Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02884050 |
| Other study ID # |
96-2009 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 1
|
| First received |
August 23, 2016 |
| Last updated |
January 9, 2017 |
| Start date |
April 2009 |
| Est. completion date |
January 2011 |
Study information
| Verified date |
January 2017 |
| Source |
University of Florida |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Food and Drug Administration |
| Study type |
Interventional
|
Clinical Trial Summary
Data generated from this pilot project will be used to support a larger, NIH funded study to
investigate the physiologic mechanisms associated with the cognitive side effects of a
commonly prescribed antiepileptic drug (AED), topiramate (TPM). This study will provide
pilot data to 1) demonstrate the viability of using quantitative electroencephalogram (EEG)
to examining physiological effects of AEDs as they relate to language function, and 2)
perform formal power estimate calculations in support of a longer-term connectivity study
using stochastic modeling techniques including power, coherence, and Granger causality
metrics to analyze AED effects on quantitative EEG. Traditionally, the cognitive side
effects of AEDs have been considered a byproduct of decreased neuronal excitation associated
with medical therapy, although recent data suggests that this may not be true for some newer
medications, such as TPM. The proposed experiments will employ quantitative EEG to
investigate the effects of topiramate on neuronal network connectivity and
pharmacokinetic/pharmacogenetic relationships in order to explore individual physiological
responses. Topiramate is selected because of its relatively unique effects on generative
verbal fluency, but unlike older AEDs, TPM is associated with little EEG change. The
investigators will compare the effects of TPM to baseline and an inactive placebo in a
randomized double blind crossover design.
Description:
Background:
Cognitive side-effects of antiepileptic drugs (AEDs) are important components of treatment
tolerability, although the physiologic mechanisms associated with their cognitive effects
are poorly understood. Quantitative EEG and other neurophysiologic measures are sensitive
indicators of central AED effects and in the older AEDs, with slowing consistent with a
diffuse encephalopathy, tend to covary with neuropsychological performance. EEG changes are
generally more sensitive than neuropsychological testing to AEDs, and have been demonstrated
for oxcarbazepine, phenytoin, carbamazepine, lamotrigine, and levetiracetam.
Recent evidence demonstrates that the cognitive effects of these agents cannot be explained
simply by diffuse reduction of neuronal excitability. Older AEDs are associated with a
mild-to-moderate generalized cognitive effect such as decreased psychomotor speed, which is
also accompanied by encephalopathic EEG patterns including increased spectral EEG power in
the lower frequency bands. Several of the newer AEDs have not demonstrated this pattern.
Some of these have reduced cognitive effects; however, one of the new AEDs, topiramate
(TPM), which also does not possess this EEG encephalopathic pattern, actually produces
greater cognitive deficits than many older AEDs.
Although newer AEDs tend to have a more favorable cognitive profile, TPM, which is indicated
for partial or primary generalized epilepsy as well as migraine prophylaxis, is being
increasingly prescribed for a wide range of neuropsychiatric disorders including bipolar
disorder, weight loss and even eating disorders despite carrying a high risk of
neuropsychological impairment with a prominent effect on verbal fluency. Although TPM's
effect on verbal fluency may reflect a more widespread disruption of frontal lobe function,
TPM's effect on verbal fluency has also been interpreted by some as reflecting a more
general effect on language. TPM has multiple mechanisms of actions including modification of
Na+ or Ca2+ dependent action potentials, enhancement of gamma-aminobutyric acid
(GABA)-mediated receptors, and inhibition of kainate-mediated conductance at glutamate
receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)/kainate
type. In addition, TPM is a carbonic anhydrase (CA) II inhibitor, and although the functions
of CA in the central nervous system (CNS) is not well-established, at least some CA
isoenzymes (CA II) have heavy human brain concentrations in oligodendrocytes and myelin.
Because TPM is unique in that its neuropsychological effects are not accompanied by
quantitative spectral EEG components, a generalized reduction in neuronal excitation is
insufficient to account for TPM's neuropsychological profile. Therefore, investigators are
investigating whether the physiologic mechanisms underlying TPM's negative cognitive effect
is reflected by altered patterns of neuronal EEG connectivity following a single dosing.
TPM's inhibitory effect on carbonic anhydrase suggests that its mechanism of cognitive
impairment may be related to white matter dysfunction altering neuronal connectivity. If
true, then TPM's effects should be greater on generative fluency than semantic-decision due
to disruption of intentional system connectivity of the frontal lobe and anterior cingulate
with other brain regions. Semantic-conceptual processing with semantic-decision should be
unaffected. However, TPM has multiple mechanisms which may contribute to its cognitive
effects. If a generalized "frontal lobe" effect is present, then similar TPM effects should
be present for working memory activations. EEG provides the opportunity to explore
differential changes in functional connectivity associated with AEDs as a function of task.
In addition, TPM appears to have a significant and selective effect on word finding and
verbal fluency in a minority of patients that isn't manifest by other AEDs. As Goldstein et
al point out in their recent review, this type of heterogeneity of response may be part be
explained by genes involved in both the metabolism and central response to TPM.
The investigators hypothesize that the physiological effects of TPM on cognition are
manifest at the functional network level, with the greatest reduction in connectivity
expected during verbal fluency. The primary objective of this project is to characterize
TPM's effects on working memory and verbal fluency during quantitative EEG recording in
healthy volunteers. This study will provide pilot data to 1) demonstrate the viability of
this approach to examining physiological effects of AEDs as they relate to language
function, and 2) perform formal power estimate calculations in support of a longer-term
connectivity study using stochastic modeling techniques including power, coherence, and
Granger causality metrics to analyze AED effects on quantitative EEG.
