Epilepsia, 50(5):11411149, 2009

doi: 10.1111/j.1528-1167.2008.01981.x

FULL-LENGTH ORIGINAL RESEARCH

Adjunctive levetiracetam in infants and young children

with refractory partial-onset seizures
*Jesus Eric Pina-Garza, yDouglas R. Nordli Jr, zDietz Rating, xHaichen Yang,
xJimmy Schiemann-Delgado, and xBenjamin Duncan; on behalf of the Levetiracetam
N01009 Study Group1
*Childrens Hospital at Vanderbilt, Nashville, Tennessee, U.S.A.; yChildrens Memorial Hospital, Feinberg School of
Medicine, Northwestern University, Chicago, Illinois, U.S.A.; zEpilepsy Centre Childrens Hospital, University of
Heidelberg, Heidelberg, Germany; and xUCB Inc, Smyrna, Georgia, U.S.A.

SUMMARY
Purpose: To evaluate the efficacy and tolerability
of adjunctive levetiracetam in very young children
(aged 1 month to <4 years) with partial-onset
seizures inadequately controlled with one or two
antiepileptic drugs.
Methods: This multicenter, double-blind, randomized, placebo-controlled study consisted of a 48-h
inpatient baseline video-EEG (electroencephalography) and a 5-day inpatient treatment period (1day up-titration; 48-h evaluation video-EEG in the
last 2 days). Children who experienced at least
two partial-onset seizures during the 48-h baseline
video-EEG were randomized to either levetiracetam [40 mg/kg/day (age 1 to <6 months); 50 mg/
kg/day (age 6 months to <4 years] or placebo.
Results: Of 175 patients screened, 116 patients
were randomized [60 levetiracetam; 56 placebo;
intent-to-treat (ITT) population], and 111 completed the study. The responder rate in average
daily partial-onset seizures frequency (48-h video-

Introduction
Children represent a disproportionately large group of
individuals with epilepsy (Hauser, 1992; Bourgeois,
Accepted October 23, 2008; Early View publication February 23,
2009.
Address correspondence to Dr. Jesus Eric Pia-Garza, Childrens Hospital at Vanderbilt, 2200 Childrens Way, Doctors Office Tower 11210,
Nashville, TN 37232, U.S.A. E-mail: eric.pina-garza@vanderbilt.edu
1
Members of the N01009 Study Group are listed in the Acknowledgments.
This article is dedicated to Mary Pia-Garza in memory of her outstanding contributions to the success of this study and to the welfare of
children with epilepsy.
Wiley Periodicals, Inc.
2009 International League Against Epilepsy

EEG monitoring; primary efficacy variable) was

43.1% for levetiracetam [modified ITT (mITT) =
58] versus 19.6% for placebo (mITT = 51; p =
0.013), with odds ratio for response 3.11 [95%
confidence interval (CI), 1.228.26]. The median
percent reduction from baseline in average daily
partial-onset seizure frequency was 43.6% for
levetiracetam and 7.1% for placebo with a median
difference between treatment groups of 39.2%
(95% CI, 17.562.2; p < 0.001). In general, levetiracetam was well tolerated. Treatment-emergent
adverse events were reported by 55.0% levetiracetam- and 44.6% placebo-treated patients (ITT population). The most frequently reported adverse
events were somnolence (13.3% levetiracetam,
1.8% placebo) and irritability (11.7% levetiracetam,
0% placebo).
Discussion: Adjunctive levetiracetam is an efficacious and well-tolerated treatment for partialonset seizures in infants and young children.
KEY WORDS: Epilepsy, Children, Levetiracetam,
Antiepileptic drug, Partial seizures.

