Pediatrics 2006 Trevathan e371 8 jurnal

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DOI: 10.1542/peds.2006-0148; originally published online July 17, 2006;2006;118;e371PediatricsMessenheimer

Edwin Trevathan, Susan P. Kerls, Anne E. Hammer, Alain Vuong and John A.

Primary Generalized Tonic-Clonic SeizuresLamotrigine Adjunctive Therapy Among Children and Adolescents With

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ARTICLE

Lamotrigine Adjunctive Therapy Among Childrenand Adolescents With Primary Generalized

Tonic-Clonic Seizures

Edwin Trevathan, MD, MPHa, Susan P. Kerls, BSb, Anne E. Hammer, BSb, Alain Vuong, BSb, John A. Messenheimer, MDb

aPediatric Epilepsy Center, Division of Pediatric and Developmental Neurology, Departments of Neurology and Pediatrics, Washington University in St Louis School of

Medicine, St Louis, Missouri; bGlaxoSmithKline, Research Triangle Park, North Carolina

Financial Disclosure: This study was funded by GlaxoSmithKline, the maker of Lamictal (lamotrigine). Dr Trevathan has served as a paid consultant to GlaxoSmithKline but did not receive compensation for

writing this article or for assisting with the analysis of these data. Ms Kerls, Ms Hammer, Mr Voung, and Dr Messenheimer are full-time employees of GlaxoSmithKline.

ABSTRACT

CONTEXT AND OBJECTIVE. Primary generalized tonic-clonic seizures are relatively more

common among children than among adults. Primary generalized tonic-clonic

seizures are associated with increased risk of injury and death. Therefore, effective

control of primary generalized tonic-clonic seizures is necessary to reduce epilep-sy-related morbidity and mortality. Lamotrigine has demonstrated efficacy from

published randomized clinical trials for childhood partial seizures, absence sei-

zures, and for the generalized seizures associated with Lennox-Gastaut syndrome.

A randomized, blinded, placebo-controlled study was conducted to assess the

efficacy and tolerability of adjunctive therapy with lamotrigine in the treatment of

primary generalized tonic-clonic seizures among patients 2 years of age; we

report the data from children and adolescents 2 to 20 years of age from this

randomized clinical trial. This is the first published analysis of data from a ran-

domized, double-blind, controlled clinical trial of primary generalized tonic-clonic

seizures focusing on children and adolescents.

PATIENTS AND METHODS. We randomly assigned (1:1) 117 patients, aged 2 to 55 years,

with primary generalized tonic-clonic seizures inadequately controlled on 1 to 2current antiepileptic drugs and with evidence of primary generalized tonic-clonic

seizures on electroencephalogram and no historical or electroencephalogram ev-

idence of partial seizures to either lamotrigine or placebo in a double-blind parallel

group clinical trial from 2001 through 2004. We analyzed the subgroup of children

and adolescents, aged 2 to 20 years (n 45), from this randomized clinical trial.

Patients having 3 primary generalized tonic-clonic seizures over an 8-week

baseline were randomly assigned (1:1) to receive either lamotrigine or placebo.

The treatment period consisted of an escalation phase (12 weeks for patients 212

years; 7 weeks for patients 12 years) and a maintenance phase (12 weeks). The

study had 4 phases: screening phase, baseline phase, escalation phase, and main-

tenance phase. During the screening phase, baseline medical examinations and

www.pediatrics.org/cgi/doi/10.1542/

peds.2006-0148

doi:10.1542/peds.2006-0148

KeyWords

generalized tonic-clonic seizures,

childhood epilepsy, clinical trial,

lamotrigine, juvenile myoclonic epilepsy

Abbreviations

PGTCprimary generalized tonic-clonic

RCTrandomized clinical trial

EEGelectroencephalogram

AEDantiepileptic drug

Accepted for publication Mar 3, 2006

Address correspondence to Edwin Trevathan,

MD, MPH, Division of Pediatric and

Developmental Neurology, Washington

University School of Medicine, Campus Box

8111, 660 S Euclid Ave, St Louis, MO 63110-

1093. E-mail: [email protected]

PEDIATRICS (ISSNNumbers:Print, 0031-4005;

