part, to the effects of titration rate and maintenance dose in both 
patients and healthy adults, these factors do not capture all inter-individual variability in 
the cognitive response to TPM.  Our rationale for this project is that our investigations 
will offer insight into the mechanisms underlying drug-induced cognitive deficits.  It will 
also lay the foundation for a new line of research that will further delineate these 
mechanisms and provide methods to predict individual patient response. In this study 
we compare the cognitive effects of TPM to that of the benzodiazepine, lorazepam, as 
well as to a non-active placebo.  A majority of the preliminary data for this study were 
collected under UMN IRB Study # 0805M33321 and published in a peer reviewed 
journal (Marino et al, 2012). 
1.2 Investigational Agent 
Please refer to the attached “prescribing information” brochures for both topiramate 
(Topamax) and lorazepam (Ativan)  
1.3 Preclinical Data 
NA:  both TPM and LZP are marketed drugs. 
       Clinical Data to Date 
NA. both TPM and LZP are marketed drugs. 
 


 
 
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1.4 Dose Rationale and Risk/Benefits 
A 2mg dose of lorazepam was chosen since that is the most common dose that has 
been used in studies of the cognitive/memory effects of this drug in healthy volunteers 
[9, 10].  The doses of 100mg, 150mg and 200 mg of topiramate chosen for this study 
are much lower than those used in the classical studies of the cognitive effects of this 
agent on cognition and language.  In their EEG study, Salinsky et al (2007) titrated 
healthy volunteers to a maximum dose of 400mg/day whereas Werz et al (2006) used a 
dose of 300 mg/day of topiramate in their study comparing the cognitive effects of TPM 
to lamotrigine in healthy volunteers.  Since there is evidence that the titration rate of 
TPM is proportional to the cognitive complaints attributable to TPM use (Meador et al, 
2001), we expect that even the relatively low doses used here will produce an effect 
since the subjects are receiving the entire dose  all at once. 
2  Study Objectives 
Primary Objective: Our primary objective is to elucidate the relationship among drug 
exposure as measured by plasma drug levels, its neurophysiological effects measured 
by EEG, and consequent effects on the cognitive processes observable in everyday 
language use. We have three (3) Specific Aims: 
Specific Aim #1: Characterize TPM-induced effects on linguistic behavior. Our 
working hypothesis is that TPM has distinct, measureable effects on the fluency and 
content of spontaneous speech. We will test this hypothesis by measuring speech and 
language characteristics with SALSA from speech audio-recorded during a 
neuropsychological assessment that includes tests of verbal, memory and executive 
functions. 
Specific Aim # 2: Determine the neurophysiological mechanisms of TPM’s action 
on executive function. Our working hypothesis is that TPM-induced effects on 
language use are partly attributable to disrupted frontal executive function. We will test 
this hypothesis by recording EEG during a verbal working memory task. We predict 
altered frontal lobe activity and frontotemporal interactions, manifesting as changes in 
event-related potentials (ERP) and EEG coherence. 
Specific Aim #3: Predict individual vulnerability to TPM-induced impairments in 
linguistic, memory, and executive functions. Our working hypotheses are 1. The 
extent of drug-induced impairments in these functions is proportional to systemic drug 
exposure, as measured by plasma drug levels. The area under the time-concentration 
curve (AUC), trough, and maximum drug concentration will be explored. 2. Drug 
exposure is a better predictor than dose of the degree of individual impairment. 
.   
3 Study Design 
3.1 General Design 
This study uses a parallel group, double-blind, randomized, crossover design to test  
neurocognitive functioning including natural language comprehension and production in 
people exposed to TPM and LZP. Healthy volunteers will be exposed to one of three 
(100mg, 150mg or 200mg) single low doses of TPM. Healthy volunteers rather than 


 
 
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patients are used as subjects in order to isolate the effects of the medication from the 
effects of the underlying disorder. In order to explore the differentially sensitivity to the 
cognitive effects of drugs from different classes, we chose LZP as an active comparator 
since unlike TPM, it is a benzodiazepine and produces its cognitive effects via a mild 
generalized sedation versus the more focal frontal lobe dysfunction of TPM. Moreover, 
LZP is not associated word-finding or fluency difficulties. 
 
Each crossover study (using one dose of TPM) will consist of five (5) sessions with at 
least a two-week washout period in between sessions. Sessions 2, 3, and 4 will each be 
followed up by a visit at approximately 24, 48, 72 or 96 hours post drug administration. 
First and last sessions are baseline sessions with no drug administered and no blood 
sample drawn during session 1. During both sessions 1 & 5, subjects will be 
administered a single brief neuropsychological assessment (see details below) 
(approximately 1 hour). However, during session 1, subjects will also be required to 
perform a verbal memory task while having their EEG recorded (approximately 2 hours). 
 
