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com
Neuropsychiatry
For numbered affiliations see
end of article
Correspondence to
Dr Eugen Trinka, Department
of Neurology, Paracelsus
Medical University, Christian
Doppler Klinik, Ignaz Harrer
Strasse 79, A-5020 Salzburg,
Austria; e.trinka@salk.at
GCM is deceased.
Received 22 April 2011
Revised 15 May 2012
Accepted 13 July 2012
Published Online First
29 August 2012
▸ http://dx.doi.org/10.1136/
jnnp-2012-303744
To cite: Trinka E,
Marson AG, Van
Paesschen W, et al. J Neurol
Neurosurg Psychiatry
2013;84:1138–1147.
1138
RESEARCH PAPER
KOMET: an unblinded, randomised, two parallel-
group, stratified trial comparing the effectiveness of
levetiracetam with controlled-release carbamazepine
and extended-release sodium valproate as
monotherapy in patients with newly diagnosed
epilepsy
Eugen Trinka,1 Anthony G Marson,2 Wim Van Paesschen,3 Reetta Kälviäinen,4
Jacqueline Marovac,5 Benjamin Duncan,6 Sonja Buyle,5 Yngve Hallström,7 Petr Hon,8
Gian Carlo Muscas,9 Mark Newton,10 Heinz-Joachim Meencke,11 Philip E Smith,12
Bernd Pohlmann-Eden,13 for the KOMET Study Group
ABSTRACT
Objective To compare the effectiveness of
levetiracetam (LEV) with extended-release sodium
valproate (VPA-ER) and controlled-release carbamazepine
(CBZ-CR) as monotherapy in patients with newly
diagnosed epilepsy.
Methods This unblinded, randomised, 52-week
superiority trial (NCT00175903) recruited patients
(≥16 years of age) with ≥2 unprovoked seizures in the
previous 2 years and ≥1 in the previous 6 months. The
physician chose VPA or CBZ as preferred standard
treatment; each patient was randomised to standard
treatment or LEV. The primary outcome was time to
treatment withdrawal (LEV vs standard antiepileptic
drugs (AEDs)). Analyses also compared LEV with VPA-
ER, and LEV with CBZ-CR.
Findings 1688 patients (mean age 41 years; 44%
female) were randomised to LEV (n=841) or standard
AEDs (n=847). Time to treatment withdrawal was not
significantly different between LEV and standard AEDs:
HR (95% CI) 0.90 (0.74 to 1.08). Time to treatment
withdrawal (HR (95% CI)) was 1.02 (0.74 to 1.41) for
LEV/VPA-ER and 0.84 (0.66 to 1.07) for LEV/CBZ-CR.
Time to first seizure (HR, 95% CI) was significantly
longer for standard AEDs, 1.20 (1.03 to 1.39), being
1.19 (0.93 to 1.54) for LEV/VPA-ER and 1.20 (0.99 to
1.46) for LEV/CBZ-CR. Estimated 12-month seizure
freedom rates from randomisation: 58.7% LEV versus
64.5% VPA-ER; 50.5% LEV versus 56.7% CBZ-CR.
Similar proportions of patients within each stratum
reported at least one adverse event: 66.1% LEV versus
62.0% VPA-ER; 73.4% LEV versus 72.5% CBZ-CR.
Conclusions LEV monotherapy was not superior to
standard AEDs for the global outcome, namely time to
treatment withdrawal, in patients with newly diagnosed
focal or generalised seizures.
INTRODUCTION
Levetiracetam (LEV) is a newer antiepileptic drug
(AED) with a unique mode of action1 2 and a
broad spectrum of efficacy against focal3–5 and
Trinka E, et al. J Neurol Neurosurg Psychiatry 2013;84:1138–1147. doi:10.1136/jnnp-2011-300376
generalised6 7 seizures. In a double-blind monother-
apy trial in newly diagnosed patients, LEV demon-
strated similar seizure freedom rates compared with
controlled-release carbamazepine (CBZ-CR) after 6
and 12 months.8
Double-blind randomised controlled trials
remain the gold standard for assessing efficacy and
tolerability for regulatory purposes. However, avail-
able regulatory trials in epilepsy often fail to
inform treatment decisions made by clinicians and
their patients. Such trials have short duration, fixed
dosing schedules and restricted patient population,
resulting in poor external validity.9 10 Treatment
decisions for epilepsy should be informed by long-
term trials that measure outcomes with real clinical
utility (of effectiveness rather than efficacy), and
recruit a broad population representative of every-
day practice. Blinding long-term epilepsy trials can
limit their external validity, as important groups,
such as women of childbearing age are under-
represented, while maintaining the blind is imprac-
tical due to problems, such as drug interactions.
Also, the blind would need to be broken for
patients who discontinue study medication in order
to inform future treatment choices. We urgently
need long-term treatment outcome data in epilepsy;
these will largely come from unblinded randomised
trials, accepting the trade-off between internal and
external validity.
The Standard and New Antiepileptic Drugs
(SANAD) trial was a long-term (up to 6 years)
unblinded study that identified lamotrigine as a
first-line treatment for patients with focal-onset sei-
zures,11 and valproate (VPA) as a first-line treat-
ment for patients with generalised-onset seizures.12
SANAD results have been used in the development
of the latest German treatment guidelines for neur-
ology,13 and have triggered an update of the UK
National Institute for Health and Clinical
Excellence epilepsy guideline.14 However, SANAD
could not include LEV, because it was not licensed
at the time when SANAD was designed. In
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Neuropsychiatry

KOMET (Keppra vs Older Monotherapy in Epilepsy Trial), we

have compared the effectiveness of LEV and extended-release
VPA (VPA-ER) and CBZ-CR.