Online, 1098-4275). Copyright 2006by the

AmericanAcademy of Pediatrics

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seizure type and seizure frequency assessments were

performed. During the 8-week baseline phase, the num-

ber and dosages of concomitant antiepileptic drugs were

maintained while seizure frequency was assessed. The

assessment of primary generalized tonic-clonic seizure

frequency was determined during the 8-week baseline

phase. Patients eligible for random assignment experi-

enced 3 primary generalized tonic-clonic seizures dur-ing the baseline phase and 1 primary generalized ton-

ic-clonic seizure in the 8 weeks before the baseline

phase. Lamotrigine was introduced and titrated using a

schedule based on the patients age and concurrent an-

tiepileptic drug regimen. During the escalation phase,

the number and doses of concomitant antiepileptic drugs

were not changed. The escalation phase was followed by

a 12-week maintenance phase during which time the

lamotrigine dose was maintained at a specific dose de-

fined by the patients age and concomitant antiepileptic

drugs, whereas the doses of concurrent antiepileptic

drugs were maintained at a constant dose. Concurrentantiepileptic drugs could not be discontinued or added

during the maintenance phase. The primary efficacy end

point measure was the median reduction in the fre-

quency of primary generalized tonic-clonic seizures from

baseline; seizure counts were recorded prospectively in

standardized daily seizure diaries. Other efficacy end

point data for analysis were as follows: the median sei-

zure counts, the median percentage change from the

baseline phase in average monthly seizure frequency for

other generalized seizure types, and the percentage of

patients with a reduction of 25%, 50%, 75%, or

100% in frequencies of primary generalized tonic-clonicseizures and all generalized seizures during the escala-

tion phase and/or maintenance phase relative to the

baseline phase. Accurate counts of absence seizure fre-

quency require electroencephalogram-video monitor-

ing; absence seizure frequency was not an outcome

measure for this analysis.

RESULTS. Forty-five (21 lamotrigine and 24 placebo) pa-

tients 2 to 19 years of age were randomly assigned and

received study drug. Eight patients (3 lamotrigine and 5

placebo) had a combination of clinical (myoclonus

and/or absence seizures) and electroencephalogram

findings that were consistent with juvenile myoclonicepilepsy. Among the 45 children randomly assigned,

74% had generalized spike, polyspike, and/or general-

ized spike and wave discharges on routine electroen-

cephalogram recordings; the remaining 26% of children

had no electroencephalogram findings suggestive of par-

tial epilepsy and a clear history consistent with primary

generalized tonic-clonic seizures. Electroencephalogram

findings were not significantly different between the

lamotrigine and the placebo treatment groups. The me-

dian percentage decrease from baseline in primary gen-

eralized tonic-clonic seizures during the entire treatment

period was 77% in the lamotrigine group and 40% in

the placebo group (P .044). The median primary gen-

eralized tonic-clonic seizure counts per month were 0.7

in the lamotrigine group and 3.6 in the placebo group

during escalation (P .008), 0.3 in the lamotrigine

group and 2.0 in the placebo group during maintenance

(P .005), and 0.4 in the lamotrigine group and 2.5 in

the placebo group during the entire treatment period (P .007). Trends were noted during escalation and main-

tenance with a median percentage decrease in primary

generalized tonic-clonic seizures during escalation of

72% in the lamotrigine group and 30% in the placebo

group (P .059), and 83% in the lamotrigine group and

42% in the placebo group during maintenance (P

.058). During the maintenance phase, 48% of lam-

otrigine patients were seizure free compared with 17%

treated with placebo (P .051). One patient from each

treatment group discontinued from the study because of

an adverse event; 1 patient who received lamotrigine

experienced disorientation; and 1 patient who re-ceived placebo had a convulsion with apnea. No rashes

occurred among patients taking lamotrigine or placebo.

