DOI 10.1212/WNL.52.7.

1330
1999;52;1330 Neurology
V. Biton, G.D. Montouris, F. Ritter, et al.
generalized tonic-clonic seizures
A randomized, placebo-controlled study of topiramate in primary
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is the official journal of the American Academy of Neurology. Published continuously Neurology
A randomized, placebo-controlled study
of topiramate in primary generalized
tonic-clonic seizures
V. Biton, MD; G.D. Montouris; F. Ritter, MD; J.J. Riviello, MD; R. Reife, MD; P. Lim, PhD;
G. Pledger, PhD; and the Topiramate YTC Study Group
Article abstractBackground and Objective: Topiramate is effective as adjunctive treatment of partial-onset seizures in
adults. The efficacy and safety of topiramate as adjunctive therapy for the treatment of primary generalized tonic-clonic
(PGTC) seizures were investigated in a randomized, double-blind, placebo-controlled study. Methods: Eighty patients, 3 to
59 years old, who experienced three or more PGTC seizures during an 8-week baseline phase were randomly assigned to
treatment with either topiramate (n 39) or placebo (n 41). Topiramate was titrated to target doses of approximately 6
mg/kg/day over 8 weeks and maintained for another 12 weeks. Results: The median percentage reduction from baseline in
PGTC seizure rate was 56.7% for topiramate patients and 9.0% for placebo patients (p 0.019). The proportion of patients
with 50% or higher reduction in PGTC seizure rate was 22/39 (56%) and 8/40 (20%) for the topiramate and placebo groups,
respectively (p 0.001). The median percentage reduction in the rate of all generalized seizures was 42.1% for topiramate
patients and 0.9% for placebo patients (p 0.003). The proportions of patients with 50% or higher reductions in
generalized seizure rate were 18/39 (46%) and 7/41 (17%) for the topiramate and placebo groups, respectively (p 0.003).
The most common adverse events were somnolence, fatigue, weight loss, difficulty with memory, and nervousness.
Treatment-limiting adverse events occurred in one patient in the topiramate group (anorexia and weight loss) and one in
the placebo group (granulocytopenia and thrombocytopenia). Conclusion: Topiramate is well-tolerated and effective for the
adjunctive treatment of PGTC seizures.
NEUROLOGY 1999;52:13301337
Topiramate is a structurally novel antiepileptic drug
(AED) derived from the D-enantiomer of fructose.
1
Topiramate appears to have multiple mechanisms of
action that may contribute to its activity in several
seizure types.
2
The efficacy and safety of topiramate
as add-on therapy to standard AEDs was extensively
investigated in randomized, double-blind, placebo-
controlled clinical trials involving adult patients
with a history of refractory partial-onset seizures,
with or without secondarily generalized seizures.
3-7
In these trials, topiramate, administered in target
dosages of 200 to 1,000 mg/day, was effective and
well-tolerated.
Although approximately 60% of all cases of epi-
lepsy are classified as partial epilepsy, approxi-
mately 30% are classified as generalized epilepsy.
8
The most debilitating seizure type within the gener-
alized epilepsies is the tonic-clonic seizure. The only
published placebo-controlled study of an AED used
to treat primary generalized tonic-clonic (PGTC) sei-
zures was a trial of gabapentin that failed to find a
statistically significant difference between gabapen-
tin efficacy and that of placebo.
9
Evidence of multiple
mechanisms of action and anecdotal reports of effi-
cacy for PGTC seizures led to the current study of
topiramates safety and efficacy as adjunctive ther-
apy in pediatric and adult patients with uncontrolled
PGTC seizures.
Methods. Study design. This was a randomized,
double-blind, parallel-group, placebo-controlled, multi-
center study. Seventeen study sites in the United States
and one in Costa Rica enrolled patients. After giving writ-
ten informed consent, patients were enrolled in an 8-week
baseline phase, followed by a 20-week double-blind phase
that consisted of an 8-week titration and a 12-week stabi-
lization period. Study visits were scheduled at 4-week in-
tervals, with an additional visit after 6 weeks of the
titration period.
Patients. Patients were eligible for the study if they
were 4 years of age or older, weighed more than 25 kg, and
if women, were premenarchal or postmenopausal or prac-
ticing an acceptable method of birth control. Patients en-
See also page 1338
From the Arkansas Epilepsy Program (Dr. Biton), Little Rock, AR; Epi-Care Center (Dr. Montouris), Memphis, TN; The Minnesota Epilepsy Group (Dr.