METHODS
Patients
Patients were recruited to this study at specialist clinics at the
discretion of the physician. Patients aged ≥16 years were
included if they had two or more unprovoked seizures in the
previous 2 years with at least one during the previous 6 months,
classified according to the International League Against
Epilepsy.15 Neuroimaging and electroencephalography were not
compulsory prior to entry, if clinical information was sufficient
for a diagnosis of epilepsy.
Patients were excluded if they had been treated with LEV,
VPA or CBZ for any indication or treated for epilepsy with any
other AED in the last 6 months. Acute seizure treatment was
allowed with a maximum of 2 weeks’ duration providing it had
been stopped at least 1 week before screening. All participants
provided written informed consent before entering the study.
The study was approved by the local ethics committees for
every study centre, and was conducted in accordance with the
International Conference on Harmonisation Good Clinical
Practice guidelines and the Declaration of Helsinki. Ongoing
medical review of all data was conducted by the sponsor.

Study design
KOMET (N01175; NCT00175903) was a multicentre,
unblinded, randomised, 52-week, controlled superiority trial
with a two-parallel-group design (figure 1).
At screening, the clinician decided whether VPA or CBZ
would be the standard first-line treatment. Central randomisa-
tion, stratified by best recommended treatment, was done.
Within the VPA stratum, patients were randomised (1:1) to
treatment with LEV (UCB Pharma, Belgium) or VPA-ER
(Sanofi-Aventis, France). Within the CBZ stratum, patients were
randomised (1:1) to treatment with LEV or CBZ-CR (Novartis,
Switzerland). Treatment allocation was concealed by use of an
Interactive Voice Response System via telephone to manage the
randomisation process.
Starting doses (LEV 500 mg/day, VPA-ER 500 mg/day,
CBZ-CR 200 mg/day, administered twice daily as equal doses)
were up-titrated over 2 weeks to the initial target doses (LEV
1000 mg/day, VPA-ER 1000 mg/day, CBZ-CR 600 mg/day). If a
seizure occurred, doses could be increased according to the clin-
ician’s judgement to a maximum of LEV 3000 mg/day, VPA-ER
2000 mg/day and CBZ-CR 1600 mg/day. Patients who did not
tolerate higher doses could revert to lower doses, but the dose
could not fall below the initial target dose.
Study visits were scheduled at weeks 0, 6, 12, 26 and 52
(evaluation visit). Patients recorded the number and type of sei-
zures and any adverse events (AEs) using daily record cards.
Their intensity (mild, moderate or severe), as judged by the
investigator, was recorded. Serious AEs were defined as those
which resulted in death, were life-threatening, required pro-
longed hospitalisation, resulted in persistent or significant dis-
ability or incapacity, or were congenital anomalies. A
health-related quality-of-life questionnaire (Patient Quality of
Life Inventory in Epilepsy-31 (QOLIE-31-P)) and a health status
questionnaire (EQ-5D) were completed at weeks 0, 6 (EQ-5D
only), 12, 26 and 52 by all patients in countries where a local
language version was available.
Figure 1 Study design. AED, antiepileptic drug; CBZ, carbamazepine;
CBZ-CR, controlled-release carbamazepine; LEV, levetiracetam; SV,
safety visit; V, visit; VPA, sodium valproate; VPA-ER, extended-release
sodium valproate; W, week.
Outcome measures
The primary outcome measure was time to withdrawal from
study medication (treatment withdrawal) calculated from ran-
domisation to the day after the last intake of study medication
for the overall comparison of LEV with standard AEDs
(VPA-ER and CBZ-CR). Patients could withdraw consent at any
time, or could be withdrawn according to the investigator’s clin-
ical judgement. Secondary outcome measures were time to first
seizure calculated from randomisation, and treatment with-
drawal and seizure freedom rates at 6 and 12 months.
Exploratory outcome measures were changes from baseline to
the last assessment for all QOLIE-31-P and EQ-5D scores.
Tolerability was evaluated by recording treatment-emergent AEs,
their intensity (mild, moderate or severe) and seriousness.
Severe AEs were those affecting the patient’s ability to work
normally or to carry out usual activities, and those of definite
clinical consequence. Serious AEs were those classed as life
threatening, resulting in death, requiring hospitalisation or
causing a persistent or significant disability/incapacity.
Statistical analysis
Sample size calculations were based on the primary outcome
(time to treatment withdrawal) for the overall comparison of

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Neuropsychiatry

Figure 2 Patient disposition. CBZ,

carbamazepine; CBZ-CR,
controlled-release carbamazepine; CRF,
case report form; GCP, good clinical
practice; ITT, intent to treat; LEV,
levetiracetam; VPA, sodium valproate;
VPA-ER, extended-release sodium
valproate.

LEV with standard AEDs across the combined VPA and CBZ
strata. The calculation was based on the log rank test of survival
in two groups followed for a fixed time (12 months) and assum-
ing a constant HR. The assumed 12-month retention rate for
the standard AED group was 60%. To detect a clinically relevant
absolute difference in retention rate between LEV and standard
AEDs of 7% (eg, 60% vs 67%) with a power of 90% using a
two-sided test (α=0.05), 982 patients per treatment group were
needed (total 1964).
Supportive analyses of the primary endpoint were also con-
ducted for each individual stratum (VPA and CBZ). Secondary
endpoints were analysed in a similar fashion.

Table 1 Baseline demographics and epilepsy characteristics (intent-to-treat population)

VPA stratum CBZ stratum
Standard AEDs
LEV (N=841) (N=847) LEV (N=349) VPA-ER (N=347) LEV (N=492) CBZ-CR (N=500)