No patient experienced worsening of the intensity or

frequency of myoclonus.

CONCLUSIONS. Adjunctive lamotrigine therapy seems effec-

tive in controlling primary generalized tonic-clonic sei-

zures among patients 2 to 20 years of age.

PRIMARY GENERALIZED TONIC-CLONIC (PGTC) seizures

are relatively more common among children thanamong adults.1 PGTC seizures are associated with idio-

pathic generalized epilepsy and several generalized epi-

lepsy syndromes including juvenile myoclonic epilepsy

and juvenile absence epilepsy. Onset of PGTC seizures is

age related and typically starts in older children, adoles-

cents, and young adults commensurate with the onset of

idiopathic generalized epilepsies.2 PGTC seizures are as-

sociated with increased risk of injury3 and death.4 There-

fore, effective control of PGTC seizures is necessary to

reduce epilepsy-related morbidity and mortality. This is

the first published analysis of data from a randomized,

double-blind, controlled clinical trial of PGTC seizuresfocusing on children and adolescents.

Lamotrigine has demonstrated efficacy from pub-

lished randomized clinical trials (RCTs) for childhood

partial seizures,5 absence seizures,6,7 and for the gener-

alized seizures associated with Lennox-Gastaut syn-

drome.8 Lamotrigine has been reported in open-label

studies9,10 and in double-blind, active-comparator RCTs

to be effective in patients with newly diagnosed, previ-

ously untreated primary or secondary generalized sei-

zures.1113 Most of these studies did not differentiate be-

tween adults and children in the analysis or did not

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specifically exclude patients whose generalized tonic-

clonic seizures were actually partial seizures with sec-

ondary generalization.

The efficacy and tolerability of adjunctive lamotrigine

in patients with generalized seizures were investigated in

a multicenter, double-blind, placebo-controlled, add-on

RCT that included both children and adults from the

United States and from Latin America.14 Patients whoexperienced partial seizures or who had electroenceph-

alogram (EEG) evidence of partial onset seizures were

excluded. The relative paucity of published RCTs of

childhood PGTC seizures led us to do a posthoc analysis

to evaluate the efficacy and safety data among children

and adolescents (aged 220 years) from a double-blind,

placebo-controlled RCT of lamotrigine in the treatment

of PGTC seizures among children and adults.

METHODS

Protocol

We randomly assigned 117 patients, aged 2 to 55 years,

with PGTC seizures inadequately controlled on 1 to 2

current antiepileptic drugs (AEDs) and with evidence of

PGTC seizures on EEG and no historical or EEG evidence

of partial seizures to either lamotrigine or placebo in a

double-blind parallel group clinical trial from 2001

through 2004. Random assignment was accomplished

by a computerized random number generator at the

central data coordinating center; subjects were randomly

assigned across all sites in a 1:1 ratio of lamotrigine/

placebo. We analyzed the subgroup of children and ad-

olescents (n 45) from this RCT.14 Children and ado-

lescents were eligible for the study if they were 2 to 20

years of age and weighed a minimum of 13 kg and if

they had a diagnosis of PGTC seizures as classified by the

International League Against Epilepsy Classification of

seizures. Patients having 3 PGTC seizures over an

8-week baseline were randomly assigned (1:1) to receive

either lamotrigine or placebo. The treatment period con-

sisted of an escalation phase (12 weeks for patients 212years and 7 weeks for patients 12 years) and a main-

tenance phase (12 weeks; see Fig 1).