Ritter), St. Paul, MN; Childrens Hospital (Dr. Riviello), Boston, MA; The Corporate Office Science and Technology, Johnson & Johnson (Dr. Reife), New
Brunswick, NJ; and the R.W. Johnson Pharmaceutical Research Institute (Drs. Lim and Pledger), Raritan, NJ.
Received April 27, 1998. Accepted in final form January 9, 1999.
Address correspondence and reprint requests to Dr. Victor Biton, Arkansas Epilepsy Program, #1 Lile Court, Suite 100, Little Rock, AR 72205; e-mail:
vbiton@worldnet.att.net
1330 Copyright 1999 by the American Academy of Neurology
rolled in the study had a history of PGTC seizures, with or
without other generalized seizure types. Patients with a
history of partial-onset seizures were excluded. Patients
could be receiving one or two standard AEDs. Patients had
to experience at least three PGTC seizures during the
baseline phase; at least one seizure must have occurred in
each 4-week period of the baseline phase. Eligible patients
had EEG findings consistent with generalized epilepsy but
no other significant findings.
Patients excluded from the study were those with a
treatable cause of seizures (e.g., metabolic disturbance,
toxic exposure, active infection, or neoplasm); progressive
neurologic disease; clinically diagnosed Lennox-Gastaut
syndrome; evidence of use of an experimental device
within 60 days before enrollment; or treatment with acet-
azolamide, zonisamide, triamterene, vitamin C (2 g per
day), antacids, or calcium supplements within 3 months
before enrollment (because of an increased possibility of
renal stone formation). In addition, patients with a history
of any of the following were excluded: generalized tonic-
clonic status epilepticus (within the previous 3 months)
while receiving appropriate AED therapy; seizures occur-
ring only in clustered patterns; significant medical disease
(within the previous 2 years); a psychiatric or mood disor-
der (within the previous 6 months); attempted suicide;
nephrolithiasis; malignancy; or alcohol or drug abuse.
Treatment. The dose of study medication was based on
the patients weight, as outlined in table 1. During the
initial 4-week interval, topiramate or matching placebo
tablets were administered once a day in the evening. Dur-
ing the second and third intervals (2 weeks each) of the
titration period, topiramate (or matching placebo) was ti-
trated to target dosages of 175, 225, or 400 mg/day, in two
divided doses. Patients then were maintained on this regi-
men during the stabilization period. This schedule applied
unless the dosage was decreased by the investigator be-
cause of adverse events. If a subject could not tolerate a
dose, an adjustment could be made by decreasing study
medication until a maximum tolerated dose was achieved.
In addition, titration intervals could be adjusted for indi-
vidual subjects to achieve their maximum tolerated dose.
Doses of concomitant AEDs were constant during the
double-blind period. In the event that a patient could not
tolerate the titration schedule, the investigator was per-
mitted to either maintain or reduce the dosage level. For
patients who were withdrawn early from the study, the
dose of study medication was tapered and discontinued.
Reasons for withdrawal from the trial were specified in the
protocol as follows: subject initiated request, death, loss to
follow-up, or limiting adverse event or events.
Each investigator was provided with masked medica-
tion, according to a computer-generated randomization
schedule prepared by the Robert Wood Johnson Pharma-
ceutical Research Institute before the beginning of the
trial. Randomization was by permuted blocks of size two
and was stratified by center. During the double-blind
phase, investigators, patients, study monitors, and observ-
ers remained masked to codes until after the clinical data-
base was finalized.
Efficacy evaluations. Patients kept a seizure diary in
which they (or a parent or legal guardian) recorded a de-
scription of and the number of seizures that occurred dur-
ing the period between study visits. At each visit, the
investigator reviewed the patients seizure diary and clas-
sified each seizure recorded in the diary according to the
International Classification of Epileptic Seizures.
10-12
On
the final visit of the double-blind phase, patients rated
their improvement in seizure severity according to the fol-
lowing scale: 0 worse; 1 none; 2 minimal; 3
moderate; or 4 marked. The primary efficacy variable
was percentage reduction in PGTC seizure rate during the
double-blind phase. The percentage reduction during the
double-blind phase in all generalized seizures; proportions
of patients with 50% or more, 75% or more, and 100%
reduction in PGTC seizures and all generalized seizures;
and global evaluation of seizure severity were secondary
efficacy variables.