Age, years, mean±SD 40.6±17.8 40.9±17.8 35.9±17.8 38.2±17.9 44.0±17.0 42.7±17.5

Age class, n (%)
≥16 to <65 726 (86.3) 734 (86.7) 311 (89.1) 307 (88.5) 415 (84.3) 427 (85.4)
≥65 115 (13.7) 113 (13.3) 38 (10.9) 40 (11.5) 77 (15.7) 73 (14.6)
Gender, n (%)
Men 466 (55.4) 476 (56.2) 191 (54.7) 202 (58.2) 275 (55.9) 274 (54.8)
Women 375 (44.6) 371 (43.8) 158 (45.3) 145 (41.8) 217 (44.1) 226 (45.2)
Number of seizures in the last 2 years*, median (Q1–Q3) 3 (2–7) 3 (2–8) 3 (2–5) 3 (2–6) 4 (2–10) 4 (2–10)
Epilepsy duration† years, median (Q1–Q3) 0.86 (0.31–2.94) 0.99 (0.35–2.74) 0.81 (0.28–2.73) 1.05 (0.34–2.59) 0.94 (0.33–3.06) 0.97 (0.35–3.36)
Seizure type‡ n (%)
Focal seizures 543 (64.6) 549 (64.8) 109 (31.2) 101 (29.1) 434 (88.2) 448 (89.6)
Primary generalised seizures 297 (35.3) 290 (34.2) 235 (67.3) 242 (69.7) 62 (12.6) 48 (9.6)
Unclassified only 18 (2.1) 18 (2.1) 11 (3.2) 11 (3.2) 7 (1.4) 7 (1.4)
Other§ 8 (1.0) 8 (0.9) 3 (0.9) 3 (0.9) 5 (1.0) 5 (1.0)
*LEV, N=822; standard AEDs, N=831.
†Time since first seizure, LEV, N=839; standard AEDs, N=844.
‡Patients are counted once in each type of seizure experienced in the past.
§Includes seizures unable to clarify at this stage and unknown seizure types.
AED, antiepileptic drug; CBZ, carbamazepine; CBZ-CR, controlled-release carbamazepine; LEV, levetiracetam; VPA, sodium valproate; VPA-ER, extended-release sodium valproate;
CBZ-CR, controlled-release carbamazepine.

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Neuropsychiatry

Table 2 Time to treatment withdrawal and time to first seizure by VPA and CBZ strata for subgroups of patients with focal or generalised
seizures only (intent-to-treat population excluding unclassified/unknown seizure types)
LEV Standard AEDs

N Event N Event HR (95% CI)*

Time to treatment withdrawal

VPA stratum
Focal seizures only 99 15 91 18 0.73 (0.37 to 1.44)
Generalised seizures only 226 54 232 49 1.16 (0.79 to 1.71)
CBZ stratum
Focal seizures only 418 109 440 130 0.84 (0.65 to 1.09)
Generalised seizures only 46 5 40 8 0.49 (0.16 to 1.49)
Time to first seizure
VPA stratum
Focal seizures only 99 44 91 37 1.03 (0.67 to 1.60)
Generalised seizures only 226 78 232 67 1.28 (0.93 to 1.78)
CBZ stratum
Focal seizures only 418 198 440 172 1.24 (1.01 to 1.52)
Generalised seizures only 46 15 40 10 1.17 (0.53 to 2.60)
*HR of <1 favours LEV.
AED, antiepileptic drug; CBZ, carbamazepine; LEV, levetiracetam; VPA, sodium valproate; N, number of patients; Event, number of patients who had the event (treatment withdrawal or
seizure); HR, HR for time to event (treatment withdrawal or first seizure).

The primary analysis was by intention-to-treat (ITT) and No adjustment for multiple comparisons was required since
included all randomised patients. In order to assess the effective- only one primary analysis was planned and conducted. For the
ness of study treatment in particular seizure types, and to assess time to treatment withdrawal and time to first seizure analyses,
a potential interaction between treatment and seizure type, a no further adjustments for dropouts or missing data were
post hoc subgroup analysis was performed using data from required, as these patients were censored accordingly.
patients who had a history of focal or generalised seizures only
(excluding unclassified, unknown or mixed seizure types). RESULTS
The safety population (tolerability analyses) consisted of all Patients
patients who received one or more doses of study medication, This study was carried out in a community setting between
including those with unknown intake. Patients who were rando- February 2005 and October 2007 in 269 centres across 23
mised but not treated, and those who did not give informed European countries and Australia.
consent, were excluded from the safety population.
Kaplan–Meier survival curves were plotted for time to treat- Table 3 Time to treatment withdrawal, treatment withdrawal
ment withdrawal and time to first seizure. For the time to treat- rates, time to first seizure and seizure freedom rates for LEV and
ment withdrawal analysis, all treated patients who withdrew standard AEDs (intent-to-treat population)
from the study prior to day 365 were considered as having the
LEV Standard AEDs p
event. Treated patients who completed the study or withdrew
(N=841) (N=847) Value* HR (95% CI)†
after day 365 were censored at day 365 or at completion of the
study (for those who completed just prior to day 365). Time to treatment withdrawal
Untreated (but randomised) patients were censored at day 1 Events 200 (23.8%) 219 (25.9%) 0.258 0.90 (0.74 to 1.08)
(1 day after randomisation). For the time to first seizure analysis, Censored 641 (76.2%) 628 (74.1%)
patients with no reported seizure during the 1-year treatment Treatment withdrawal rate
and observation period were censored at the date of last intake 6 months 18.0% 20.8%
of study medication, date of early termination, date of week 52 12 months 23.9% 25.9%
visit or day 364, whichever was earliest. Time to treatment with- Time to first seizure
drawal and time to first seizure were calculated from Events 355 (42.2%) 305 (36.0%) 0.022 1.20 (1.03 to 1.39)
randomisation. Censored 484 (57.8%) 542 (64.0%)
Time to treatment withdrawal and time to first seizure were Seizure freedom rate
analysed using a Cox’s proportional hazards regression model. 6 months 59.8% 64.5%
The treatment effect (HR) was described using two-sided 95% 12 months 53.9% 59.9%
CIs. In this model, a HR of <1 favoured LEV, while a HR of HR of <1 favours LEV.
>1 favoured standard AEDs. This superiority trial was to be Patients who completed the 1-year treatment period without any reason to withdraw
considered positive if the null hypothesis of no difference from treatment were censored at the date of the last intake of study medication.
Patients with no documented date of discontinuation were censored at the last
between LEV and standard AEDs was rejected in favour of LEV. known date when they had been receiving study medication.
The primary analysis (time to treatment withdrawal, LEV vs *p value obtained from the Wald test (Cox’s Proportional Hazard Regression
Analysis).
standard AEDs) was stratified according to the standard recom- †HR and 95% CI obtained from Cox’s Proportional Hazard Regression Analysis.
mended treatment at baseline. Results for each stratum are also n, number of patients; Event, number of patients who had the event (treatment
reported for the subgroups with only focal or only generalised withdrawal or seizure); HR, HR for time to event (treatment withdrawal or first
seizure).
seizures.