Lamotrigine has demonstrated efficacy in the treat-

ment of partial seizures; therefore, an algorithm was

used to exclude patients who also had partial seizures

with secondary generalization based on historical and

EEG data. The EEG and clinical history were together

consistent with the diagnosis of PGTC seizures for all of

the patients who met inclusion criteria. Patients with a

normal interictal EEG could meet inclusion criteria if the

clinical history was believed to be clinically consistent

with PGTC seizures. Patients with EEG and/or clinicalevidence of partial seizures were excluded. Rare, low

voltage focal spikes that did not disrupt the EEG back-

ground that were in the context of clear primary gener-

alized spikes and/or spike and wave were not an exclu-

sion criteria; these spike fragments are commonly seen

in the EEGs of children with primary generalized epi-

lepsy. However, children were excluded if their EEGs

demonstrated focal spikes that were thought by the elec-

troencephalographers to be typical for partial epilepsy.

Other exclusion criteria included a diagnosis of Lennox-

Gastaut syndrome, the use of any investigational drug

FIGURE 1

Study design: double-blind, randomized, parallel-group multicenter trial.



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within 30 days of study enrollment, and any previous

exposure to lamotrigine. Patients were not excluded if

they had both PGTC seizures and other primary gener-

alized seizures, as occurs, for example, in juvenile myo-

clonic epilepsy in which patients may have absence sei-

zures, PTGC seizures, and myoclonic seizures.

Patients were also excluded from the study if they

were breastfeeding, pregnant, attempting to becomepregnant, capable of bearing children without using ac-

ceptable forms of contraceptives, following the ketogenic

diet, had a coexisting disease that the investigators be-

lieved would interfere with the completion of the study,

abused alcohol or other illicit drugs, received chronic

treatment with a medication that could interfere with

seizure treatment, and/or planned vagal nerve stimula-

tor implantation or epilepsy surgery during the study

period. Informed consent was obtained, and the study

protocol was approved by an institutional review board

for each of the 38 sites that enrolled adults and/or chil-

dren.The study had 4 phases: screening phase, baseline

phase, escalation phase, and maintenance phase (Fig 1).

During the screening phase, baseline medical examina-

tions and seizure type and seizure frequency assessments

were performed, allowing for determination of the pa-

tients eligibility for the study. During the 8-week base-

line phase, the number and dosages of concomitant

AEDs were maintained while seizure frequency was as-

sessed. The assessment of PGTC seizures was prospec-

tively determined during the 8-week baseline phase. For

patients with reliable documentation of prestudy seizure

type and seizure frequency, the baseline assessment ofPGTC seizures could be obtained from either a historical

prestudy baseline or a combination of the historical and

prospective baselines (total: 8 weeks) before random

assignment. Patients eligible for random assignment ex-

perienced 3 PGTC seizures during the baseline phase

and 1 PGTC seizure in the 8 weeks before the baseline

phase. Patients meeting exclusion-inclusion criteria

were randomly assigned 1:1 to either lamotrigine or

placebo during the escalation and maintenance phases.

Lamotrigine was introduced and titrated using a

schedule based on the patients age and concurrent AED

regimen (Table 1). During the escalation phase, whichlasted 7 weeks for patients 12 to 20 years of age and 12

weeks for patients 2 to 12 years of age, the number and

doses of concomitant AEDs were not changed. The es-

calation phase was followed by a 12-week maintenance

phase during which time the lamotrigine dose was main-

tained at a specific dose defined by the patients age and

concomitant AEDs, while the doses of concurrent AEDs

were maintained at a constant dose. Concurrent AEDs

could not be discontinued or added during the mainte-

nance phase. After completion of the maintenance

phase, patients were offered the opportunity to receive

open-label lamotrigine for up to 1 year during a contin-uation phase of the study. Adjustment of concomitant

AEDs was allowed during the continuation phase.

Acute treatment with benzodiazepines (72 hours)

was permitted 3 times during both the escalation and

the maintenance phases to control clinically significant

increases in seizure frequency, duration, and/or inten-

sity. Patients who discontinued the study medication

during the study or at the end of the study were advised

to reduce the dose in a gradual stepwise fashion over a

minimum of 2 weeks, unless safety concerns (eg, rash)

required a more rapid dose reduction.