1995). Although epilepsy in childhood is frequently well

controlled with existing antiepileptic drugs (AEDs), more
than 25% of these children and adolescents have uncontrolled seizures or significant side effects (Pellock &
Appleton, 1999). Partial-onset epilepsies usually start in
childhood or adolescence and may require lifelong AED
treatment (Connock et al., 2006).
Levetiracetam (Keppra, UCB Pharma Sa, BraineIAllend, Belgium) is a newer AED with a novel mechanism of action. It acts primarily through interaction with the
synaptic vesicle protein 2A (Lynch et al., 2004), which is
implicated in the control of synaptic vesicle fusion, exocytosis, and neurotransmitter release (Crowder et al., 1999). It
has favorable dose-proportional pharmacokinetics with
low potential for clinically significant pharmacokinetic

1141

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J. E. Pina-Garza et al.
drug interactions in adults (Perucca et al., 2003; Patsalos,
2004; Gidal et al., 2005) and children aged 4 years (Pellock et al., 2001; Fountain et al., 2007; Otoul et al., 2007;
Toublanc et al., 2008). The pharmacokinetic profile of
single-dose levetiracetam in children aged 246 months is
similar to that reported in children aged 4 years and is
characterized by rapid absorption, resulting in peak
plasma concentrations within 1.4 h of dosing and a halflife of approximately 5 h (Glauser et al., 2007).
Levetiracetam has been shown to be effective in controlling partial-onset seizures as initial monotherapy in
adults (Brodie et al., 2007) and as add-on therapy in adults
(Ben-Menachem & Falter, 2000; Cereghino et al., 2000;
Boon et al., 2002) and children aged 416 years (Glauser
et al., 2006). Adjunctive levetiracetam has also been demonstrated to be effective in controlling myoclonic
(Noachtar et al., 2008) and generalized tonicclonic seizures (Berkovic et al., 2007) in patients with idiopathic
generalized epilepsy (IGE), demonstrating a broad spectrum of activity in epilepsy across different seizure types.
Open-label prospective (Wheless & Ng, 2002; Lagae
et al., 2003; Coppola et al., 2004; Grosso et al., 2005) and
retrospective (Grosso et al., 2007; Perry & Benatar, 2007)
studies in children with refractory partial-onset or generalized seizures have suggested that levetiracetam could be
effective and well tolerated in children younger than
4 years.
In this study, the efficacy and tolerability of levetiracetam in very young children (1 month to <4 years) with
inadequately controlled partial-onset seizures was evaluated. Accurately classifying seizures in children can be
challenging because of the different manifestations of
childhood epilepsy: the younger the child, the greater the
likelihood of misinterpretation. Neonates and very young
infants frequently have electrographic seizures without
clinical manifestations (Clancy, 1996). Video-electroencephalography (EEG) was used in this study to reliably
identify and assess partial-onset seizures in infants and
young children.

Methods
Study design
This was a randomized, double-blind, multicenter,
placebo-controlled, inpatient study of levetiracetam oral
solution as adjunctive therapy of inadequately controlled
partial-onset seizures over a 5-day evaluation period.
This study (N01009; NCT 00175890) was conducted in
62 centers in 13 countries (Belgium, Brazil, Czech Republic, France, Germany, Hungary, Italy, Mexico, Poland,
Romania, Russia, United Kingdom, and U.S.A.). It began
on 15 October 2004 and was completed on 26 January
2007. It consisted of selection (up to 9 days), evaluation
(1-day up-titration; 4-day stable dose regimen), plus either
a 2-week down-titration and posttreatment follow-up (day
Epilepsia, 50(5):11411149, 2009
doi: 10.1111/j.1528-1167.2008.01981.x