Safety evaluations. The evaluation of safety was based
on physical and neurologic examinations, vital signs and
body weight, EKGs, clinical laboratory tests, and adverse
events. At the final visit, patients rated their improvement
in mental status relative to the beginning of the study for
alertness, interaction with the environment, ability to per-
form activities of daily living, and responsiveness to verbal
requests. This global evaluation was rated on a 5-point
scale: 0 worse; 1 none; 2 minimal; 3 moderate; or
4 marked.
Drug concentration determinations. Blood samples for
determination of background AED concentrations were ob-
tained at each visit. Plasma topiramate concentrations
were determined from blood samples obtained during
double-blind treatment.
Statistical analyses. Analyses were based on data from
all randomized patients during the baseline and double-
blind phases of the study. Seizure data for patients who
were withdrawn from the study were averaged for the
Table 1 Dosing schedule for study medication (topiramate or matching placebo)
Weight, kg
Week during double-blind treatment
Target dose,* mg/kg/day
Titration period Stabilization period
14 56 78 920
2533.9 50 mg PM 50 mg twice a day 75 mg twice a day 75 mg twice a day 5.27.0
3442.9 50 mg PM 50 mg twice a day 75 mg twice a day 100 mg twice a day 5.26.6
43 50 mg PM 75 mg twice a day 150 mg twice a day 200 mg twice a day 9.3
Twice a day AM and PM.
* Theoretic dosage range based on protocol-defined topiramate maximum (target) dosages of 175, 225, or 400 mg/day.
April (2 of 2) 1999 NEUROLOGY 52 1331
portion of the double-blind phase completed up to the time
of study drug discontinuation. Additional analyses were
performed on patients who completed the double-blind
phase, but these analyses were considered to be secondary.
The percentage reduction in seizure rate from baseline
during the double-blind phase (for PGTC and all seizures)
was analyzed using a two-way analysis of variance
(ANOVA) based on ranks, using the SAS (Cary, NC) proce-
dure for general linear models,
13
to compare treatment
groups.
14
The Cochran-Mantel-Haenszel method
15
was
used to analyze differences in percentage responders
(those with at least a 50%, 75%, or 100% reduction from
baseline in average monthly rates of PGTC and of all gen-
eralized seizures) between treatment groups stratified by
center. All statistical tests were two-sided. A sample of 36
subjects per treatment group was estimated to be adequate
to detect a 30% between-group difference in PGTC seizure
rate. This assumed a type I error level of 5%, power of
80%, and population standard deviation of 45%.
Global evaluation of improvement in seizure severity
was analyzed using the exact Wilcoxon rank-sum test.
16
Treatment-emergent adverse events were tabulated, and
the cumulative incidence of treatment-emergent adverse
events over time was estimated using the Kaplan-Meier
method.
17
The patients global evaluations of mental sta-
tus, clinical laboratory test results, vital signs, and EKGs
were summarized.
The relationship between steady-state plasma topira-
mate concentration during the stabilization period and
clinical efficacy was evaluated: percentage reduction in sei-
zure rate (PGTC and all generalized seizures) during the
stabilization period was plotted against the mean plasma
topiramate concentration and Kendalls
b
correlation coef-
ficients for these variables were calculated across data for
all patients. Comparability between the topiramate and
placebo groups relative to plasma concentrations of con-
comitant AEDs was analyzed using a one-way ANOVA
based on the mean changes in plasma AED concentrations
from baseline to the double-blind phase.
Results. Patient characteristics. A total of 80 patients
were randomized to topiramate (39 patients) or placebo (41
patients; see figure 1). Demographic characteristics for
these 80 patients are summarized in table 2. The most
common background AEDs, in descending order, were val-
proic acid, phenytoin, carbamazepine, and lamotrigine.
Thirty-six patients in each treatment group achieved their
target dosage at some time during the double-blind treat-
Figure 1. Trial profile.
a
See table 1 for
topiramate dosages.
b
One patient had
no primary generalized tonic-clonic sei-
zures and was not included in the anal-
ysis of these seizures.
c
Noncompliance
(1); inadvertent premature discontinua-
tion (1).