The primary research goal of this project is to establish the relationship of single dose
TPM on quantitative cognitive EEG in order to investigate the physiological mechanisms
underlying the cognitive effects of AEDs. Investigators will examine neuronal network
connectivity and potential pharmacokinetic relationships to individual physiological
responses.
Specific Aim 1a. To determine the change in functional EEG connectivity following single
dose TPM compared to placebo during a working memory task.
The secondary research goal of this project is to collect preliminary data on the genetics
of TPM metabolism and genetic influences on TPM-induced changes in verbal fluency and
working memory.
Specific Aim 2. To investigate the association between genotype and changes in verbal
fluency and working memory as a result of taking a single 100 mg TPM versus a placebo.
Design: This is a double-blind, placebo-controlled, double crossover study designed to
investigate the physiologic effect of a single dose of TPM (100 mg) or placebo on cognition
and working memory. Subjects will undergo cognitive EEG recording, neuropsychological
testing and blood draws.
Informed Consent:
The nature of the research study and the possible risks will be explained to each potential
subject. The subjects will be made aware that their medical care is not contingent on their
participation. Written informed consent will be obtained from each subject by one of the
co-investigators.
Design Overview:
On the study days, subjects will be initially directed to the University of Florida (UF)
Neuroinformatics Lab in the J. Crayton Pruitt Family Department of Biomedical Engineering:
- After signing the informed consent, subjects will be randomly assigned to a study
treatment sequence. All medication will be purchased by the UF Pharmacy. Subjects will
be asked to abstain from alcoholic beverages or over-the-counter medications for at
least 48 hours prior to testing though they will be permitted to consume caffeinated
beverages on the day of their assessment if that is part of their standard morning
routine.
- After being ask to consent to the study, a brief demographic, medical and medication
history will be taken on the first visit to assure that subjects are not currently on
any medications that can interact with either TPM.
- Vital signs will be recorded.
- Subject will be fitted with EEG electrodes. On the 2nd and 3rd visits, study medication
will be consumed just prior to the electrode placement.
- After completing the EEG recording session (approx. 2.5 hours), electrodes will be
removed, Blood will be drawn for serum concentrations (a genetic sample will be taken
at this time on the first visit ONLY after separate consent is obtained).
- The subject will then be given a small snack after which a brief neuropsychological
assessment (~ 20 minutes) will be administered by a blinded tester.
This same procedure will be repeated at least one week apart until all study conditions have
been obtained. All testing will be performed at approximately the same time of day. Subjects
will be required to arrange for transportation home each day following completion of the
experiments.
EEG RECORDING AND WORKING MEMORY TASK The EEG portion of this project will be conducted in
the Neuroinformatics Lab in the J. Crayton Pruitt Family Department of Biomedical
Engineering at the University of Florida. Subjects will be comfortably seated inside an
acoustically and electrically shielded booth designed to reduce ambient noise and 60 Hz
activity. 128 small electrodes will be placed on the research subjects' scalp using spandex
electrode cap. Standard procedures are used to reduce the electrical resistance at each
recording site by injecting a small amount of conductive gel into each electrode holder on
the cap. The scalp in each electrode site will be rubbed lightly before the gel injected. In
addition, seven additional flat-type electrodes are to be used, (a) two for each lateral
side of both eyes, (b) two for the above and below of the left eye, (c) two for right behind
each ear and (d) one for one of the arms depending on the subject's hand orientation.
The subject then is seated on a non-metal wooden chair in front of a computer screen inside
the electromagnetically and acoustically shielded chamber located in the lab. The subject
should memorize different set of numbers (maximum of five different digits) that will appear
on the screen. A few seconds later a probe (one digit number) will appear on the screen and
the subject need to responds as quickly as possible by pressing a button to indicate whether
the number belongs to the set.
One hour paradigm consists of four 15 minute blocks. Practice block will be given before the
actual one and one minute break time between the blocks will be given. Investigators can
communicate with the subject either by looking at the closed-circuit TV (CCTV) system from
outside or by talking through the wired radio system during the task.
NEUROPSYCHOLOGY BATTERY A battery of neuropsychological tests that includes measures from
our cognitive AED protocol as well as additional language-specific measures will be used:
Controlled Oral Word Association Test (COWA), which tests the ability to generate words
beginning with a specific letter of the alphabet; Action Verb Fluency, in which the subject
lists as many action verbs (run, climb) as they can in one minute; Category Fluency, in
which the subject lists as many names (i.e., of animals, pieces of clothing, etc) as they
can in one minute; Category Switching, where the subject switches between recall of names
from two different categories, i.e., between fruits and furniture; Hopkins Verbal Learning
Test (HVLT),which offers a brief assessment of verbal learning and memory (recognition and
recall) for individuals 16 years and older. It is a word list learning task; Symbol Digit
Modalities Test (SDMT), a test of graphomotor and psychomotor speed. Additional
psychological tests that will be administered include Boston Naming Test, action verb
fluency test, and the Boston Diagnostic Aphasia Examination Picture Description Task (PictA)
in which the subject is asked to describe a black-and-white schematic pencil drawing of a
scene containing several types of elicitation stimuli. (<5 min). Alternate versions of this
task include the Minnesota Test for Differential Diagnosis of Aphasia (PictB) and the
Nichols-Brookshire "Rescue" Picture Description Task (PictC) Administration of this battery
will take approximately 20-25 minutes. All tests will be audiotaped for further speech and
language analysis.