20) for patients discontinuing the study or enrollment in a

long-term follow-up study (N01148; NCT 00152516)
(Fig. 1).
The selection period comprised outpatient and inpatient
periods. During the outpatient period, all patients were
prescreened for eligibility and age stratification by the
UCB Clinical Research Physician or designee, before
enrollment by individual trial investigators. Investigators
obtained informed consent, assessed entry criteria, and
performed screening procedures. During the inpatient
period patients were monitored by video-EEG for 48 h.
Partial-onset seizure frequency for infants aged 1 to
<6 months was based on electroclinical or electrographic
seizures; for children aged 6 months to <4 years it was
based on electroclinical seizures only. Electroclinical seizures had to be accompanied by corresponding clinical
events as noted on video or reported by a medically qualified observer; electrographic seizures did not have a corresponding clinical event. Data for electroclinical and
electrographic seizures were collected during the baseline
48-h and the evaluation 48-h video-EEG (days 4 and 6),
and subsequently read by a blinded central video-EEG
reader.
Electrographic seizures were defined as short-duration
seizures (minimum 10 s) that could be verified, involved
at least two adjacent electrodes, and were clearly focal or
asymmetric if more diffuse (or consistent with a focal epileptic discharge). Patients who experienced at least two
partial-onset seizures with or without secondary generalizations during the baseline 48-h video-EEG, were randomized to levetiracetam or placebo (1:1) using an
interactive voice response system and were stratified into
one of four age groups: 1 to <6 months, 6 months to
<1 year, 1 to <2 years, and 2 to <4 years.
The dose of levetiracetam was stratified by age, since a
previous study had shown that levetiracetam plasma clearance in infants aged under 6 months is slower compared
to that in children aged 6 months to 4 years (1.23 ml/min/
kg vs. 1.57 ml/min/kg) (Glauser et al., 2007). In patients
aged 1 to <6 months, levetiracetam was initiated at
20 mg/kg/day and titrated to 40 mg/kg/day; in patients
aged 6 months to <4 years, levetiracetam was initiated at
25 mg/kg/day and titrated to 50 mg/kg/day. Levetiracetam was administered as a 10% (100 mg/ml) oral solution.
Blinding was maintained through the use of matching
grape-flavored oral solutions of levetiracetam and placebo. The study treatment blinding was maintained for
all patients except for one in the levetiracetam group
who had severe food aversion (considered related to the
study drug) and was subsequently discontinued from the
study.
The study was conducted in accordance with the International Conference on Harmonisation Guideline for
Good Clinical Practice [CPMP/ICH/135/95] (2002) and
the Declaration of Helsinki. The study protocol was

1143
Levetiracetam in Infants and Children

Figure 1.
Study design.
*If a patient entered into the follow-up study, he or she would not go through down-titration. LEV, levetiracetam.
Epilepsia ILAE
approved by an independent ethics committee or institutional review board at each study center. The parent(s) or
legally authorized representative(s) of all subjects provided written informed consent before the enrollment of
the subjects.
Patients
Pediatric patients aged 1 month to <4 years and weighing 4.0 kg were eligible if they had partial-onset seizures
[International League Against Epilepsy (ILAE) classification, ILEA, 1981] inadequately controlled by one or two
AEDs. Subjects must have experienced at least two
partial-onset seizures, with or without secondary generalization, during each 7-day period during the 2 weeks prior
to entering the study. Subjects 1 to <6 months of age must
have had at least two partial-onset seizures (10 s duration) during the baseline 48-h video-EEG, with or without
a corresponding clinical event. Subjects aged 6 months to
<4 years must have had at least two partial-onset seizures
during the baseline 48-h video-EEG, accompanied by a
corresponding clinical event.
Patients were maintained on a stable regimen of one or
two concomitant AEDs for the selection and evaluation
periods. During the 2-week period prior to the baseline
visit, the addition or discontinuation of AEDs was not permitted but minor adjustments to the current AED dose, at

the investigators discretion, were allowed. Vagus nerve

stimulation implanted for at least 6 months prior to the
baseline visit, and with stable settings for at least 2 months
prior to that visit, was allowed and considered as one of
the two AEDs.
The main exclusion criteria included a diagnosis of a
treatable seizure etiology, for example, metabolic, toxic,
and infectious disorders, febrile seizures; status epilepticus that required hospitalization during the month before
the baseline visit; current diagnosis of Lennox-Gastaut
syndrome; epilepsy secondary to a progressive cerebral or
neurodegenerative disease; a history of, or the presence
of, pseudoseizures; previous use of levetiracetam;
and clinically significant abnormal laboratory value or
medical condition.
Assessments
Efficacy
The primary efficacy variable was the 50% responder
rate for partial-onset seizures, defined as the percentage of
subjects with a 50% reduction in their average daily partial-onset seizure frequency, as recorded on the evaluation
48-h video-EEG compared with the baseline 48-h videoEEG. Secondary efficacy variables included responder
rate for all seizures, absolute reduction, and percent
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1144
J. E. Pina-Garza et al.
reduction in average daily frequency of partial-onset and
all seizures. The results for all seizures were consistent
with those of partial-onset seizures, and so only the latter
are presented in this report.
Safety and tolerability
Safety assessments consisted of monitoring all adverse
events (AEs), physical and neurologic examinations, vital
signs, and laboratory tests (blood chemistry, hematology).
AEs were assessed throughout the study by the following
methods: observation by investigator, spontaneous reporting by the patient and/or parent/legal guardian, and
standard questions from site staff.
Statistical analysis
The sample size was calculated based on the primary
efficacy variable of responder rate, to detect a 26.5% difference between the responder rates in the two treatment
groups, assuming that 40% of the levetiracetam-treated
subjects and 13.5% of the placebo-treated subjects
respond to study treatment.
The intent-to-treat (ITT) population consisted of all
randomized subjects who took at least one dose of study
medication. The modified ITT (mITT) population
included all ITT subjects who had at least 24 h of useable
baseline video-EEG and at least 24 h of the evaluation
video-EEG, and also included any randomized subjects
who withdrew before the first 24 h of evaluation videoEEG, with reasons linked to lack or loss of efficacy
(nonresponders for the primary efficacy endpoint). The
efficacy analyses were performed on the mITT popula-