1332 NEUROLOGY 52 April (2 of 2) 1999
ment phase. Thirty of 39 (77%) in the topiramate group
and 34 of 41 (83%) patients in the placebo group completed
the stabilization period on their target dosage. The mean
(SD) duration of double-blind treatment was 139.9 (25.4)
days in the topiramate group and 138.8 (29.3) in the pla-
cebo group. The mean (SD) dosage of topiramate was 3.6
(1.2) mg/kg/day during the entire double-blind phase and
5.0 (1.6) mg/kg/day during the stabilization period. The
mean (SD) plasma topiramate concentration for the entire
double-blind treatment phase was 5.1 (2.5) g/mL.
Protocol variations and withdrawal information. One
patient in the placebo group did not experience PGTC sei-
zures as required by protocol and was not included in the
analyses of PGTC seizures. Based on information obtained
after study completion, one patient in the topiramate
group was considered to have had symptoms that fulfilled
the diagnostic criteria for Lennox-Gastaut syndrome; this
patient was included in analyses. Eight patients (five in
the topiramate group and three in the placebo group) were
withdrawn early from the double-blind treatment phase
(see figure 1). Among the patients who were withdrawn in
the topiramate group, one patient was inadvertently ad-
vanced to an open-label extension of this trial as a result of
pharmacist distribution error.
Efficacy. The 56.7% median percentage reduction from
baseline in the average monthly PGTC seizure rate during
the double-blind phase in the topiramate group was signif-
icantly ( p 0.019) greater than the 9.0% reduction in
placebo-treated patients (figure 2). Topiramate was signif-
icantly ( p 0.003) better than placebo in terms of reduc-
ing the average monthly seizure rate for all generalized
seizures, 42.1% and 0.9%, respectively (see figure 2). For
generalized seizure subtypes, too few patients were ob-
served to draw any conclusions about comparative seizure
rate changes; however, the available data on those sei-
Table 2 Demographic and baseline characteristics
Variable
Placebo
(n 41)
Topiramate
(n 39)
Male/female 21/20 24/15
Race, n
White 36 32
Black 5 6
Hispanic 0 1
Age, y
Mean SD 25.6 13.4 26.8 12.8
Range 3.050.0 5.059.0
16 13 8
16 28 31
Weight, kg
Mean SD 61.3 25.1 71.8 28.5
Range 17129 22143
Baseline seizure rate,
seizures/month*
PGTC seizures, median
(range)
4.5 (1300) 5.0 (1298)
All seizures, median (range) 17.5 (279,109) 15.3 (11134)
Baseline seizure type, n
Tonic-clonic 40 39
Tonic-clonic only 13 13
Absence 16 16
Tonic 10 9
Myoclonic 8 8
Drop attack 5 2
Atypical absence 4 2
Clonic 1 1
Other 1 1
Background AEDs, n
One AED 9 9
Two AEDs 22 19
More than two AEDs 10 11
Valproic acid 20 19
Phenytoin 13 12
Carbamazepine 9 11
Lamotrigine 10 6
Phenobarbital 3 8
Clonazepam 6 6
Gabapentin 3 5
Primidone 6 0
* Average monthly seizure rate per 28 days.
One patient in the placebo group did not experience PGTC sei-
zures during the baseline phase, as required by protocol.
PGTC primary generalized tonic-clonic seizures; AED anti-
epileptic drug.
Figure 2. Median percentage reduction from baseline in
average monthly rates of primary generalized tonic-clonic
(PGTC) seizures and of all seizures. White bars, placebo;
black bars, topiramate.
April (2 of 2) 1999 NEUROLOGY 52 1333
zures experienced by at least nine patients per treatment
group (absence, myoclonic, and tonic seizures) showed no
seizure exacerbation in topiramate-treated patients.
Although no significant correlation between plasma
topiramate concentration and percentage reduction in av-
erage monthly PGTC seizure rate was determined (
b

0.189; p 0.118), a weak correlation was found between
plasma topiramate concentration and percentage reduction
in the average monthly rate of all generalized seizures
(
b
0.257; p 0.032). Twelve patients with topiramate
plasma concentrations of less than 5.04 g/mL, 12 patients
with concentrations between 5.04 g/mL and 8.46 g/mL,
and 11 patients with concentrations of 8.46 or more g/mL
had median percentage reductions in PGTC seizures of
39.5%, 60.8%, and 51.8%, respectively, and median per-
centage reductions in all seizures of 2.9%, 59.0%, and
51.5%, respectively.