For the treatment sessions (sessions 2, 3, and 4), the sequence in which TPM, LZP, 
and PLA will be assigned to the three middle sessions will be determined according to a 
Latin square design balanced for first-order carry-over effects (6 possible sequences). A 
neuropsychological battery consisting of tests of verbal working memory capacity 
including the reading span test (Session 1 only) (Daneman & Carpenter, 1980; 
sentence comprehension), tests of executive behaviors drawn from the NIH Common 
Data Elements for Epilepsy (www.commondataelements.ninds.nih.gov/Epilepsy.aspx), 
two discourse-level language/verbal tests and one discourse-level memory test 
(described in the next section), as well as an assessment of postural sway (AgiliSway 
System, Agile Medicine, Minneapolis MN:  www.agilemedicine/agilisway.com) will be 
administered 0.5, 2.5, 6 and either 24, 48, 72 or 96 hours after dosing for each of the 
three treatments, as well as once during each of the two baseline sessions (sessions 1 
& 5).   Alternate versions of each test will used during each session to reduce practice 
effects.  Each testing battery is expected to take approximately 45-60 minutes to 
complete.  A portion of the test battery will be audio-recorded for speech analysis using 
SALSA. A single, trained examiner will administer all tests for one subject.  Blood 
samples will be collected for pharmacokinetic-pharmacodynamics analysis.  
 
Pharmacokinetic (PK)-pharmacodynamics(PD) analysis:  Blood samples will be 
collected from all participants at all 3 treatment sessions  in the three parallel three-way 
crossover studies (one for each TPM dose: 100, 150, and 200 mg). Blood samples will 
be collected immediately prior to drug administration (time 0),  5 additional times after 
dose and at 1 time in the post-absorption phase (at either approximately 24, 48, 72, or 
96 hours - randomly assigned).  Preliminary results that include intensive PK sampling 
in healthy volunteers during the whole dosing interval enables the use of sparse 
sampling in order to limit the burden of additional sampling on subjects.  The time of 
drug administration and the time of each blood draw will be recorded.  Samples will be 
immediately centrifuged and the plasma frozen until analysis.  TPM plasma levels will 
be measured by a simultaneous LCMS assay, developed by Subramanian, Birnbaum 


 
 
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and Remmel (2008). LZP plasma levels will be measured by an assay validated in our 
laboratory.  
 
In one session only, and with separate subject consent, a sample will be drawn from 
part of the collected blood samples for subsequent genetic testing with the primary 
hypothesis, related to Specific Aim 3, that inter-individual differences in plasma drug 
concentrations may be due to polymorphisms in metabolic genes. 
 
EEG:  EEG recording will immediately follow the completion of the neuropsychological 
testing battery in session 1 and after the battery administered approximately 2.5 hours 
after drug dose in sessions 2, 3, and 4. EEG recording will be conducted in an 
acoustically and electrically shielded chamber in the UMN Center for Neurobehavioral 
Development.   Subjects will be seated in a comfortable non-metal chair in the chamber 
and instructed to     attend to a CRT monitor during recording.  EEG will be recorded 
using a 128-channel Sensor Net System. EEG will be recorded during the presentation 
of the working memory paradigm.  
 
 
 
 
3.2 Primary Study Endpoints 
Our primary end point is a composite measure of disfluency comprised of the following 
measurements: 
a. spoken discourse fluency 
i. speaker normalized duration and frequency of silent and filled pauses 
ii. speaker normalized frequency of repetitions 
iii. speaker normalized frequency of false starts 
iv. speaker normalized speaking rate (syllables per second) 
 
Our secondary end points will consist of the following characteristics: 
 
For spoken samples, we will examine the following measures of linguistic fluency:  
 Average fundamental frequency fluctuations/variability  
 Average length of hesitations before noun phrases 
 Total speech duration 
 The ratio of speech to silence 
 The ratio of hesitant to fluent speech 
 Average speaker normalized length of rhythmic phrases 
 Any other promising prosodic variables identified in Aim 1. 
 
 
We will examine the following linguistic measures computed based on the transcripts of 
the spoken and written samples: 
 Language model entropy/perplexity computed from the discrepancies 
between the distribution of three-word sequences in the transcripts to the 
general English patterns as well as patterns obtained from baseline 
assessments.  


 
 
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 Number of verbs, nouns, adjectives and adverbs (separate counts for each 
part-of-speech) 
 Ratio of content words (verbs, nouns, adjectives and adverbs) to function 
words (prepositions, pronouns, auxiliaries) 
 Syntactic complexity scores  
 Any other promising linguistic complexity variables identified in Aim 1 
 
 
3.2 Primary Safety Endpoints  
N/A 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
1.        Healthy men and women are  >18 and <50 (post menopausal or using approved 
birth control methods) 
2.        Capable of giving informed consent obtained 
3.        Native English speakers (due to speech and language analysis) 
 
4.2 Exclusion Criteria 
1. Presence of clinically significant cardiovascular, endocrine, hematopoietic, hepatic, 
renal, neurologic, psychiatric disease including suicidality 
2. Presence or history of drug or alcohol abuse 
3. Vision or hearing impairments 
3. The use of concomitant medications which are known to affect topiramate, 
lorazepam, or the use of any concomitant medications that may alter cognitive function, 
including  antidepressants, anxiolytics, psychostimulants such as Ritalin, prescribed 
analgesics, and antipsychotics. 
4. Prior adverse reaction to or prior hypersensitivity to topiramate, lorazepam or to 
related compounds 
5. A positive pregnancy test (administered to all women before enrollment, and prior to 
each study session). 
5. Subjects who have received any investigational drug within the previous thirty days 
6. Dominant left hand (Note: to control for brain lateralization of language functions, 
subjects need to have a dominant right hand. 
Subject Recruitment and Screening 
Subjects will be recruited from the general population using an IRB-approved 
advertisement.  After responding to the ad, one of the researchers or study coordinator 
will screen each applicant for inclusion/exclusion criteria.  If the applicant is suited for 
participation in the study, the researcher/coordinator will send a copy of the consent 
form to the potential subject in order to provide him or her with sufficient time to carefully 