tion, whereas all safety summaries were conducted on the

ITT population.
The primary efficacy variable of responder rates was
compared using Fishers exact test with a 0.05 two-sided
significance level. The Cochran-Mantel-Haenszel test was
used for comparing responder rates between treatment
groups stratified by age group. The youngest two age
groups (1 to <6 months and 6 months to <1 year) were
combined into one group for analysis purposes, resulting
in three age-group strata. The absolute and percent reduction in average daily frequency of seizures were compared
between treatment groups using the Mann-Whitney test,
and the confidence interval (CI) of the median of difference between treatment groups was computed by the
Hodges-Lehmann method. The odds ratio (OR) with 95%
CI was also computed. Descriptive statistics were used for
all safety variables.
To account for baseline seizure frequency imbalance,
post hoc exploratory logistic regression analyses were also
conducted on the primary endpoint. Both the raw and log
transformation (natural log +1) of the baseline seizure
average daily frequency were examined (in two separate
models). Both models were used to assess baseline seizure
average daily frequency by treatment-group interaction.

Results
Patient disposition
Of 175 patients screened, 116 were randomized (60 levetiracetam; 56 placebo) and were considered the ITT population (Fig. 2). A total of 111 patients (58, 96.7%

Figure 2.
Patient disposition.
Note: Not all completed
subjects had at least 24 h of
evaluable video-EEG
(electroencephalography). ITT,
intent-to-treat; mITT, modified
intent-to-treat.
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1145
Levetiracetam in Infants and Children
levetiracetam; 53, 94.6% placebo) completed the study
and entered the long-term follow-up study. The mITT
population consisted of 109 patients (58 levetiracetam; 51
placebo).
Major protocol violations were reported in 17 patients
(8, 13.3% levetiracetam; 9, 16.1% placebo) and consisted
mainly of addition or discontinuation of an AED
<2 weeks before randomization and no partial-onset seizures detected during the 48-h baseline video-EEG.
Demographics and baseline characteristics
The treatment groups were well matched in terms of
age, gender, weight, seizure type, and age at onset of epilepsy (Table 1). The majority of patients (90%) on levetiracetam were Caucasian, compared with 69.6% on
placebo. The median daily partial-onset seizure frequency
during the 2 weeks prior to screening was 5.8 in the levetiracetam and 3.3 in the placebo group.
The following comorbidities were reported in more
than 10% of the overall population: developmental delay
(30.0% levetiracetam; 30.4% placebo); microcephaly
(20.0% levetiracetam; 17.9% placebo); hemiparesis
(23.3% levetiracetam; 14.3% placebo); hypotonia (18.3%
levetiracetam; 14.3% placebo), gastroesophageal reflux
disease (13.3% levetiracetam; 12.5% placebo), and mental
retardation of unspecified severity (10.0% levetiracetam;
10.7% placebo). There were no relevant differences in the
abnormalities in the general medical history between
treatment groups.
The baseline median daily partial-onset seizure frequency (baseline 48-h video-EEG) was higher in the levetiracetam group (15.2) compared with placebo (6.8).
During the baseline 48-h video-EEG, only one patient
experienced a generalized seizure in addition to the
partial-onset seizures (as interpreted by the central
reader). During the evaluation 48-h video-EEG, only one
of the patients experienced generalized seizures. Therefore, the results of all (total) seizure summaries and analyses for the mITT population are virtually identical to the
results on partial-onset seizures.
The majority of patients were taking two concomitant
AEDs (levetiracetam 71.7%, placebo 69.6%), whereas a
smaller proportion took one AED (levetiracetam 21.7%,
placebo 21.4%) (Table 1). Overall, the most common concomitant AEDs were valproic acid (39.7%), phenobarbital
(34.5%), topiramate (31.9%), oxcarbazepine (19.0%),
vigabatrin (16.4%), and carbamazepine (15.5%). A similar proportion of patients took medications other than
AEDs (levetiracetam 60.0%; placebo 55.4%).
Efficacy
The mean daily dose of levetiracetam during the stable
dose period for patients aged 1 to <6 months was
40.5 mg/kg/day and for patients aged 6 months to
<4 years was 50.5 mg/kg/day.