OutcomeMeasure

Patients and/or their caregivers (parents or guardians)

recorded PGTC seizure counts prospectively in standard-

ized daily seizure diaries throughout the study. These

TABLE 1 Dosing of Lamotrigine byAgeand byConcomitant AED

Variable Week of Dose Escalation Phase Week of Maintenance Phase

12 34 5 6 7 8 9 10 11 12 1324

Patients 212 Years Old

Lamotrigine dose, mg/kg per d

Taking valproate 0.15 0.3 0.6 0.9 1.2 1.5 1.8 2.1 2.4 2.7 Target: 3.0; range: 2.253.75 to a

maximum of 200 mg/dTaking an enzyme-inducing AEDa 0.6 1.2 2.4 3.6 4.8 6.0 7.2 8.4 9.6 10.8 Target: 12.0; range: 9.015.0 to a

maximum of 400 mg/d

Taking an AED other than valproate or

an enzyme-inducing AEDa0.3 0.6 1.2 1.8 2.4 3.0 3.6 4.2 4.8 5.4 Target: 6.0; range: 4.57.5 to a

maximum of 300 mg/d

Variable Week of Dose Escalation Phase Week of Maintenance Phase

12 34 5 6 7 824

Patients1220 Years Old

Lamotrigine dose, mg/kg per day

Taking valproate 12.5 25 50 100 150 Target: 200; range: 150250

Taking an enzyme-inducing AEDa 50 100 150 200 300 Target: 400; range: 300500

Taking an AED other than valproate or an enzyme-inducing AEDa 25 50 100 150 200 Target: 300; range: 225375

a Enzyme-inducing AEDs used in this study were phenytoin, phenobarbital, carbamazepine, and primidone.



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seizure diaries were reviewed by the investigators at

clinic visits during each study phase. Accurate counts of

absence seizure frequency require EEG-video monitor-

ing; absence seizure frequency was not an outcome

measure for this analysis. Adverse events were recorded

regardless of cause and defined as any untoward medical

occurrences reported by patients or noted by investiga-

tors at any time during the study. Investigators recordedwhether they thought the adverse event was likely

caused by the study medication. Weight, vital signs, and

physical examination findings were recorded at each

clinic visit. Serum lamotrigine concentrations were mea-

sured by standard liquid chromatography/mass spec-

trometry at the screening visit and at treatment weeks 7,

11, and 19 for patients 12 to 20 years of age and at

treatment weeks 7, 11, and 24 for patients 2 to 12 years

of age.

DataAnalysis

The median percentage of change in average monthly

PGTC seizure frequency from the baseline phase was the

primary efficacy end point. Other efficacy end point data

for analysis were as follows: the median seizure counts,

the median percentage of change from the baseline

phase in average monthly seizure frequency for other

generalized seizure types, and the percentage of patients

with a reduction of 25%, 50%, 75%, or 100% in

frequencies of PGTC seizures and all generalized seizures

during the escalation phase and/or maintenance phase

relative to the baseline phase. In addition, the number of

adverse events that was reported during the double-

blind treatment considered by the investigator to be

possibly, probably, or definitely drug related was also

summarized. Seizure frequency end points were calcu-

lated for both the escalation phase and the maintenance

phases separately and for these phases combined.

Differences between the placebo group and the lam-

otrigine group were determined using a 2-way analysis

of variance based on ranks with treatment group and age

categories as predictors of percent changes in average

seizure frequency, with Fishers exact test for percent-

ages of patients with specific percent reductions in sei-

zure frequency, and with a 2-way analysis of variance

based on ranks with treatment group and age category as

predictors for seizure counts.

Power calculations for the overall clinical trial (adults

and children 2 years of age) were performed based on

an 80% power to detect a difference of 25% in the

median percent reduction in PGTC seizures between

baseline and completion of the double-blind treatment

phase, with an SD of 45% at a significance level of .05.

It was estimated that 150 patients (adults and children

2 years) would need to be enrolled to randomly assign

104 patients required to satisfy the power calculations.