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One thousand seven hundred and one patients were screened
and 1698 were randomised (figure 2). Ten patients were excluded
from the ITT population (six with no documented informed
consent; four because of non-compliance with International
Conference on Harmonisation Good Clinical Practice). Patients
in the VPA stratum (n=696) were randomised to LEV (n=349)
or VPA-ER (n=347) and those in the CBZ stratum (n=992) were
randomised to LEV (n=492) or CBZ-CR (n=500).
The LEV and standard AED treatment groups were similar
with respect to baseline demographics and epilepsy characteris-
tics (table 1). Within the VPA stratum, 65.8% (458/696) had
only primary generalised seizures (table 2). Within the CBZ
stratum 86.5% (858/992) had only focal seizures.
Overall, 1266 patients (75.0%) in the ITT population were
still taking their randomised drug at 12 months with a similar
proportion in the LEV and standard AED groups (figure 2).
Treatment was discontinued because of AEs in 181 patients
(10.7%) and because of lack of efficacy in 60 (3.6%).
Seventy-four patients (4.4%) withdrew consent for personal
reasons not related to AEs or efficacy, 37 (2.2%) discontinued
for other reasons and 70 (4.1%) were lost to follow-up.
Median (range) daily doses (including the up-titration period)
were: LEV 987 mg/day (250–2807), VPA-ER 987 mg/day (500–
2263), CBZ-CR 588 mg/day (180–1422).
LEV versus standard AEDs
The time to treatment withdrawal was longer in patients treated
with LEV compared with standard AEDs, but the difference was
not significant (HR 0.90, 95% CI 0.74 to 1.08) (table 3; figure
3A). Time to first seizure was significantly longer for patients in
the standard AEDs group compared with the LEV group (HR
1.20, 95% CI 1.03 to 1.39) (table 3; figure 4A).
LEV versus VPA-ER
Time to treatment withdrawal was similar for LEV and VPA-ER
(HR 1.02, 95% CI 0.74 to 1.41) (figure 3B). For the compari-
sons by seizure type, no significant differences were found, but
there were trends favouring VPA-ER in patients with primary

Figure 3 Kaplan–Meier survival

curves for the time to treatment
withdrawal (intent-to-treat population)
for: (A) LEV vs standard AEDs; (B) LEV
vs VPA-ER in the VPA stratum; (C) LEV
vs CBZ-CR in the CBZ stratum. AED,
antiepileptic drug; CBZ,
carbamazepine; CBZ-CR,
controlled-release carbamazepine; LEV,
levetiracetam; VPA, sodium valproate;
VPA-ER, extended-release sodium
valproate.

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Figure 4 Kaplan–Meier survival
curves for the time to first seizure
(intent-to-treat population) for: (A) LEV
vs standard AEDs; (B) LEV vs VPA-ER
in the VPA stratum; (C) LEV vs CBZ-CR
in the CBZ stratum. AED, antiepileptic
drug; CBZ, carbamazepine; CBZ-CR,
controlled-release carbamazepine; LEV,
levetiracetam; VPA, sodium valproate;
VPA-ER, extended-release sodium
valproate.
generalised seizures (HR 1.16, 95% CI 0.79 to 1.71), and LEV
in those with focal seizures (HR 0.73, 95% CI 0.37 to 1.44)
(table 2).
Estimated treatment withdrawal rates at 6 and 12 months
were similar for LEV and VPA-ER, both for all patients and
those with generalised seizures only (table 4). The estimated
overall withdrawal rates (95% CI) at 12 months were 22.0%
(18.0–26.7) with LEV and 21.6% (17.7–26.4) with VPA-ER.
Time to first seizure favoured VPA-ER over LEV (HR 1.19,
95% CI 0.93 to 1.54), but this was not statistically significant
(figure 4B). A similar effect was seen when analysis included
patients with generalised seizures only and those with focal sei-
zures only (table 2).
Estimated seizure freedom rates at 6 and 12 months were
higher with VPA-ER than LEV, both for all patients and in those
with generalised seizures only (table 4). The estimated overall
seizure freedom rate (95% CI) at 12 months was 58.7% (53.1–
63.9) for all patients in the VPA stratum (excluding those with
unclassified/unknown seizure types) treated with LEV and
64.5% (58.9–69.5) for those treated with VPA-ER.
Trinka E, et al. J Neurol Neurosurg Psychiatry 2013;84:1138–1147. doi:10.1136/jnnp-2011-300376
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LEV versus CBZ-CR
Time to treatment withdrawal was longer for LEV than for
CBZ-CR, but the difference was not statistically significant (HR
0.84, 95% CI 0.66 to 1.07) (figure 3C). Results in patients with
focal seizures only were similar to those in all patients (HR 0.84,
95% CI 0.65 to 1.09) (table 2). In the group of patients with gen-
eralised seizures only, the HR favoured LEV (HR 0.49, 95% CI
0.16 to 1.49), but the number of patients was very small (table 2).
Estimated treatment withdrawal rates at 6 and 12 months
were higher with CBZ-CR than LEV, both for all patients and
those with focal seizures only (table 4). The estimated overall
withdrawal rate (95% CI) at 12 months was 25.2% (21.6 to
29.3) for LEV and 28.8% (25.1 to 33.0) for CBZ-CR.
Time to first seizure was longer in the CBZ-CR group com-
pared with the LEV group, but the difference was not statistic-
ally significant (HR 1.20, 95% CI 0.99 to 1.46) (figure 4C).
Results in patients with focal or generalised seizures only were
similar to those in all patients (table 2), with a significant differ-
ence between treatment groups in those with focal seizures only
in favour of CBZ-CR (HR 1.24, 95% CI 1.01 to 1.52).
1143
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Table 4 Treatment withdrawal and seizure freedom rates (Kaplan–Meier estimates) for the VPA stratum for all patients and those with
generalised seizures only, and for the CBZ stratum for all patients and those with focal seizures only (intent-to-treat population excluding
unclassified/unknown seizure types)
VPA stratum