Table 1. Baseline demographics and clinical

epilepsy characteristics (intent-to-treat
population)
Levetiracetam
(n = 60)
Gender, male, n (%)
30 (50.0)
Agea, months, mean (SD)
23.4 (13.4)
<6 months n (%)
4 (6.7)
6 to <12 months, n (%)
8 (13.3)
12 to <24 months, n (%)
20 (33.3)
24 to <48 months, n (%)
28 (46.7)
Race, n (%)
Caucasian
54 (90.0)
American Indian/Alaskan
4 (6.7)
African American
0
Asian
0
Other/mixed race
2 (3.3)
Weight, kg, mean (SD)
11.2 (3.6)
Age of epilepsy onset,
5.8 (8.4)
months mean (SD)
Etiology, n (%)
Unknown
16 (26.7)
Genetic origin (familial epilepsy)
3 (5.0)
Congenital malformation
16 (26.7)
Perinatal events
18 (30.0)
Cranial trauma
2 (3.3)
Brain surgery
0
Primary degenerative lesion
1 (1.7)
Cerebrovascular accident
2 (3.3)
Cerebral infection
4 (6.7)
Other
6 (10.0)
Seizure historyb, n (%)
Partial-onset
58 (96.7)c
Generalized onset
16 (26.7)
Unclassified
3 (5.0)
Average daily seizure frequency
during 2 weeks prior to
screening, median (Q1Q3)
Partial-onset
5.8 (1.914.3)
Generalized onset
0
Unclassified
0
Average daily partial-onset seizure 15.2 (4.539.0)
frequency at baseline, median
(Q1Q3)
Number of concomitant AED(s), n (%)
None
0
1
13 (21.7)
2
43 (71.7)
>2
4 (6.7)
Concomitant AEDs, n (%)
Valproic acid
25 (41.7)
Phenobarbital
22 (36.7)
Topiramate
21 (35.0)
Oxcarbazepine
14 (23.3)
Vigabatrin
8 (13.3)
Clobazam
7 (11.7)
Carbamazepine
5 (8.3)
Clonazepam
3 (5.0)

Placebo
(n = 56)
27 (48.2)
23.5 (12.1)
4 (7.1)
7 (12.5)
18 (32.1)
27 (48.2)
39 (69.6)
2 (3.6)
6 (10.7)
1 (1.8)
8 (14.3)
11.7 (4.1)
6.8 (8.3)

14 (25.0)
3 (5.4)
17 (30.4)
8 (14.3)
6 (10.7)
1 (1.8)
1 (1.8)
2 (3.6)
4 (7.1)
11 (19.6)
56 (100)
5 (8.9)
8 (14.3)

3.3 (1.55.6)
0
0
6.8 (2.016.2)

0
12 (21.4)
39 (69.6)
5 (8.9)
21 (37.5)
18 (32.1)
16 (28.6)
8 (14.3)
11 (19.6)
3 (5.4)
13 (23.2)
9 (16.1)

AED, antiepileptic drug; Q1 (25th percentile); Q3 (75th percentile).