The clinical trial was not specifically powered for this

posthoc subanalysis of the children and adolescents

(220 years).

RESULTS

A total of 45 (21 lamotrigine and 24 placebo) patients 2

to 19 years of age were randomly assigned and received

study drug (Table 2). The most common concomitant

AED used for both those randomly assigned to lam-otrigine and placebo was valproate, which was used in

more than half of the placebo group and in two thirds of

those randomly assigned to lamotrigine (Table 3). The

majority of patients in both the lamotrigine and the

placebo groups had idiopathic epilepsy. All of the pa-

tients had PGTC seizures, and some patients had other

primary generalized seizure types (Table 4) as well. Eight

patients (3 lamotrigine and 5 placebo) had a combina-

tion of clinical (myoclonus and/or absence seizures) and

EEG findings that were consistent with juvenile myo-

clonic epilepsy. A single patient with atonic seizures did

not meet diagnostic criteria for Lennox-Gastaut syn-drome. Among the 45 children randomly assigned, 74%

had generalized spike, polyspike, and/or generalized

spike and wave discharges on routine EEG recordings;

the remaining 26% of children had no EEG findings

suggestive of partial epilepsy and a clear history consis-

tent with PGTC seizures. EEG findings were not signifi-

cantly different between the lamotrigine and the placebo

treatment groups.

The median percent decrease from baseline in PGTC

seizures (the primary efficacy end point) during the

entire treatment period was 77% in the lamotrigine

group and 40% in the placebo group (P

.044). Strongtrends were noted during escalation and maintenance

with a median percent decrease in PGTC seizures during

escalation of 72% in the lamotrigine group and 30% in

the placebo group (P .059) and 83% in the lam-

otrigine group and 42% in the placebo group (P .058)

during maintenance (Fig 2). The median PGTC seizure

TABLE 2 Demographics andBaselineCharacteristics

Variable LTG (n 21) PBO (n 24)

Age

Mean age (SD), y 11 (5.6) 11 (5.2)

Minimum 2 2

Maximum 19 19

Median 11 13

Age strata, y (%)

212 12 (57) 11 (46)

12 9 (43) 13 (54)

Female, % 48 25

Race, %

White 33 29

Black 19 17

Hispanic 48 54

Mean age (SD) at first seizure, y 5.7 (5.4) 6.8 (4.7)

Median number of PGTC seizures per month 2.0 3.8

LTG indicates lamotrigine; PBO, placebo.



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counts per month were 0.7 in the lamotrigine group and

3.6 in the placebo group during escalation, 0.3 in the

lamotrigine group and 2.0 in the placebo group duringmaintenance, and 0.4 in the lamotrigine group and 2.5

in the placebo group during the entire treatment period

(P .008, 0.005, and 0.007, respectively). Thirty-three

percent of patients on lamotrigine and 21% of patients

on placebo were seizure free during the dose escalation

phase (P .501), whereas during the maintenance

phase 48% of lamotrigine patients were seizure free

compared with only 17% treated with placebo (P

.051).

The most common adverse events were headache

(10% lamotrigine and 25% placebo), nasopharyngitis

(14% lamotrigine and 4% placebo), and convulsion

(10% lamotrigine and 17% placebo). One patient from

each treatment group discontinued from the study be-

cause of an adverse event; 1 patient who received lam-

otrigine experienced disorientation, and 1 patient who

received placebo had a convulsion with apnea. No rashes

occurred among patients taking lamotrigine or placebo.

Among patients who received lamotrigine, only 2

(9.5%) of 21 patients had an increase in seizure fre-

quency (29% and 31% increases) during the treatment

phase compared with baseline, whereas 7 (29%) of 24

patients who received placebo had an increase in seizure

frequency (18%, 35%, 38%, 51%, 115%, 189%, and

380% increases) compared with baseline. No patient

experienced worsening of the intensity or frequency of

myoclonus.