LEV VPA-ER Estimated absolute difference* (95% CI)

Treatment withdrawal rate, % (95% CI)

All patients N=325 N=323
6 months 16.9 (13.4 to 21.3) 17.9 (14.2 to 22.3) −1.0 (−6.6 to 4.7)
12 months 22.0 (18.0 to 26.7) 21.6 (17.7 to 26.4) 0.3 (−5.8 to 6.5)
Generalised seizures only N=226 N=232
6 months 19.1 (14.5 to 24.8) 18.1 (13.7 to 23.7) 0.9 (−6.2 to 8.1)
12 months 24.1 (19.0 to 30.3) 21.1 (16.4 to 27.0) 3.0 (−4.7 to 10.7)
Seizure freedom rate, % (95% CI)
All patients N=325 N=323
6 months 63.8 (58.3 to 68.8) 69.2 (63.8 to 73.9) −5.4 (−12.7 to 1.9)
12 months 58.7 (53.1 to 63.9) 64.5 (58.9 to 69.5) −5.7 (−13.4 to 1.9)
Generalised seizures only N=226 N=232
6 months 66.0 (59.0 to 72.1) 73.0 (66.5 to 78.4) −7.5 (−16.4 to 1.3)
12 months 61.1 (53.9 to 67.5) 68.3 (61.5 to 74.1) −7.2 (−16.5 to 2.1)

CBZ stratum

LEV CBZ-CR Estimated absolute difference† (95% CI)

Treatment withdrawal rate, % (95% CI)

All patients n=464 n=480
6 months 18.7 (15.5 to 22.4) 22.8 (19.4 to 26.7) −4.1 (−9.1 to 0.9)
12 months 25.2 (21.6 to 29.3) 28.8 (25.1 to 33.0) −3.6 (−9.1 to 1.9)
Focal seizures only n=418 n=440
6 months 19.6 (16.1 to 23.8) 23.4 (19.7 to 27.7) −3.8 (−9.3 to 1.7)
12 months 26.1 (22.2 to 30.6) 29.6 (25.5 to 34.1) −3.4 (−9.4 to 2.5)
Seizure freedom rate, % (95% CI)
All patients n=464 n=480
6 months 57.5 (52.8 to 61.9) 62.0 (57.2 to 66.3) −4.2 (−10.7 to 2.2)
12 months 50.5 (45.8 to 55.1) 56.7 (51.8 to 61.2) −6.1 (−12.8 to 0.5)
Focal seizures only n=418 n=440
6 months 55.5 (50.3 to 60.3) 61.0 (56.0 to 65.7) −5.3 (−12.2 to 1.7)
12 months 48.1 (42.9 to 53.1) 56.2 (51.0 to 61.0) −8.1 (−15.3 to −1.0)
*LEV/VPA-ER.
†LEV/CBZ-CR.
CBZ, carbamazepine; CBZ-CR, controlled-release carbamazepine; LEV, levetiracetam; VPA, sodium valproate; VPA-ER, extended-release sodium valproate.

The estimated seizure freedom rates at 6 and 12 months were
higher with CBZ-CR than LEV, both for all patients and those
with focal seizures only (table 4). Overall, the estimated seizure
freedom rate (95% CI) at 12 months was 50.5% (45.8 to 55.1)
for all patients in the CBZ stratum (excluding those with unclas-
sified/unknown seizure types) treated with LEV and 56.7%
(51.8 to 61.2) with CBZ-CR.
Quality of life
There were no clear differences between LEV and standard
AEDs in the impact on health-related quality of life as measured
by the QOLIE-31-P, or health status as measured by the EQ-5D
(data not shown). No clear trends over time were noted, apart
from an improvement in the seizure worry subscale score in all
treatment groups.
Tolerability
In the VPA stratum, similar numbers of patients treated with LEV
and VPA-ER reported at least one treatment-emergent AE, and
similar numbers of drug-related AEs were reported (table 5).
Most treatment-emergent AEs reported (table 6) were mild or
moderate. Serious AEs were reported by 39 patients (11.3%)
treated with LEV and 20 (5.8%) with VPA-ER. The most
common serious AEs were convulsion (LEV seven patients,
VPA-ER three patients) and epilepsy (LEV three patients; VPA-ER
four patients). Discontinuation of treatment due to AEs was
similar in patients treated with LEV (6.1%) and VPA-ER (4.7%).
In the CBZ stratum, similar numbers of patients treated with
LEV and CBZ-CR reported at least one treatment-emergent AE
(table 5). More drug-related AEs were reported in the CBZ-CR
group. Most treatment-emergent AEs were mild or moderate
(table 6). Serious AEs were reported by 67 patients (13.7%)
treated with LEV and 41 (8.2%) with CBZ-CR. The most
common serious AEs were convulsion (LEV nine patients;
CBZ-CR four patients) and ‘grand mal convulsion’ (generalised
tonic-clonic seizure) (LEV four patients; CBZ-CR one patient).
More patients treated with CBZ-CR discontinued treatment due
to AEs than those treated with LEV (18.8% vs 9.8%).

1144 Trinka E, et al. J Neurol Neurosurg Psychiatry 2013;84:1138–1147. doi:10.1136/jnnp-2011-300376

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Neuropsychiatry

Table 5 Summary of treatment-emergent AEs (safety population)

Patients, n (%)

VPA stratum CBZ stratum

LEV (N=835) Standard AEDs (N=841) LEV (N=345) VPA-ER (N=342) LEV (N=489) CBZ-CR (N=499)

≥1 TEAE 587 (70.3) 574 (68.3) 228 (66.1) 212 (62.0) 359 (73.4) 362 (72.5)
AEs that led to permanent study drug discontinuation 69 (8.3) 110 (13.1) 21 (6.1) 16 (4.7) 48 (9.8) 94 (18.8)
Drug-related AEs 381 (45.6) 418 (49.7) 152 (44.1) 157 (45.9) 229 (46.8) 261 (52.3)
Severe AEs 130 (15.6) 92 (10.9) 46 (13.3) 22 (6.4) 84 (17.2) 70 (14.0)
Serious AEs 106 (12.7) 61 (7.3) 39 (11.3) 20 (5.8) 67 (13.7) 41 (8.2)
Death 5 (0.6) 3 (0.4) 2 (0.6) 1 (0.3) 3 (0.6) 2 (0.4)
Note: one patient who received LEV was not randomised and therefore not assigned to a stratum. This patient is not included in the by-stratum AE counts.
AE, adverse event; AED, antiepileptic drug; CBZ, carbamazepine; CBZ-CR, controlled-release carbamazepine; LEV, levetiracetam; TEAE, treatment-emergent adverse event; VPA, sodium
valproate; VPA-ER, extended-release sodium valproate.