 
 
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read the forms, to call the researcher if there are any questions,  and make an informed 
decision as to whether or not to proceed with enrolling in the study. If the 
applicant chooses to enroll, a study date will be scheduled and on the morning of the 
first session, a researcher/study coordinator will consent the subject and procure the 
required signatures.   
4.3 Early Withdrawal of Subjects 
4.3.1 When and How to Withdraw Subjects 
Subjects will be asked to withdraw from the study if they show any adverse reactions to 
the study drugs, including allergic reactions or greater than expected cognitive effects. 
Subjects who are noncompliant with study visits may be asked to withdraw from the 
study. 
4.3.2 Data Collection and Follow-up for Withdrawn Subjects 
Data collected from subjects who either withdraw from the study voluntarily or who are 
dismissed because of safety concerns will be analyzed and retained in the database. 
Subjects who had any serious adverse event will be followed up by the researcher(s). 
5 Study Drug  
5.1 Description 
Both TPM and LZP are marketed agents and will be given orally in tablet form.   
See section 1.4 for dosage information and justification. 
5.2 Treatment Regimen 
Subjects will be given either a single 100 mg, 150mg OR 200 mg oral dose of 
topiramate (3 parallel groups – one for each dose of TPM). Each subject will also 
receive a single 2mg oral dose of lorazepam during a separate experimental session.  
5.3 Method for Assigning Subjects to Treatment Groups 
A randomization number and associated treatment assignment will be made by the 
University of Minnesota Investigational Pharmacy.  The number will be associated with 
a treatment kit prepared for each subject.    
5.4 Preparation and Administration of Study Drug 
We have contracted with the University of Minnesota Investigational Pharmacy to 
overencapsulate the study drugs as well as prepare a matching, inactive placebo.  All 
drug will be stored and dispensed to study staff by the pharmacy. 
5.5 Subject Compliance Monitoring 
NA 


 
 
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5.6 Prior and Concomitant Therapy 
Subjects will be asked for a list of their current medications when they inquire about 
participating.  We will inform them at that time if they are on any drugs that interact with 
either TPM or LZP. 
5.7 Packaging 
There is no packaging necessary since the pharmacy will deliver the appropriate study 
drug according to their randomization scheme on the morning of the test session. 
5.8 Blinding of Study Drug 
Tablets will be overencapsulated using a gel capsule 
Receiving, Storage, Dispensing and Return 
5.8.1 
Receipt of Drug Supplies 
The study drugs will be purchased by the principal investigator and delivered to the 
pharmacy. Upon receipt of the of the study treatment supplies, an inventory will be 
performed and a drug receipt log filled out and signed by the person accepting the 
shipment.  The designated study staff will count and verify that the shipment 
contains all the items noted in the shipment inventory.  Any damaged or unusable 
study drug in a given shipment (active drug or comparator) will be documented in 
the study files. 
5.8.2 Storage 
Both TPM and LZP will be stored in the University of Minnesota Investigational 
Pharmacy according to the stated FDA requirements. 
5.8.3 Dispensing of Study Drug 
         Only one dose per subject per test session will be dispensed. 
5.8.4 Return or Destruction of Study Drug 
 
At the completion of the study, there will be a final reconciliation of drug shipped, 
drug consumed, and drug remaining.  This reconciliation will be logged on the drug 
reconciliation form, signed and dated.  Any discrepancies noted will be 
investigated, resolved, and documented prior to return or destruction of unused 
study drug.  Drug destroyed on site will be documented in the study files. 
6 Study Procedures 
6.1 Session 1 (Baseline) 
After being consented for the study, a brief demographic, medical and medication 
history will be taken during the first session to assure that subjects are not currently on 
any drugs that can interact with either TPM or LZP or potentially interfere with cognitive 


 
 
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functioning.  Each participant will be administered the entire test battery once only (see 
below) (Week 1-baseline) after which they will perform a working memory task while 
having their EEG recorded, and be randomly assigned to a study treatment sequence 
(TPM or LZP).   
6.2 Session 2 
The first drug testing session will be conducted approximately 14 days after the baseline 
testing. At that time, an intravenous catheter will be inserted (left arm) after which he or 
she will be given either one of three doses of TPM (depending on whether they have 
been assigned to thee 100mg, 150mg or 200mg group),OR  2mg LZP OR  placebo. Six 
blood samples will be drawn between 0 – 6 hours after dose.  Vitals signs will also be 
recorded.  One (1) additional sample (using a single needle stick) will be drawn either at 
(approximately) 24, 48, 72, or 96 hours postdose(randomly assigned) to capture a 
sampling in the post-absorption phase as well as limiting the burden of additional 
sampling on subjects. Neurocognitive and postural sway assessments will be collected 
at times approximately 0.5, 2.5, 6 and either 24, 48, 72 or 96 hours after treatment 
administration. Alternate test forms will be used for each time point.  After the 2.5 hr 
blood draw and assessment are complete, the subject will be fitted with electrodes for 
the EEG portion of the study, after which he or she will return to the CTSI for the 
remaining blood samples and another neuropsychological test administration. A 
separate visit is required for collection of the post-absorption blood sample and testing. 
 