Twenty-two of 39 (56%) topiramate-treated and 8 of 40
(20%) placebo-treated patients exhibited at least a 50%
reduction from baseline in average monthly PGTC seizure
rate ( p 0.001). For all generalized seizures, 46% (18/39)
of topiramate patients and 17% (7/41) of placebo patients
had (50% reduction in seizure rate ( p 0.003; figure 3). A
significantly ( p 0.037) greater proportion of topiramate-
treated (33%; 13/39) than placebo-treated (13%; 5/40) pa-
tients had a 75% or higher reduction in PGTC seizure rate.
Moreover, a greater percentage of topiramate-treated
(13%; 5/39) than placebo-treated (5%; 2/40) patients were
PGTC seizure-free (100% reduction in PGTC seizure rate),
although this difference did not achieve statistical signifi-
cance ( p 0.225). The same trends were observed for all
generalized seizures with 10 of 39 (26%) topiramate-
treated patients compared with 3 of 41 (7%) placebo-
treated patients achieving a 75% seizure rate reduction
( p 0.026) and 2 of 39 (5%) topiramate-treated patients
achieving seizure freedom in comparison to no placebo-
treated patients ( p 0.173; see figure 3). Reductions in
PGTC seizures by age (16 years and 16 years) are pre-
sented in figure 4 and show that the response to topira-
mate was not age-dependent. Patients global evaluations
of improvement in seizure severity were similar in the
topiramate and placebo groups.
When seizure response rates were evaluated for pa-
tients who completed the double-blind phase, results were
consistent with those described for the intent-to-treat pop-
ulation. For the topiramate- versus placebo-treated pa-
tients who completed the study, 21 of 34 (62%) versus 7 of
37 (19%) had at least a 50% reduction ( p 0.001), 12 of 34
(35%) versus 4 of 37 (11%) had at least a 75% reduction
( p 0.020) and 5 of 34 (15%) versus 1 of 37 (3%) had a
100% reduction ( p 0.095) from baseline in PGTC sei-
zures. For all generalized seizures, of the double-blind
phase completers, 17 of 34 (50%) of the topiramate group
versus 7 of 38 (18%) of the placebo group had at least a
50% reduction from baseline in average monthly seizure
rate ( p 0.001), 10 of 34 (29%) versus 3 of 38 (8%),
respectively, at least a 75% reduction ( p 0.017) and 2 of
34 (6%) versus 0 of 38 patients, respectively, were seizure
free ( p 0.173).
The AEDs used concomitantly during the study by at
least five patients in each treatment group included val-
proic acid (20 patients in each group), phenytoin (12 in the
placebo group and 15 in the topiramate group, carbamaz-
epine (9 in the placebo group and 13 in the topiramate
group), lamotrigine (11 in the placebo group and 6 in the
topiramate group), and phenobarbital (7 in the placebo
group and 9 in the topiramate group). Mean changes in
plasma concentrations of valproic acid, phenytoin, carbam-
azepine, lamotrigine, and phenobarbital during the double-
blind phase relative to baseline were small in both the
topiramate and placebo patients and except for carbamaz-
Figure 3. Percentages of patients achieving a 50%,
75%, or 100% reduction from baseline in the average
monthly rate of all generalized seizures. White bars, pla-
cebo (n 41); black bars, topiramate (n 39).
Figure 4. Reductions in primary generalized tonic-clonic
(PGTC) seizures by age. White bars, placebo; black bars,
topiramate.
1334 NEUROLOGY 52 April (2 of 2) 1999
epine were not statistically significantly different. During
the double-blind phase, the mean plasma concentration of
carbamazepine increased by 0.7 g/mL in the placebo
group (from a baseline mean of 9.6 g/mL) and decreased
by 1.4 g/mL (from a mean baseline of 8.9 g/mL) in the
topiramate group ( p 0.009).