DISCUSSION

Adjunctive lamotrigine seems effective in the treatment

of PGTC seizures in children and adolescents and was

well tolerated in this double-blind, placebo-controlledRCT. These results support the hypotheses developed

from open-label reports suggesting that lamotrigine

might be effective in PGTC seizures.9,10,15 Previous clinical

trials have shown that lamotrigine is effective in the

treatment of primarily generalized absence seizures6,7

and in partial seizures in childhood.5 Lamotrigine is also

effective in the treatment of generalized seizures associ-

ated with the Lennox-Gastaut syndrome.8 The broad

spectrum of efficacy of lamotrigine in childhood epilepsy

contrasts with some other major AEDs used for partial

seizures of childhood (eg, carbamazepine) that are

known to exacerbate primarily generalized epilepsy,16,17

including PGTC seizures like those associated with juve-

nile myoclonic epilepsy.18 Lamotrigine is currently US

Food and Drug Administration approved as adjunctive

therapy for children and adults with partial seizures and

for the generalized seizures associated with Lennox-

Gastaut syndrome in adults and children.

This report is a posthoc analysis of the pediatric and

adolescent data from a larger RCT that included both

adults and children14 and, as such, has limitations. Spe-

cifically, this RCT was not powered for this subgroup

analysis. However, the magnitude of the difference be-

tween the lamotrigine and the placebo groups is verysimilar between the overall clinical trial and this sub-

group analysis.14 The significant percentage reduction in

PGTC seizures during the escalation plus maintenance

phase among patients who received lamotrigine is not

likely due to chance; we believe that it is unlikely that a

larger sample size would have altered our overall con-

clusions. Despite the underpowered nature of this sub-

group analysis, this is the first report of pediatric-only

data from a placebo-controlled clinical trial of PGTC

seizures that demonstrates efficacy.

The relatively high placebo response rate in the sub-

group of children and adolescents was very similar to the

placebo response rate in the overall clinical trial.14 There-

fore, the high placebo response in our subanalysis is not

likely because of inadequate sample size. High placebo

response rates have been reported in other clinical trials

of AEDs.8 Placebo-controlled trials in children have pre-

viously corrected misperceptions of drug efficacy from

open-label trials. For example, in the 1980s, open-label

studies of cinromide showed impressive reduction in

seizure frequency among children with multiple seizure

types, including generalized seizures. Yet the cinromide

placebo-controlled clinical trial demonstrated both a

high placebo response rate and no evidence of cinromide

TABLE 3 MostCommon Concurrent AEDs

AEDa LTG (n 21), % PBO (n 24), %

Valproate 67 58

Topiramate 19 17

Clonazepam 14 13

Clobazam 14 8

Phenobarbital 10 13

Phenytoin 14 8

Levetiracetam 10 8

LTG indicates lamotrigine; PBO, placebo.a Patients may have been taking 1 or 2 concurrent AEDs.

TABLE 4 SeizureEtiologic Classification andGeneralized Seizure

Types

Variable LTG (n 21) PBO (n 24)

Seizure etiologic classification, n(%)

Idiopathic 16 (76) 16 (67)

Symptomatic 1 (5) 3 (13)

Cryptogenic 4 (19) 5 (21)

Generalized seizure type, n(%)a

Typical absence 8 (38) 6 (25)Myoclonic 3 (14) 5 (21)

Clonic 0 0

Tonic 4 (19) 3 (13)

Tonic-clonic 21 (100) 24 (100)

Atonic 0 1 (4)

LTG indicates lamotrigine; PBO, placebo.a All patients had PGTC seizures. Some patients had additional generalized seizure types as

shown above. No patient had partial seizures.



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efficacy19; cinromide development as an AED was termi-

nated. Pediatricians should view the results from open-label reports of treatment effectiveness with a degree of

skepticism and, whenever possible, base clinical treat-

ment decisions on the results of RCTs.