Eight deaths were reported; five in patients treated with LEV:
brain neoplasm (two); suspected cardiac arrhythmia; head
injury sustained in road traffic accident; radiation injury (one
each), two in the CBZ-CR group (subarachnoid haemorrhage;
acute myocardial infarction), and one in the VPA-ER group
(sudden unexpected death in epilepsy). None of the deaths were
considered to be related to study medication.
DISCUSSION
The choice of first AED is probably the most important treat-
ment decision that a patient with epilepsy will make. Such treat-
ment decisions should be informed by pragmatic, longer-term,
head-to-head trials, accepting the trade-off between external
and internal validity if unblinded. Monotherapy studies in
patients with newly diagnosed epilepsy present a number of
methodological and statistical challenges.
In KOMET, we have compared LEV with the standard
treatments for generalised (VPA) and focal (CBZ) seizures.
Dosing regimens were flexible and modified-release (ER or
CR) formulations of standard treatments were used, given
reports that they are better tolerated than immediate-release
formulations.16–20
The results across strata for our primary outcome and time to
treatment withdrawal, yielded a HR (95% CI) of 0.90 (0.74 to
1.08) suggesting that LEV is not superior to standard AEDs.
Overall results across strata for time to first seizure, the main
efficacy outcome, suggest an advantage for standard treatments
compared with LEV (HR 1.20, 95% CI 1.03 to 1.39).
VPA is widely regarded as the treatment of choice for general-
ised epilepsies or difficult-to-classify seizures.12 In SANAD, VPA
was better tolerated than topiramate and more efficacious than
lamotrigine. For time to treatment failure, VPA was significantly
better than topiramate (HR 1.57, 95% CI 1.19 to 2.08), with
no significant difference between VPA and lamotrigine (HR
1.25, 95% CI 0.94 to 1.68). For the subgroup of patients with
idiopathic generalised epilepsy, VPA was significantly better than
either lamotrigine (HR 1.55, 95% CI 1.07 to 2.24) or topira-
mate (HR 1.89, 95% CI 1.32 to 2.70).12
In our trial, for the stratum comparing LEV and VPA-ER, the
HR (95% CI) for time to treatment withdrawal was 1.02 (0.74
to 1.41), suggesting similarity, but the CI does not exclude the
possibility that LEV is 26% better or 41% worse (HR Scale).
This stratum included predominantly (∼70%) patients with gen-
eralised seizures, although some had focal seizures and arguably

Table 6 Incidence of treatment-emergent AEs ≥5% in any of the treatment groups (safety population)
Incidence of TEAEs, n (%)

VPA stratum CBZ stratum

TEAE LEV (N=835) Standard AEDs (N=841) LEV (N=345) VPA-ER (N=342) LEV (N=489) CBZ-CR (N=499)

Headache 161 (19.3) 170 (20.2) 60 (17.4) 58 (17.0) 101 (20.7) 112 (22.4)
Fatigue 120 (14.4) 134 (15.9) 46 (13.3) 39 (11.4) 74 (15.1) 95 (19.0)
Dizziness 68 (8.1) 70 (8.3) 23 (6.7) 18 (5.3) 45 (9.2) 52 (10.4)
Somnolence 68 (8.1) 48 (5.7) 29 (8.4) 13 (3.8) 39 (8.0) 35 (7.0)
Weight increased 47 (5.6) 98 (11.7) 21 (6.1) 65 (19.0) 26 (5.3) 33 (6.6)
Nausea 44 (5.3) 57 (6.8) 12 (3.5) 18 (5.3) 32 (6.5) 39 (7.8)
Depression 43 (5.1) 20 (2.4) 21 (6.1) 7 (2.0) 22 (4.5) 13 (2.6)
Vertigo 40 (4.8) 36 (4.3) 24 (7.0) 11 (3.2) 16 (3.3) 25 (5.0)
Nasopharyngitis 40 (4.8) 46 (5.5) 16 (4.6) 14 (4.1) 24 (4.9) 32 (6.4)
Diarrhoea 38 (4.6) 39 (4.6) 19 (5.5) 19 (5.6) 19 (3.9) 20 (4.0)
Weight decreased 29 (3.5) 19 (2.3) 21 (6.1) 8 (2.3) 8 (1.6) 11 (2.2)
Tremor 14 (1.7) 43 (5.1) 4 (1.2) 32 (9.4) 10 (2.0) 11 (2.2)
Alopecia 11 (1.3) 23 (2.7) 6 (1.7) 18 (5.3) 5 (1.0) 5 (1.0)
Rash 9 (1.1) 29 (3.4) 0 0 9 (1.8) 29 (5.8)
Note: one patient who received LEV was not randomised and therefore not assigned to a stratum. This patient is not included in the by-stratum AE counts.
AED, antiepileptic drug; CBZ, carbamazepine; CBZ-CR, controlled-release carbamazepine; LEV, levetiracetam; TEAE, treatment-emergent adverse event; VPA, sodium valproate; VPA-ER,
extended-release sodium valproate.