6.3 Session 3 
Participants will return approximately two (2) weeks later in order to repeat the testing 
protocol after switching drugs.  
 
6.4  Session 4 
The fourth session will occur approximately two (2) weeks after the second drug 
administration for the third drug (or placebo) treatment.  
 
6.5   Session 5 (Post baseline) 
The last session will occur approximately two (2) weeks after the third drug or placebo 
administration. Participants will not be given any drug at this session. One blood sample 
will be drawn to determine if any drug from the previous session is still present. The 
entire test battery will be administered. The baseline and postbaseline scores will be 
averaged in order to correct for any practice effects that might have occurred across the 
four testing sessions.  This average will be used to compute the change score of each 
test administered under drug conditions.  Oral samples in all tests will be audiotaped. 
 
 
Neuropsychological Battery 
 
We will employ a battery of neuropsychological tests that includes measures from our 
cognitive Anti-Epileptic Drug (AED) protocol as well as additional language-specific 
measures: 
Verbal Working Memory:  


 
 
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1. Reading Span: Subjects read aloud a set of unrelated sentences, and then at the end 
of the set they recall the last word of each sentence in the set (see Daneman & 
Carpenter, 1980, 1983). As in the speaking span test, subjects are presented with 
increasingly longer sets until all sentences have been presented. Reading span is the 
total number of correct sentence-final words recalled. This test will only be administered 
during the first baseline session (session 1). 
 
Executive function, processing speed, and word-level language/verbal tests: 
 1. Phonemic generative verbal fluency will be evaluated using the COWA test. COWA 
requires the subject to generate words other than proper names or numbers beginning 
with a specific letter of the alphabet; three 60-second trials are obtained, using three 
different letters, usually F-A-S or B-H-R.  
2. Semantic generative verbal fluency will be evaluated using the Animal Fluency test. 
Subjects are asked to generate as many different animal exemplars as they can within 
60 seconds. The primary dependent measure for both phonemic and semantic 
generative fluency is the number of correct words meeting scoring criteria normalized to 
individual (averaged) baseline.  
3. Trails A and B will be used to assess visual search, mental flexibility, and task 
alternation. The subject is required to draw lines between circles in ascending order 
(“connect the dots”). Trail Making Part A requires the patient to connect the numbers 
from 1-25. Trail Making B requires subjects to alternate between numbered and lettered 
circles in ascending numerical/alphabetical order (e.g., 1-A-2-B, etc.) The primary 
dependent measure is time of completion.  
4. Digit span subtest from the WAIS-IV will be used to assess immediate attention. It 
tests forward and backward digit span, includes a sequencing trial in which the subject 
is the repeat back the digits in ascending order. 
 5. Symbol Digit Modalities Test will be used to generate the Processing Speed Index 
(primary dependent measure). These are timed tasks that measure the ability to rapidly 
transcribe symbols that are paired with numbers (Coding). 
 
Computerized psycholinguistic assessment. Spontaneous speech will be elicited using 
two discourse level verbal tasks:  
1. In the picture description task, the subjects will be asked to describe a simple 
picture (e.g., The “Cookie Theft” stimulus from the Boston Diagnostic Aphasia 
Examination (Goodglass & Kaplan 1983).  
2.  Memory will be tested using a third discourse level task, the MCG Story Recall 
task, where subjects will recall a short but detailed description of a situation 
verbally presented to them (Meador et al 1993; Meador et al 1995). 
3. Spontaneous narrative.  Subject will be asked to speak on one of four (4) themes 
(adapted from the Trier Test) for two minutes.   
 
Working Memory Paradigm:  A modified Sternberg working memory task (Sternberg, 
1969) will be presented to each subject during EEG recording to test the effect of TPM 
on verbal and executive brain functions.   A set of English (nonsense) syllables of 
comparable length will be presented on a CRT monitor for 1.5 seconds, followed by a 
5s retention period, followed by the probe syllable.  Subjects will be instructed to press a 
“Yes” or “No” button to indicate whether or not the probe stimulus belonged to the 


 
 
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previously viewed set.  Memory-load is a function of the size of the syllable set.  The 
paradigm consists of six blocks of 60 trials/block (360 trials in total). Presentation of the 
syllables and the memory loads will be randomized (120 trials/memory load).  A practice 
block of 60 trials will be presented prior to testing and a one-minute break will be 
provided between each block to reduce fatigue effects.  The main advantage of this 
paradigm over the classical Sternberg task, where the items are presented sequentially 
rather than all at once, as was done in our preliminary studies, is that the periods of 
encoding, retention, and recall are all well separated in time to permit the study of both 
the temporal and spatial development of neural activity during the different stages of the 
working memory process.    
 