Corrected for preterm infants less than 12 months of age.
b
Patients may report more than one seizure type history.
c
Two patients did not have partial-onset seizures prior to selection
but had at least two partial-onset seizures during the baseline 48-h
video-EEG.
a

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J. E. Pina-Garza et al.
Electrographic seizures were recorded in the 1 month
to <6 month group (mITT population) in 1 of 7 patients
during the baseline 48-h video-EEG and 1 of 7 patients
during the 48-h evaluation video-EEG.
The 50% responder rate in average daily partial-onset
seizure frequency (48h video-EEG) was higher in the
levetiracetam group compared with placebo (43.1% vs.
19.6%, p = 0.013; OR 3.11, 95% CI 1.228.26, mITT).
The results were consistent across all age groups (Fig. 3),
although a slightly higher responder rate and OR were
observed in the subgroup of infants aged 1 to <12 months
than in other subgroups [OR 4.8; 95% CI 0.562.3, compared with 2.7 (95% CI 0.515.4) for the 12 to <24 month
age group and 2.9 (95% CI 0.714.7) for the 24 to <48month age group).
The median percent reduction from baseline (48-h
video-EEG) in average daily partial-onset seizure frequency was greater in the levetiracetam group (43.6%)
compared with placebo (7.1%). The median difference

(levetiracetamplacebo) was 39.2% (95% CI 17.562.2;

p < 0.001) (Table 2). Similarly, a greater median
absolute reduction from baseline in average daily partialonset seizure frequency was observed in the levetiracetam group compared with placebo [median difference
(levetiracetamplacebo) 5.0; 95% CI 2.28.0; p < 0.001)
(Table 2). A post hoc analysis of 48-h video-EEG data
showed 100% reduction in partial-onset and all seizures
in 15.5% of subjects on levetiracetam and 5.9% on
placebo.
To account for the imbalance in baseline median daily
seizure frequency observed between the levetiracetam and
the placebo groups, post hoc logistic regression analyses
were conducted. No significant interactions were found
based on raw (p = 0.929) and log-transformed
(p = 0.755) baseline average daily seizure frequency data,
confirming the robustness and the consistency of the
primary efficacy results across patients with different
baseline seizure frequency.

Figure 3.
Fifty percent responder rate in daily partial-onset seizure frequency overall and by age group.
*p = 0.013 versus placebo; Fishers exact test. mITT, modified intent-to-treat.
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Levetiracetam in Infants and Children
Table 2. Percent and absolute reduction
from baseline in average daily frequency for
partial-onset seizures (modified intent-totreat population)
Levetiracetam
(n = 58)

Placebo
(n = 51)

Average daily frequency of partial-onset seizures

Baseline
Median
15.2
6.8
Q1Q3
4.539.0
2.016.2
Evaluation
Median
8.3
6.5
Q1Q3
0.525.0
1.517.0
Percent reduction from baselinea
Median
43.6
7.1
Q1Q3
11.785.7
)42.335.1
Median differenceb
39.2 (CI 17.562.2); p < 0.001
Absolute reduction
Median
4.77
0.13
Q1Q3
0.010.5
)2.22.5
Median differencec
5.0 (CI 2.28.0); p < 0.001
a
Four patients were excluded from this analysis as they had
no seizures at baseline.
b
Median difference (levetiracetamplacebo) and its 95% confidence interval (CI) for percent reduction from baseline.
c
Median difference (levetiracetamplacebo) and its 95% CI
for absolute reduction from baseline.

Tolerability and safety

At least one treatment-emergent AE was reported by 33
of 60 levetiracetam- (55.0%) and 25 of 56 placebo-treated
(44.6%) patients during the 5-day evaluation period. The
most frequently reported AEs in the levetiracetam group,
somnolence (13.3% levetiracetam; 1.8% placebo) and
irritability (11.7% levetiracetam; 0% placebo) (Table 3),
were transient and most likely related to the rapid

Table 3. Treatment-emergent adverse

events occurring with an incidence of >5% in
either treatment group during the evaluation
perioda (intent-to-treat population)

Adverse event

Levetiracetam
(n = 60)
n (%)

Placebo
(n = 56)
n (%)

Somnolence
Irritability
Pyrexia
Constipation
Vomiting
Insomnia
Rash

8 (13.3)
7 (11.7)
3 (5.0)
2 (3.3)
2 (3.3)
1 (1.7)
1 (1.7)

1 (1.8)
0
4 (7.1)
3 (5.4)
3 (5.4)
3 (5.4)
3 (5.4)

a
Evaluation period = 1-day up-titration + 4-day full dose
maintenance periods.