Safety. The most common treatment-emergent ad-
verse events are summarized in table 3. Among these,
seasonal illnesses (upper respiratory tract infection, phar-
yngitis, otitis media) and associated symptoms (fever, vom-
iting, abdominal pain, and nausea) were the most
frequently reported. Somnolence, anorexia, difficulty with
memory, nervousness, psychomotor slowing, fatigue, and
speech disorders and related speech problems were CNS
treatment-emergent adverse events that were reported
more frequently for topiramate than for placebo. In com-
parison, headache, dizziness, insomnia, and personality
disorder were treatment-emergent CNS adverse events
that were reported more frequently for placebo treatment
than for topiramate.
Two patients in the placebo group and four patients in
the topiramate group had one or more treatment-emergent
adverse events that required a dosage reduction in study
medication. In both groups, these adverse events were
CNS-related and included such events as personality dis-
order, difficulty with memory, somnolence, insomnia, and
abnormal gait.
Most of the treatment-emergent adverse events re-
ported during the trial were mild to moderate in severity.
Five treatment-emergent adverse events in the topiramate
group (one report each of injury, pain, abnormal gait,
speech disorders and related speech problems, and viral
infection) and six in the placebo group (two reports of
headache and one report each of chest pain, dyspepsia,
increased saliva, impotence, and granulocytopenia) were
considered to be of marked severity. Serious treatment-
emergent adverse events were experienced by two placebo-
treated patients (one with abscess and one with chest pain)
and by four topiramate-treated patients (one with pneumo-
nia, one with grand mal convulsions, one with tremor,
speech disorder [slurred speech], abnormal gait, and ner-
vousness and one with thrombophlebitis, micturition disor-
der, urinary incontinence, prostatic disorder, and viral
infection). Two patients withdrew from the study because
of adverse experiences: one patient in the placebo group
with granulocytopenia and thrombocytopenia and one pa-
tient in the topiramate group with anorexia and weight
loss. Results of an analysis using the Kaplan-Meier
method did not show a significantly consistent relation
between the first occurrence of treatment-emergent ad-
verse events and duration of exposure to topiramate.
The results of the patients global evaluation of mental
status indicated that topiramate-treated patients tended
to show more improvement than did placebo-treated pa-
tients (figure 5). Among the various items rated (alertness,
interaction with the environment, ability to perform activ-
ities of daily living, and responsiveness to verbal requests),
the proportion of patients who evaluated themselves as
Table 3 Incidence of the most common* treatment-emergent
adverse events
Adverse event
Patients, %
Placebo,
n 41
Topiramate,
n 39
Somnolence 15 26
Anorexia 7 15
Difficulty with memory 0 13
Nervousness 0 10
Psychomotor slowing 2 10
Upper respiratory tract
infection
32 41
Pharyngitis 5 10
Fatigue 7 18
Weight loss 2 15
Headache 20 13
Dizziness 15 10
Speech disorders and related
speech problems
2 10
Abdominal pain 5 10
* Experienced by 10% of patients in the topiramate group.
Figure 5. Global evaluations of im-
provement in mental status in 39 topi-
ramate patients (black bars) and 38
placebo patients (white bars).
April (2 of 2) 1999 NEUROLOGY 52 1335
showing improvement (minimal, moderate, or marked)
ranged from 41% to 49% in the topiramate group and from
29% to 39% in the placebo group.
There were no clinically significant mean changes in
any laboratory test value other than those associated with
carbonic anhydrase inhibition. There were no clinically
meaningful treatment-emergent changes in vital signs,
neurologic examination findings, physical examination
findings, or EKG results. As noted previously, one patient
in the topiramate treatment group was withdrawn early
from the study because of anorexia and a decrease in
weight. Topiramate-treated patients had a mean weight
decrease of 1.8 kg (2.2%), whereas placebo-treated pa-
tients had a mean increase of 1.1 kg (2.0%).
Discussion. The results of this randomized,
double-blind, placebo-controlled trial demonstrated
that topiramate is effective for the treatment of
PGTC seizures in children and adults. This is the
first study to demonstrate a statistically significant
effect of an AED compared with placebo in patients
with PGTC seizures. The only other published
placebo-controlled study investigated the effect of
gabapentin in patients with generalized tonic-clonic
seizures.
9
Although gabapentin tended to reduce the
frequency of generalized tonic-clonic seizures to a
greater degree than did placebo, the difference be-
tween treatment groups failed to achieve statistical
significance. The study of gabapentin was conducted
in a heterogeneous population that included patients
with symptomatic generalized epilepsy in addition to
those with idiopathic generalized epilepsy.