Postural Sway Assessment:  Postural sway: Sway will be measured by the AgiliSway 
System (Agile Medicine, Minneapolis MN:  www.agilemedicine/agilisway.com) 
The dependent measures are total distance, medial/lateral distance, and 
anterior/posterior distance swayed. 
 
A patient’s center of pressure is measured using a force platform, in this case a 
modified Wii balance board, that records the pressure on each of four sensors once 
every 100 milliseconds. Prior to recording the patient data, 10 seconds of calibration 
data are recorded. After obtaining these readings, subjects are asked to stand on the 
board for 10 sec in each of three positions:  with 1. feet together, 2. one foot raised and 
3. in a tandem position, while several different measures of sway are calculated, 
including total distance, medial/lateral distance, and anterior/posterior distance swayed 
(all in centimeters). With additional computation, other measures such as 
average/maximum velocity of sway can also be calculated. 
The calculations for measuring distance swayed are: 
      P(tl) = Pressure top left (TopLeft - CalAvgTopLeft) 
      P(tr) = Pressure top right (TopRight - CalAvgTopRight) 
      P(bl) = Pressure bottom left (BottomLeft - CalAvgBottomLeft) 
      P(br) = Pressure bottom right (BottomRight - CalAvgBottomRight) 
      
      Total (T) = P(tl) + P(tr) + P(bl)  + P(br) 
 
 
 
7 Statistical Plan 
7.1 Sample Size Determination 
Each TPM dose will be used in a three-way crossover study with 24 participants. Table 
1 below shows the magnitude of group differences that will be detectable for 24 
participants with 90% power, two-sided alpha =0.05, using Tukey-Kramer adjustment for 
multiple comparisons among the three drug groups. Detectable differences are based 
on pilot data (collected as part of IRB study # 0805M33321) estimates of within-person 
and between-person variability in each of the outcomes shown; in general, within-
person correlation was weak, well below 0.5. Our budget allows for recruiting 4 extra 
participants per dose study in case of dropout. 
 


 
 
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MCG 
outcomes 
Smallest 
detectable 
group  
difference 
Pilot observed 
smallest / 
biggest group 
difference 
 
Picture 
Description 
outcomes 
Smallest 
detectable 
group  
difference 
Pilot observed 
smallest / 
biggest group 
difference 
Disfluency 
rate 
0.31 
0.20 / 0.43 
 
Disfluency 
rate 
0.18 
0.02 / 0.50 
Words 
correctly 
recalled 
0.22 
0.10 / 0.45 
 
Mean pause 
duration 
0.02 
0.01 / 0.14 
Mean pause 
duration 
0.24 
0.03/0.28 
 
Correct units 
of 
information 
0.09 
0.02 / 0.13 
Speaking rate 
0.04 
0.01/0.08 
 
Speaking rate 
0.03 
0.06 / 0.12 
 
 
 
 
Word count 
0.15 
0.001 / 0.02 
 
7.2 Statistical Methods 
 
Statistical Analysis 
Aim 1 Statistical considerations: Neuropsychological and speech data will be 
analyzed on both the group and individual level.  For each individual neuropsychological 
and speech measure, the two baseline scores will be averaged to correct for any 
practice effects associated with repeated testing across the entire study. This average is 
then used in a change score, for each measure for each participant, associated with 
drug conditions, computed as (drug session score - average baseline score)/average 
baseline score.  Neuropsychological and speech change scores will each be 
summarized by drug group at each collection time (0.5, 2.5, and 6 hours post dose) with 
means and standard deviations. Change scores at 2.5 hours post dose are our primary 
outcome; change scores at 0.5 and 6 hours post dose will be used in exploratory 
analyses.  Change scores will each be independently taken as the outcome in a 
repeated measures ANOVA with drug group (TPM, LZP, PLA) as the primary factor of 
interest. The Tukey-Kramer procedure will be used to adjust type I error rates for the 
multiple comparisons among the three drug groups. All ANOVAs will be adjusted for 
treatment order and session number, and include a random effect for participant to 
control for within-person correlation across the three sessions. Separate ANOVAs will 
examine the three TPM dose groups compared to each other. As exploratory work, we 
will also examine whether age or gender modify any of the drug effects. 
 
Aim 2 (EEG) Statistical considerations: Behavioral data (error rate) and 
electrophysiological summary data will be analyzed in a repeated measures ANOVA 
with a 3x5 factorial for memory load (1, 3, 5 syllables) by drug (TPM, LZP, PLA, two 
baselines). The Tukey-Kramer procedure will be used to adjust type I error rates for the 
multiple comparisons among the drug groups at specific memory loads, and across 
memory loads. ANOVAs will adjust for treatment order and session number, and include 
a random effect for participant to control for within-person correlation across the three 
sessions. Electrophysiological measures (amplitudes, peak latency, will be analyzed 
separately with repeated measures multivariate analyses of variance (RM-MANOVA; 


 
 
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maximum-likelihood analogs may be used if missing data are non-trivial) with factors 
and adjusting variables as above. Correlations between ERP difference (e.g., TPM vs 
PLA) and drug concentration (collected as part of Aim 3, below) will be computed. With 
24 participants per drug/dose combination, and two-sided α=0.05, we will have power 
75% to detect a correlation of size ≥0.5, 90% power to detect a correlation of size ≥0.6, 
and 98% to detect a correlation of size ≥0.7.   
 