up-titration. Irritability was reported in the levetiracetam

group only and most frequently on days 3 and 4.
Thirteen levetiracetam patients (21.7%) and four placebo patients (7.1%) reported an AE that was considered
to be related to study treatment. Somnolence and irritability were the most frequently reported drug-related AEs,
and their incidence was higher in the levetiracetam group
(somnolence 8.3%; irritability 5.0%) than the placebo
group (somnolence 1.8%; irritability 0%). Most drugrelated AEs were mild or moderate in intensity; one severe
drug-related AE (food aversion) was reported in the levetiracetam group.
One patient on levetiracetam and one on placebo
experienced a treatment-emergent serious AE (pyrexia
and urinary tract infection). Two patients (3.3%) on levetiracetam experienced a treatment-emergent AE that led to
permanent drug discontinuation (convulsion and food
aversion). In addition, one patient on placebo experienced
severe aspiration pneumonia reported as a serious AE.
The onset of the event was before randomization; however, the subject took one day of study medication before
discontinuing from the study.
Four subjects on levetiracetam had a potential clinically
significant (PCS) lymphocyte count that was too high at
the end of the 5-day evaluation period but no longer met
PCS criteria at the posttreatment evaluation. Two of the
four subjects also had clinically significant elevated lymphocyte counts at baseline. Overall, the incidences of PCS
values in the hematology and blood chemistry parameters
were rare and did not reveal any trends. No clinically
relevant changes from baseline were observed in these
parameters.
Vital signs were evaluated daily during the inpatient
period. There was high variability in heart rate and blood
pressure before and during study drug treatment. No trend
indicating a clinically significant impact of levetiracetam
on blood pressure or heart rate was detected.

Discussion
This double-blind, placebo-controlled study demonstrated that adjunctive levetiracetam was effective and
well tolerated in infants and young children (1 month to
<4 years) with partial-onset seizures inadequately controlled with one or two AEDs.
One of the key strengths of this study was the use of
video-EEG to assess seizure count. In young children, it is
difficult to diagnose, classify, and count partial-onset seizures. Very young children often have seizures that are
only detectable using EEG and not detected clinically
(Connell et al., 1989; Weiner et al., 1991). As a result, it is
difficult to conduct well-controlled efficacy studies in
very young children with epilepsy. Therefore, few doubleblind, placebo-controlled studies have been reported to
date (Pia-Garza et al., 2005) and evidence-based options
Epilepsia, 50(5):11411149, 2009
doi: 10.1111/j.1528-1167.2008.01981.x

1148
J. E. Pina-Garza et al.
for treating seizures in infants and young children are
limited.
Five-day treatment with levetiracetam resulted in significantly higher responder rates (43.1%) compared with
placebo (19.6%; OR 3.11, 95% CI 1.228.26; p = 0.013).
The percent reduction and absolute reduction from baseline in average daily partial-onset seizure frequency were
significantly greater in the levetiracetam group compared
with placebo. These results are consistent with those of a
previous double-blind, placebo-controlled study (14-week
treatment) in which adjunctive levetiracetam was significantly more effective than placebo in reducing partialonset seizure frequency per week in children aged
416 years (responder rate: levetiracetam 44.6%; placebo
19.6%; OR 3.3; p = 0.002) (Glauser et al., 2006). Our
findings are also in line with the results of uncontrolled
open-label studies including children younger than
4 years, which demonstrated the efficacy of levetiracetam
(Wheless & Ng, 2002; Lagae et al., 2003; Coppola et al.,
2004; Grosso et al., 2005). A retrospective review of the
efficacy and tolerability of levetiracetam in children younger than 4 years demonstrated that levetiracetam was
effective in multiple seizure types, with 57% of subjects
achieving seizure remission (Perry & Benatar, 2007).
In this patient population of infants and young children
with partial-onset seizures, the efficacy of adjunctive
levetiracetam was observed during the first 5 days of
treatment. The rapid-onset action of levetiracetam has also
been reported in children 4 years of age (Glauser et al.,
2006) and in adults (French & Arrigo, 2005) with partialonset seizures, as well as in patients with IGE and
myoclonic (Noachtar et al., 2008) and generalized tonic
clonic seizures (Berkovic et al., 2007).
Levetiracetam was well tolerated, even though the dose
was titrated rapidly and many of the children in this pediatric population had concomitant diseases or congenital
abnormalities. AEs were mostly mild-to-moderate; few
resulted in the discontinuation of study medication. Most
of the AEs reported occurred with similar incidence in
both groups and were not unexpected in young children
(pyrexia, constipation, and vomiting). Only two AEs
occurred with a higher incidence in the levetiracetam
group (somnolence 13.3%; irritability 11.7%) compared
with placebo (somnolence 1.8%; irritability 0%). Both
AEs were transient and most likely related to the rapid uptitration of levetiracetam. A previous study in children
aged 416 years treated with levetiracetam reported a
similar tolerability profile (Glauser et al., 2006).
A limitation of this study was the short treatment and
evaluation periods, which were defined in order to address
the need to minimize the duration of exposure to placebo,
and the need for inpatient video-EEG monitoring and
evaluation. Based on the rapid onset of levetiracetam efficacy previously reported in adults and children 4 years
of age (French & Arrigo, 2005; Glauser et al. 2006), it was
Epilepsia, 50(5):11411149, 2009
doi: 10.1111/j.1528-1167.2008.01981.x