Patient selection is a key factor in the conduct of
clinical investigations. In the present study, topira-
mate was evaluated as adjunctive therapy for PGTC
seizures, defined as tonic-clonic seizures that gener-
alized from the outset (i.e., without evidence of a
focal onset). Every effort was made to establish and
follow strict entry criteria and to verify diagnosis
with rigorous neurologic, clinical, and electroen-
cephalographic evaluations. Patients with Lennox-
Gastaut syndrome were excluded. Although
approximately 70% of the patients had other gener-
alized seizure types (typically absence, myoclonic, or
tonic seizures) that frequently accompany PGTC sei-
zures, no attempt was made to group patients by
syndrome.
In the present study, maximum daily topiramate
doses varied, depending on body weight, to approxi-
mate 6 mg/kg/day (175 mg for those 34 kg, 225 mg
for those 34 to 43 kg), or 400 mg (43 kg). The
daily target dose used in the present trial for chil-
dren, 6 mg/kg/day, is approximately equivalent to a
daily dose of 400 mg in adults; this dose has been
shown to be fully effective as adjunctive treatment
for partial-onset seizures in adults.
4
Because gener-
alized seizures usually require lower doses of AEDs,
this dose would be expected to be adequate to treat
generalized seizures.
In the current study, mean changes from baseline
in plasma concentrations of concomitant background
AEDs during the double-blind period were small in
magnitude and generally similar in topiramate-
treated and placebo-treated patients, indicating that
the study drug effects observed were not mediated
through changes in plasma concentrations of con-
comitant AEDs. The significant difference between
the decrease in the topiramate group and the in-
crease in the placebo group in carbamazepine con-
centration changes from baseline (1.4 g/mL and
0.7 g/mL, respectively; p 0.009) would not be
expected to favor topiramate over placebo in treat-
ment comparisons. The apparent lack of effect of
topiramate on plasma concentrations of concomitant
AEDs observed in the present study is consistent
with findings from other topiramate clinical studies
involving patients with partial-onset seizures, with
or without secondarily generalized seizures.
3,4,6
Topiramate was well-tolerated in this population
of pediatric and adult patients with PGTC seizures.
More than three-fourths of topiramate-treated pa-
tients achieved and maintained their target dosage.
The adverse-event profile for topiramate observed in
our study was consistent with that seen in topira-
mate studies involving adults with partial-onset sei-
zures, with or without secondarily generalized
seizures.
3-7
In those studies, the most frequent ad-
verse events were related to the CNS. Unlike the
case in other clinical studies, however,
4-6
in which
the most common reasons for discontinuation were
CNS-related adverse events, no patients in our study
were withdrawn early for such reasons. This may be
attributed to the slower titration schedule (8 weeks)
and smaller dosage increments used in our study,
compared with previous studies in which topiramate
was rapidly titrated to 200 to 1,000 mg/day over a
period of 2 to 5 weeks in weekly increments of 100
mg/day initially, followed by 100 mg twice daily.
3-7
In
the present study, patients or parents/guardians re-
ported that somewhat higher frequencies of patients
treated with topiramate showed improvement in
mental status, although most patients in both groups
showed no change. The absence of clinically signifi-
cant abnormalities in liver function, renal function,
and hematology test values was notable. Consistent
with our results that showed a mean weight de-
crease of 1.8 kg (2.2%) at the end of double-blind
treatment, weight decrease among topiramate-
treated patients has been reported in other topira-
mate clinical studies.
3,4
Thus, topiramate was effective and well-tolerated
when administered as adjunctive therapy for 20
weeks in dosages up to 400 mg/day in pediatric and
adult patients with PGTC seizures. Topiramate was
effective in reducing the rate of PGTC seizures and
the overall rate of all generalized seizures. Despite
concomitant administration of topiramate with back-
ground AEDs, topiramate was well-tolerated. The re-
sults of this study support topiramates promise as
an effective new AED for adjunctive therapy of pedi-
atric and adult patients with PGTC seizures.
1336 NEUROLOGY 52 April (2 of 2) 1999
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April (2 of 2) 1999 NEUROLOGY 52 1337
DOI 10.1212/WNL.52.7.1330
1999;52;1330 Neurology
V. Biton, G.D. Montouris, F. Ritter, et al.
tonic-clonic seizures
A randomized, placebo-controlled study of topiramate in primary generalized
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