Aim 3 (Pk/PD) Statistical considerations: For PK analyses, variables are added and a 
model chosen using a forward selection process (cutoff of p<.005), followed by a 
backward elimination process (cutoff of p<.001) to avoid type I errors due to multiple 
statistical tests. The estimation step of a Nonlinear Mixed Effects Model (NONMEM) will 
be implemented using first order conditional estimation with an interaction term. 
Maximum a posteriori (MAP) Bayesian post-hoc estimates of each individual’s PK 
parameter will be used to derive measures of drug exposure (e.g., AUC, steady-state 
concentrations) using standard PK equations. PD modeling will investigate if a 
relationship exists between outcomes of interest contained in the neuropsychological 
battery. 
Separately for the three TPM doses and for LZP, neuropsychological and speech data 
change scores will each be used as the outcome in a linear regression with the three 
pharmacokinetic parameters (AUC, trough, maximum) as the primary predictors of 
interest. If AUC, trough, and maximum are highly collinear, we will consider them one at 
a time. With 24 participants per drug/dose combination, and two-sided p=0.05, we will 
have power 75% to detect a correlation of size ≥0.5, 90% power to detect a correlation 
of size ≥0.6, and 98% to detect a correlation of size ≥0.7. All regressions will be 
adjusted for session number, age, and gender. We will also compare the R-square from 
the model with AUC as predictor to the R-square from the model with dose as predictor. 
Population pharmacokinetic modeling will be used to calculate individual measures of 
exposures (i.e., AUC, trough, and maximum drug concentration) to be used in the 
analyses above. 
 
 
7.3 Subject Population(s) for Analysis 
• We will be using a protocol-compliant population consisting of healthy volunteers, 
18-50 years of age.  
 
Safety and Adverse Events 
7.4 Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops 
or worsens in severity during the course of the study.  Intercurrent illnesses or 


 
 
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injuries should be regarded as adverse events.  Abnormal results of diagnostic 
procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse 
event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, 
but are clearly of major clinical significance.   They may jeopardize the subject, and 
may require intervention to prevent one of the other serious outcomes noted 
above.  For example, drug overdose or abuse, a seizure that did not result in in-
patient hospitalization, or intensive treatment of bronchospasm in an emergency 
department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be 
regarded as non-serious adverse events.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally 
defined as the period from the initiation of any study procedures to the end of the 
study treatment follow-up.  For this study, the study treatment follow-up is defined 
as 30 days following the last administration of study treatment.  
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a 
preexisting condition.  At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event must also be 
recorded and documented as an adverse event.  
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the 
events are resolved, the subject is lost to follow-up, or the adverse event is 
otherwise explained.  At the last scheduled visit, the investigator should instruct 


 
 
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each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this 
study.   
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any 
one of the following conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to 
confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. 
change of dose, discontinuation of the drug, more frequent follow-up 
assessments, further diagnostic investigation, etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization 
should be documented and reported as a serious adverse event unless specifically 
instructed otherwise in this protocol.  Any condition responsible for surgery should 
be documented as an adverse event if the condition meets the criteria for and 
adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are 
reported as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for a preexisting condition.  Surgery should not be 
reported as an outcome of an adverse event if the purpose of the surgery 
was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease 
of the study, unless it is a worsening or increase in frequency of hospital 
admissions as judged by the clinical investigator. 
7.5 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse 
events by specific questioning and, as appropriate, by examination.  Information on all 
adverse events should be recorded immediately in the source document, and also in the 
appropriate adverse event module of the case report form (CRF).  All clearly related 
signs, symptoms, and abnormal diagnostic procedures results should recorded in the 
source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical 
course of each event should be followed until resolution, stabilization, or until it has 


 
 
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been determined that the study treatment or participation is not the cause.  Serious 
adverse events that are still ongoing at the end of the study period must be followed up 
to determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study 
participation should be recorded and reported immediately. 
7.6 Reporting of Serious Adverse Events 
7.6.1 Study Sponsor Notification by Investigator 
A serious adverse event must be reported to the study sponsor by telephone 
within 24 hours of the event.  A Serious Adverse Event (SAE) form must be 
completed by the investigator and faxed to the study sponsor within 24 hours.  
The investigator will keep a copy of this SAE form on file at the study site.  
Report serious adverse events by phone and facsimile to: 
 
Susan E Marino PhD              612-501-8626 (cell)     612-626-0148 (fax) 
John Rarick    
 
     612-626-2170 (phone) 
Ilo Leppik MD                          612-625-7139 (phone) 
 
At the time of the initial report, the following information should be provided: 
• Study identifier 
• Study Center 
• Subject number 
• A description of the event 
• Date of onset 
• Current status 
• Whether study treatment was 
discontinued 
• The reason why the event is 
classified as serious 
• Investigator assessment of the 
association between the event 
and study treatment 
 
Within the following 48 hours, the investigator must provide further information on 
the serious adverse event in the form of a written narrative.  This should include 
a copy of the completed Serious Adverse Event form, and any other diagnostic 
information that will assist the understanding of the event.  Significant new 
information on ongoing serious adverse events should be provided promptly to 
the study sponsor 
7.6.2 IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) must be 
submitted to the IRB within 10 working days if it falls under the UPIRTSO 
guidelines.  Copies of each report and documentation of IRB notification and 
receipt will be kept in the Clinical Investigator’s binder. 
7.6.3 FDA Notification by Sponsor 
The study sponsor shall notify the FDA by telephone or by facsimile transmission 
of any unexpected fatal or life-threatening experience associated with the use of 


 
 
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the drug as soon as possible but no later than 7 calendar days from the 
sponsor’s original receipt of the information. 
 