Trinka E, et al. J Neurol Neurosurg Psychiatry 2013;84:1138–1147. doi:10.1136/jnnp-2011-300376 1145

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Neuropsychiatry
were not offered the best standard treatment. A subgroup ana-
lysis of only the patients classified with generalised seizures
gives an HR for treatment withdrawal of 1.16 (95% CI 0.79 to
1.71) suggesting a non-significant advantage for VPA-ER;
however, the differences in the proportion withdrawing from
treatment at 6 and 12 months is small with narrow 95% CIs;
0.9% at 6 months (CI −6.2 to 8.1) and 3.0% at 12 months (CI
−4.7 to 10.7).
For time to first seizure in the VPA stratum, results (HR 1.19,
95% CI 0.93 to 1.54) are similar to the overall results, suggest-
ing an advantage for VPA-ER. Time to first seizure can be influ-
enced by initial titration rates and drug pharmacokinetics, and
ideally a longer-term measure of seizure control is required. We
were able to assess the proportion of patients remaining seizure-
free at 12 months. For the VPA stratum, 58.7% were seizure-
free on LEV and 64.5% on VPA-ER. The estimated absolute dif-
ference was −5.7% (95% CI −13.4% to 1.9%) suggesting a
small advantage for VPA-ER.
Women of childbearing age represented a significant propor-
tion of the epilepsy population. Increased human teratogen-
icity21–23 and risk of impaired cognitive function in children
exposed in utero to VPA24 25 are perhaps the most important
adverse effects of VPA. It is therefore imperative that we identify
effective treatments that are safer in pregnancy. Our study is the
first to point towards a comparable time to treatment with-
drawal for a newer AED compared with VPA-ER in patients
with predominantly generalised seizures. Recent preliminary
data suggest a low risk of teratogenicity with LEV (UK and UCB
AED pregnancy registries)26 27 and a lower risk of delayed
development following in utero exposure to LEV compared
with VPA.28 29 Based on these results, LEV might be a viable
first-line treatment for patients with generalised seizures, par-
ticularly for women of childbearing age.
The choice of CBZ as a standard treatment for patients with
focal seizures was underscored in the 2006 International League
Against Epilepsy treatment guidelines.30 SANAD identified
lamotrigine as a preferred option for patients with focal sei-
zures11 but these results were not available when KOMET was
planned. In the CBZ stratum, our results for time to treatment
withdrawal suggest a non-significant advantage for LEV com-
pared with CBZ-CR (HR 0.84, 95% CI 0.66 to 1.07). Results
were similar when restricted to patients with focal seizures (HR
0.84, 95% CI 0.65 to 1.09). For time to first seizure we found a
non-significant advantage for CBZ-CR (HR 1.20, 95% CI 0.99
to 1.46), and a significant advantage for CBZ-CR when the ana-
lysis was restricted to patients with focal seizures (HR 1.24,
95% CI 1.01 to 1.52). Estimates of the proportion of patients
remaining seizure-free at 12 months find only a small advantage
for CBZ-CR: 50.5% on LEV and 56.7% on CBZ-CR were
seizure-free at 12 months (absolute difference −6.1% (95% CI
−12.8% to 0.5%)). The analysis restricted to patients with focal
seizures finds a similar absolute difference (−8.1, 95% CI −15.3
to 1.0).
The results for time to treatment withdrawal and time to first
seizure suggest a trade-off between efficacy and tolerability, with
LEV being better tolerated but CBZ-CR being slightly more
effective. Better tolerability of LEV is supported by the lower
incidence of treatment withdrawal due to side effects (9.8% vs
18.8%), although longer-term outcome data are required to
confirm the latter. It should be noted that the initial target dose
of CBZ-CR (600 mg/day) may have been unnecessarily high,
resulting in a higher discontinuation rate due to AEs. In add-
ition, a higher incidence of serious AEs was observed with LEV
than CBZ-CR (13.7% vs 8.2%).
1146 Trinka E, et al. J Neurol Neurosurg Psychiatry 2013;84:1138–1147. doi:10.1136/jnnp-2011-300376
Interpretation of our findings should take into account study
limitations. Possible sources of bias include selection of patients
at the discretion of the physician, and unblinded treatment.
Additionally, the choice of best recommended treatment was not
standardised in accordance with expert recommendations.
KOMET was designed to be relevant to routine clinical practice
and, thus, it was not mandatory for clinicians to confirm the
diagnosis using brain imaging or electroencephalograph before
selecting treatment with VPA or CBZ. Finally, although patients
in KOMET were followed up over a 12-month treatment period,
there is still a need for data collected over a longer duration.
We have found LEV to be non-superior to both VPA-ER and
CBZ-CR for the global outcome and time to treatment with-
drawal. KOMET provides data for clinicians and patients consid-
ering LEV as a first-line treatment. Guidelines and policy
decisions will be further informed by studies collecting longer-
term seizure data.
Author affiliations
1
Department of Neurology, Paracelsus Medical University, Christian Doppler Klinik,
Salzburg, Austria
2
Department of Molecular and Clinical Pharmacology, University of Liverpool,
Liverpool, UK
3
Department of Neurology, University Hospital Gasthuisberg, Katholieke Universiteit
Leuven, Leuven, Belgium
4
Department of Neurology, Kuopio Epilepsy Center, Kuopio University Hospital and
University of Eastern Finland, Kuopio, Finland
5
UCB Pharma, Brussels, Belgium
6
UCB Pharma, Raleigh, North Carolina, USA
7
Neuro Center, St Goran’s Hospital, Stockholm, Sweden
8
Department of Neurology, University Hospital Ostrava, Ostrava, Czech Republic
9
Department of Neuroscience, 3rd Neurology Division and Epilepsy Center, Careggi
Hospital, Florence, Italy
10
Epilepsy Research Centre Heidelberg West, Melbourne, Australia
11
12
Department of Epileptology, Hospital Königin Elisabeth Herzberge, Berlin, Germany
Wales Epilepsy Research Network, University Hospital of Wales, Cardiff, UK
13
Epilepsy Program, QE II Health Centre, Dalhousie University, Halifax, Canada
Acknowledgements Bernd Pohlmann-Eden, MD, PhD, former head of Epilepsy
Centre Bethel, Bielefeld-Germany, now at the Epilepsy Program, QE II Health Science