This is the first RCT of PGTC seizures that has used

prospective EEG data with clinical data to exclude pa-

tients with partial seizures. A study of topiramate in the

treatment of PGTC seizures required that historical EEG

data not show evidence of partial seizures, but prospec-

tive EEG data were not required for entry into the

study.20 In a study of gabapentin in PGTC seizures, the

only other randomized, controlled clinical trial among

patients with PGTC seizures, efficacy was not demon-strated, and patients with partial seizures were not ex-

cluded.21 Failure to properly exclude patients with par-

tial seizures in studies of PGTC seizures may impact the

efficacy data, especially when the study drug has known

efficacy in partial seizures as well.

The majority of children with PGTC seizures respond

to the first AED prescribed.22 By choosing children who

had failed to respond to their first or second AED, this

study selected for children whose seizures were more

refractory to therapy than the typical child in the general

population with PGTC seizures. The majority of the chil-

dren who enrolled in this study failed previous treat-

ment with valproate, and all of the children enrolled in

this study failed previous treatment with marketed AEDs

that were believed to be effective in the treatment of

PGTC seizures.

There are very few proven options for treating PGTC

seizures among children. Valproate, which also has an

intravenous formulation, is commonly used for treat-

ment of PGTC seizures. Valproate is associated with rare

but serious idiosyncratic adverse events (ie, hepatic fail-

ure, aplastic anemia, and pancreatitis) and more com-

mon adverse events (eg, weight gain and polycystic

ovarian syndrome) that make its use problematic for

some children and adolescents.2325 Phenytoin and car-

bamazepine are frequently used to treat tonic-clonicseizures, yet these drugs are known to exacerbate PGTC

seizures among some patients.1618 Topiramate seems ef-

fective in the treatment of tonic-clonic seizures, but cog-

nitive slowing associated with topiramate has limited its

use as well.26

Lamotrigine has been associated with an increased

risk of potentially serious rash (including Stevens-John-

son syndrome and toxic epidermal necrolysis). The risk

of lamotrigine-associated rash is increased by using rapid

dose-escalation schedules, and the risk is reduced by the

dose-escalation schedules recommended in the lam-

otrigine (Lamictal [GlaxoSmithKline, Research TrianglePark, NC]) package insert.27,28 There are rare case reports

of lamotrigine-associated exacerbation of myoclonus,29

an adverse event that was not seen among the patients

in this study. Unlike valproate, lamotrigine is not asso-

ciated with significant weight gain.24

Lamotrigine seems effective in the treatment of PGTC

seizures and has demonstrated a good safety profile

among children and adolescents. Pediatricians continue

to have limited options for treating PGTC seizures in

children and adolescents. New drug development for

primary generalized seizures is needed, as are additional

clinical trials of PGTC seizures in children. The popula-

tion of children with PGTC seizures is relatively hetero-

geneous, as demonstrated in our study. Future clinical

trials of generalized epilepsy should ideally be performed

among more homogeneous patient populations with

specific epilepsy syndromes.

ACKNOWLEDGMENTS

We thank the following physicians for enrolling children

and adolescents in this clinical trial: Alexandre Todorov,

Tonia Sabo-Graham, Leonard Kaminow, Kore Liow,

Marilyn Duke-Woodside (deceased), Luis Pagani, Mutaz

Tabbaa, Walter Carlini, Ronald Davis, Yong Park, Stella

FIGURE 2Median percentage decrease from baseline in PGTC sei-

zures.



9/10

Legarda, Prakesh Kotagal, Suzanne Gazda, Shiva Natara-

jan, Osvaldo Grippo, Stella Ferraro, Jaime Godoy,

Patrick Parcella, and Patricia Campos.

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DOI: 10.1542/peds.2006-0148; originally published online July 17, 2006;2006;118;e371Pediatrics

MessenheimerEdwin Trevathan, Susan P. Kerls, Anne E. Hammer, Alain Vuong and John A.

Primary Generalized Tonic-Clonic SeizuresLamotrigine Adjunctive Therapy Among Children and Adolescents With

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