If a previous adverse event that was not initially deemed reportable is later found 
to fit the criteria for reporting, the study sponsor will submit the adverse event in a 
written report to the FDA as soon as possible, but no later than 15 calendar days 
from the time the determination is made. 
7.7 Unblinding Procedures 
Subjects who experience any serious adverse event, including what appears to be an 
allergic reaction or an expected, negative cognitive effect will be unblinded by the 
researcher who will call the Investigational Pharmacy for the necessary information. 
This information will be noted in the documents and the subject will be withdrawn from 
the study.  Any necessary medical treatment will be delivered and subject will be 
followed up for at least 24 hours to make sure there are no continuing medical 
problems.   
7.8 Stopping Rules  
If there are any adverse effects reported by the subject or detected by the nurse or 
study coordinator, subjects will be asked to supply details regarding the nature of the 
adverse effect and its severity. Dr. Leppik (see 7.9) will determine the course of follow-
up and whether or not the subject requires further medical care or should be 
discontinued from further participation in the study. Participation in the study would also 
be discontinued if, during the course of the study, the subject develops a significant 
medical condition or is initiated on medication that can be expected to interact with any 
of the study drugs. The subject has the option of discontinuing their participation at any 
time for any reason. Any adverse effects not commonly associated with the drugs under 
study or any serious adverse events will be reported to the IRB. 
7.9 Medical Monitoring 
Dr. Leppik, who is a co-investigator and Medical Director of this project, will be 
responsible or monitoring adverse events. At each visit subjects will be asked whether 
they are experiencing any side effects. Vital signs are also monitored before and after 
drug administration. Dr. Leppik is an epileptologist with first hand knowledge of TPM in 
epilepsy patients. He is also the study physician on the preliminary TPM/LZP/PLA 
studies performed by this research group. This safety monitoring will include careful 
assessment and appropriate reporting of adverse events as noted above, as well as the 
construction and implementation of a site data and safety-monitoring plan (see section 9 
Auditing, Monitoring and Inspecting).  Medical monitoring will include a regular 
assessment of the number and type of serious adverse events. 


 
 
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8 Data Handling and Record Keeping 
8.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the subject 
of the following:  
• What protected health information (PHI) will be collected from subjects in this 
study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use 
PHI, attempts should be made to obtain permission to collect at least vital status (i.e. 
that the subject is alive) at the end of their scheduled study period. 
8.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents   Examples of these original 
documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial. 
 
Data generated by the methods described in the protocol will be recorded in the 
subjects' medical records and/or study progress notes. Data may be transcribed legibly 
on CRFs supplied for each subject or directly inputted into an electronic system or any 
combination thereof. 
8.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF must be recorded.  All missing data must be explained.  
If a space on the CRF is left blank because the procedure was not done or the question 
was not asked, write “N/D”.  If the item is not applicable to the individual case, write 
“N/A”.  All entries should be printed legibly in black ink.  If any entry error has been 
made, to correct such an error, draw a single straight line through the incorrect entry 
and enter the correct data above it.  All such changes must be initialed and dated.  DO 


 
 
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NOT ERASE OR WHITE OUT ERRORS.  For clarification of illegible or uncertain 
entries, print the clarification above the item, then initial and date it. 
8.4 Records Retention 
 
It is the investigator’s responsibility to retain study essential documents for at least 2 
years after the last approval of a marketing application in their country and until there 
are no pending or contemplated marketing applications in their country or at least 2 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  These documents should be retained for a longer period if 
required by an agreement with the sponsor.  In such an instance, it is the responsibility 
of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.  
 
9 Study Monitoring, Auditing, and Inspecting 
9.1 Study Monitoring Plan 
This study will be monitored according to FDA/GCP guidelines.  The investigator will 
allocate adequate time for such monitoring activities.  The Investigator will also ensure 
that the monitor or other compliance or quality assurance reviewer is given access to all 
the above noted study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 
9.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
the sponsor, government regulatory bodies, and University compliance and quality 
assurance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.).  The investigator will ensure 
the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection 
by government regulatory authorities and applicable University compliance and quality 
assurance offices. 
10 Ethical Considerations 
This study is to be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization 
guidelines), applicable government regulations and Institutional research policies and 
procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the IRB 


 
 
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This material is the property of the University of Minnesota.  Do not disclose or use except as authorized in writing by the study sponsor 
concerning the conduct of the study will be made in writing to the investigator and a 
copy of this decision will be provided to the sponsor before commencement of this 
study.  The investigator should provide a list of IRB members and their affiliate to the 
sponsor. 
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  The consent form will be submitted with the protocol for 
review and approval by the IRB for the study.  The formal consent of a subject, using 
the IRB-approved consent form, must be obtained before that subject is submitted to 
any study procedure.  This consent form must be signed by the subject or legally 
acceptable surrogate, and the investigator-designated research professional obtaining 
the consent.  
 