Centre, Dalhousie University, Halifax, Canada, was the primary investigator and
coordinator of this trial. The authors would like to thank the members of the
KOMET Study Group for their contribution to the study and collection of data. The
KOMET Study Group comprised 269 principal investigators who recruited patients in
269 sites across 24 countries. The authors thank Pascal Edrich, MSc, Biostatistician,
(UCB Pharma employee at the time of study conduct and preparation of the clinical
study report) for initial statistical analysis, Michel Bourgois, PhD, (Business &
Decision (Life\Sciences), Brussels, Belgium; UCB Pharma consultant) for support with
additional post hoc statistical analysis, Françoise Tonner, MD, (UCB Pharma
employee at the time of study conduct and preparation of the clinical study report)
and Robert Chan, MD, (UCB Pharma) for critical review of the manuscript and
Svetlana Dimova, MD, PhD, (UCB Pharma) for critical review and coordination of the
manuscript preparation.
Contributors ET contributed to study design, data collection, analysis and
interpretation, and preparation of the manuscript. AGM contributed to data
collection, analysis and interpretation, and preparation of the manuscript. WVP, RK,
YH, MN, H-JM and PES contributed to data collection and interpretation, and critical
review of the manuscript. JM and SB contributed to study design and conduct, data
interpretation, and critical review of the manuscript. BD contributed to data analysis
and interpretation, and critical review of the manuscript. BP-E was the primary
investigator and coordinator of the study, and contributed to data collection, analysis
and interpretation, and preparation of the manuscript. All above authors approved
the final version. GCM, deceased 22 September 2010, contributed to data collection
and interpretation, and critical review of the manuscript. The remaining authors
made minor changes to the manuscript beyond Dr GCM’ contribution.
Funding KOMET was funded and sponsored by UCB Pharma who was responsible
for the design and conduct of the study, and collection, management, analysis and
interpretation of the data. Medical writing and editorial assistance was provided by
Jennifer Stewart, MSc, (QXV Communications, Macclesfield, UK), and was funded by
UCB Pharma.
Competing interests ET has acted as a paid consultant to Eisai, Medtronics, Bial
and UCB Pharma. He has received research funding from UCB Pharma, and
speakers’ honoraria from Bial, Cyberonics, Desitin Pharma, Eisai, Gerot and UCB
 Downloaded from http://jnnp.bmj.com/ on February 23, 2015 - Published by group.bmj.com
Pharma. AGM has received research funding from UCB Pharma, Eisai,
GlaxoSmithKline (GSK) and Pfizer, has acted as a paid consultant to UCB Pharma
and Cyberonics and has received speakers’ honoraria from Sanofi-Aventis and GSK,
and travel grants from GSK, UCB Pharma, Janssen-Cilag, Eisai and Sanofi-Aventis.
WVP has acted as a paid consultant to and has received speakers’ honoraria from
UCB Pharma, Pfizer, Janssen-Cilag, Valeant, Johnson & Johnson ( J&J), Eisai,
Sanofi-Aventis, Novartis and GSK. He has received research funding from UCB
Pharma, and travel grants from UCB Pharma, Pfizer, GSK, Janssen-Cilag and
Novartis. RK has acted as a board member for UCB Pharma and Eisai, and as a
paid consultant to UCB Pharma, Eisai, Orion Pharma and Janssen-Cilag, and has
received research grants from UCB Pharma, speakers’ honoraria from UCB Pharma,
Eisai, Pfizer, Orion Pharma, Sanofi-Aventis and Janssen-Cilag, and travel grants from
UCB Pharma, Eisai, Pfizer, Orion Pharma, Sanofi-Aventis, Cephalon and J&J. JM and
SB were full-time employees of UCB Pharma at the time when the KOMET study
was conducted and the results analysed. BD is a full-time employee of UCB Pharma.
YH has been a paid advisory board member to UCB Pharma and Pfizer. PH has no
relevant financial relationships outside the submitted work. GCM (deceased) had
received speakers’ or consultancy fees and/or travel/accommodation grants for
participation in medical congresses and investigators’ meetings from Cyberonics,
Eisai, Eli Lilly, Novartis, Pfizer, Sanofi-Aventis and UCB Pharma. MN has received a
speakers’ honorarium from UCB Pharma. H-JM was a paid consultant to UCB
Pharma and Eisai. He has received unrestricted research grants from Janssen-Cilag,
Pfizer, and UCB Pharma and speakers’ honoraria from Cyberonics, Desitin Pharma,
Eisai, Novartis, Janssen-Cilag, Pfizer, and UCB Pharma. PS has received an
unrestricted research grant from UCB Pharma, speakers’ honoraria from UCB Pharma
and Eisai, and travel grants from UCB Pharma and Janssen-Cilag. B P-E was a paid
consultant to Desitin Pharma, UCB Pharma, Janssen-Cilag and Pfizer. He received
research and trial grants from UCB Pharma and Pfizer, and speakers’ honoraria from
UCB Pharma, Pfizer, Desitin Pharma, Eisai and Janssen-Cilag.
Ethics approval The study was approved by the local ethics committees for every
study centre.
Provenance and peer review Not commissioned; externally peer reviewed.
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KOMET: an unblinded, randomised, two

parallel-group, stratified trial comparing the
effectiveness of levetiracetam with
controlled-release carbamazepine and
extended-release sodium valproate as
monotherapy in patients with newly
diagnosed epilepsy
Eugen Trinka, Anthony G Marson, Wim Van Paesschen, Reetta
Kälviäinen, Jacqueline Marovac, Benjamin Duncan, Sonja Buyle, Yngve
Hallström, Petr Hon, Gian Carlo Muscas, Mark Newton, Heinz-Joachim
Meencke, Philip E Smith, Bernd Pohlmann-Eden and for the KOMET
Study Group

J Neurol Neurosurg Psychiatry 2013 84: 1138-1147 originally published

online August 29, 2012
doi: 10.1136/jnnp-2011-300376

Updated information and services can be found at:

http://jnnp.bmj.com/content/84/10/1138

These include:

References This article cites 27 articles, 3 of which you can access for free at:
http://jnnp.bmj.com/content/84/10/1138#BIBL

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Topic Articles on similar topics can be found in the following collections

Collections Epilepsy and seizures (740)
Drugs: psychiatry (183)

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