anticipated that a 5-day evaluation period would be sufficient to assess levetiracetam efficacy in children younger
than 4 years.
This is the first well-controlled study providing information on the efficacy and tolerability of levetiracetam in
infants and young children with inadequately controlled
partial-onset seizures. The results of this study, together
with the favorable pharmacokinetic profile of levetiracetam (Pellock et al., 2001; Fountain et al., 2007; Glauser
et al., 2007) and its low potential for pharmacokinetic drug
interactions (Otoul et al., 2007; Toublanc et al., 2008),
suggest that levetiracetam is a valuable treatment option
in very young patients with partial-onset epilepsy.

Acknowledgments
This study was sponsored by UCB. The authors thank the members of
the N01009 Study Group for their valuable contributions to this study.
Belgium: L. Lagae, P. Van Bogaert. Brazil: S.A. Antoniuk, J. Costa da
Costa, A. Cukiert, M.L.G. de Manreza, M.H. Ferreira-Mendes,
M.M. Guerreiro, A.C. Sakamoto. Czech Republic: J. Hadac, V. Komarek, H. Oslejskova. France: C. Chiron, A. De Saint Martin, D. Parain,
L. Valle. Germany: U. Brandl, J.P. Ernst, H.-J. Meencke, D. Rating,
U. Stephani, R. Trollmann. Hungary: A. Fogarasi, K. Kollr. Italy:
R. Gaggero, R. Guerrini, A. Romeo; F. Vigevano. Mexico: S. GarzaMorales, M. Ruiz-Garcia. Poland: M. Mazurkiewicz-Beldizinska.
Romania: I. Benga, V. Foisoreanu, S. Magureanu. Russia: S. Aivazian,
N. Berezina, A. Broutian, I. Dykhanova, N. Koroleva, M. Lobov. U.K.:
H. Cross. U.S.A.: R. Ayala, D. Bettis, L.W. Brown, C. Crosley, M. Duchowny, V. Faircloth, J. Ferreira, M. Frost, M. Goyal, R.S. Greenwood,
A. Hernandez, A. Kalra, M. Kohrman, P. Kotagal, E. Liu, P. Maertens,
M. Mintz, W.G. Mitchell, G. Montouris, R.P. Morse, L. Morton, Y. Park,
E. Pia-Garza, C. Roberts, M. Sam, C. Tardo, C.B. Van Orman, D. Wang,
A. Weinstock, M.L. Zupanc.
The authors also thank Charles Romano, UCB Inc, Smyrna, GA, USA
and Mia Rasmussen, UCB SA, Braine lAlleud, Belgium for their contributions to the trial. The authors also thank Sally Doss, Ph.D., for assistance with the preparation of the manuscript.
Conflict of interest: We confirm that we have read the Journals position
on issues involved in ethical publication and confirm that this report is
consistent with those guidelines.
Statistical analysis: B. Duncan, MS, UCB Inc, Smyrna, GA, USA.
Dr. Pia-Garza has received support from, and/or, has been a paid consultant for UCB. Dr. Rating has received support from UCB. Dr. Yang, Dr
Schiemann-Delgado, and Mr. Duncan are employees of UCB Inc,
Smyrna, GA, USA. Dr. Nordli has no conflicts of interest to disclose.

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