11 Study Finances 
11.1 Funding Source 
This study is funded from an R01 grant from the NIH/NINDS 1 R01NS076665-01A1. 
 
 
11.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) 
must refer to the Regents Policies on Individual Conflict of Interest Policy or Institutional 
Conflict of Interest Policy. These policies require University Faculty and staff to report 
external professional activities and business and significant financial interests related to 
his or her University activities by submitting a REPA (Report of External Professional 
Activities) at least once per year. Faculty and staff should also file a REPA when 
substantial changes in business or financial interests occur, when an activity that 
presents a potential conflict of interest is anticipated, or when submitting an application 
for research support or technology transfer, submitting research protocols to the IRB, or 
receiving financial contributions. All University of Minnesota investigators will follow the 
University conflict of interest policy.   
 
None of the investigators have a conflict of interest with this study. 
11.3 Subject Stipends or Payments 
 
Subjects will not incur any costs as a result of participation in the study. Compensation 
will be $75.00 for each of the two baseline sessions and $150.00 for each of the three 
drug (2 study drugs and 1 placebo) test sessions, and $50.00 for each of three visits at 
either 24, 48, 72 or 96 hours following sessions 2, 3, and 4, for a total of $750.00 for 
completing all 5 sessions  to compensate them for their time and inconvenience. If a 


 
 
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This material is the property of the University of Minnesota.  Do not disclose or use except as authorized in writing by the study sponsor 
subject cannot continue or chooses to drop out of the study, their payment will be 
prorated for the sessions completed.  Compensation will be paid by check issued from 
the University of Minnesota. 
 
 
Lunch will be provided at sessions 2, 3, and 4 and snacks will be available at all visits.  
Transportation by taxi will be provided for free at all visits. 
 
 
12 Publication Plan 
 
Neither the complete nor any part of the results of the study carried out under this 
protocol, nor any of the information provided by the sponsor for the purposes of 
performing the study, will be published or passed on to any third party without the 
consent of the co-principal investigators.  Any investigator involved with this study is 
obligated to provide the co-principal investigators with complete test results and all data 
derived from the study. 
13 References 
Daneman M, Carpenter PA. 1980. Individual differences in working memory and reading. J. of 
Verbal Learning & Verbal Behavior 19:450-466. 
 
Daneman M, Green I. 1986. Individual differences in comprehending and producing words in 
context. J of Memory and Language 25:1-18. 
 
Daneman M. 1991.  Working memory as a predictor of verbal fluency. J of Psycholinguistic Res 
20(6):445-464. 
 
Goodglass H, Kaplan E. 1983. The Assessment of Aphasia and Related Disorders. Philadelphia: 
Lea and Febiger. 
 
Kockelmann, E., C. E. Elger, and C. Helmstaedter, "Significant improvement in frontal lobe 
 associated neuropsychological functions after withdrawal of Topiramate in epilepsy patients," 
 Epilepsy Research, vol. 54, pp. 171-178, 2003/5 2003. 
 
Marino, SE,  Pakhomov SV, et al.  The effect of topiramate plasma concentration on 
linguistic behavior, verbal recall, and working memory. Epilepsy Behav. 2012, 24(3): 
365–372. 
 
Meador KJ, Loring DW, Abney OL, Allen ME, Moore EE, et al. 1993. Effects of carbamazepine 
 and phenytoin on EEG and memory in healthy adults. Epilepsia 34:153-7 
 
Meador KJ, Loring DW, Moore EE, Thompson WO, Nichols ME, et al. 1995. Comparative  
cognitive effects of phenobarbital, phenytoin, and valproate in healthy adults. Neurology  
45:1494-9 


 
 
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Meador, K.J.,  D. W. Loring, P. G. Ray, et al., "Differential cognitive and behavioral effects of 
carbamazepine and lamotrigine," Neurology, vol. 56, pp. 1177-82, May 8 2001. 
 
Meador, K.J., D. W. Loring, J. F. Hulihan, et al., "Differential cognitive and behavioral effects of  
topiramate and valproate," Neurology, vol. 60, pp. 1483-8, May 13 2003. 
 
Roark, B.,  J. Hosom, M. Mitchell, and J. A. Kaye, "Automatically derived spoken language 
 markers for detecting Mild Cognitive Impairment," in International Conference on Technology 
 and Aging (ICTA), 2007. 
 
Subramanian M, Birnbaum AK, Remmel RP. 2008. High-speed simultaneous determination of 
nine antiepileptic drugs using liquid chromatography-mass spectrometry. Ther Drug Monit 
30:347-56 
Werz MA, Schoenberg MR, Meador KJ, Loring DW, Ray PG, Kaul-Gupta R, Ogrocki P. 
Subjective preference for lamotrigine or topiramate in healthy volunteers: relationship to 
cognitive and behavioral functioning. Epilepsy Behav. 2006 Feb;8(1):181-91. 
 
Yngve,  V.H. "A model and a hypothesis for language structure," The American Philosophical 
Society, vol. 104, pp. 444-466, 1960.