Epilepsy Research 176 (2021) 106705

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Epilepsy Research
journal homepage: www.elsevier.com/locate/epilepsyres

Safety and efficacy of adjunctive lacosamide in Chinese and Japanese adults

with epilepsy and focal seizures: A long-term, open-label extension of a
randomized, controlled trial
Yushi Inoue a, *, Weiping Liao b, Xuefeng Wang c, Xinlu Du d, Frank Tennigkeit e,
Hiroshi Sasamoto f, Toru Osakabe f, Naoki Hoshii f, Nancy Yuen g, Zhen Hong h, **
a
NHO Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka, 420-8688, Japan
b
The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Road, Guangzhou, Guangdong, 510260, China
c
The First Affiliated Hospital of Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, China
d
UCB Pharma, 14 Taikoo Wan Road, Taikoo, Hong Kong, China
e
UCB Pharma, Alfred-Nobel-Straße 10, 40789, Monheim am Rhein, Germany
f
UCB Pharma, Shinjuku Grand Tower, 8-17-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo, Japan
g
UCB Pharma, 8010 Arco Corporate Drive, Raleigh, NC, 27617, United States
h
Huashan Hospital Fudan University, 12 Wulumuqi Middle Road, Shanghai, 200040, China

A R T I C L E I N F O A B S T R A C T

Keywords: This Phase III, long-term, open-label extension (OLE) trial (EP0009; NCT01832038) was conducted to evaluate
Efficacy the long-term safety, tolerability, and efficacy of adjunctive lacosamide (100–400 mg/day) in Chinese and
Epilepsy Japanese people with epilepsy (PWE) (16–70 years) who had completed a double-blind, randomized, placebo-
Focal seizure
controlled trial of adjunctive lacosamide (EP0008; NCT01710657). PWE entered the OLE trial on 200 mg/day
Lacosamide
Safety
lacosamide and up to 3 concomitant antiseizure medications. Dose adjustments were permitted to optimize
Tolerability tolerability and seizure reduction. Safety variables were treatment-emergent adverse events (TEAEs) and dis­
continuations due to TEAEs. Efficacy variables were percent change in focal seizure frequency per 28 days from
Baseline of the double-blind trial, ≥50 % and ≥75 % responder rates, seizure-freedom, and proportion of PWE on
lacosamide monotherapy.
Overall, 473 PWE (74.0 % Chinese and 26.0 % Japanese) were enrolled; 238 (50.3 %) PWE completed the
trial and 235 (49.7 %) discontinued, most commonly due to lack of efficacy (81 [17.1 %]), adverse events (55
[11.6 %]), and consent withdrawn (49 [10.4 %]). During the trial, PWE received lacosamide for a median of
1016.0 days (~3 years), with a total exposure of 1454.8 person-years; 321 (67.9 %) PWE received lacosamide
for >24 months, and 246 (52.0 %) for >36 months. The median modal dose of lacosamide was 300 mg/day.
Overall, 410/473 (86.7 %) PWE reported TEAEs, 244 (51.6 %) had a TEAE that was considered drug-related,
and 49 (10.4 %) discontinued due to a TEAE. The most common TEAEs (≥20 % of PWE) were nasophar­
yngitis, dizziness, and upper respiratory tract infection. The median reduction in focal seizure frequency per
28 days from Baseline was 57.1 %, and the ≥50 % and ≥75 % responder rates were 57.1 % (269/471) and
29.7 % (140/471), respectively. Among PWE who completed 12, 24, and 36 months of treatment, the 12-, 24-
, and 36-month seizure-freedom rates were 3.5 % (13/375), 3.4 % (11/321), and 2.0 % (5/247), respectively.
Among PWE exposed to lacosamide for ≥6 months and ≥12 months, the proportions of PWE that maintained
continuous monotherapy for ≥6 months and ≥12 months were 5.0 % (21/421) and 5.0 % (19/378),
respectively.

Abbreviations: ASM, antiseizure medication; FAS, Full Analysis Set; PWE, people with epilepsy; SD, standard deviation; SS, safety set; TEAE, treatment-emergent
adverse event.
* Corresponding author at: NHO Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka, 420-8688, Japan.
** Corresponding author at: Huashan Hospital, 12 Wulumuqi Middle Rd, Jing’an District, Fudan University, Shanghai, 200040, China.
E-mail addresses: yshinoue@gmail.com (Y. Inoue), wpliao@163.net (W. Liao), xfyp@163.com (X. Wang), Chinaduxinlu@163.com (X. Du), Frank.Tennigkeit@
ucb.com (F. Tennigkeit), Hiroshi.Sasamoto@ucb.com (H. Sasamoto), Toru.Osakabe@ucb.com (T. Osakabe), Naoki.Hoshii@ucb.com (N. Hoshii), Nancy.Yuen@
ucb.com (N. Yuen), profzhong@sina.com (Z. Hong).

https://doi.org/10.1016/j.eplepsyres.2021.106705
Received 21 January 2021; Received in revised form 11 June 2021; Accepted 27 June 2021
Available online 29 June 2021
0920-1211/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Y. Inoue et al.
Overall, lacosamide was well-tolerated as long-term adjunctive therapy in Chinese and Japanese PWE and
uncontrolled focal seizures, with improvements in seizure reduction maintained over 36 months of treatment.
1. Introduction
Lacosamide is a functionalized amino acid and antiseizure medica­
tion (ASM) that exerts its anticonvulsant effects via selectively aug­
menting the slow inactivation of voltage-gated sodium channels
(Rogawski et al., 2015). The efficacy, safety, and tolerability of lacosa­
mide as adjunctive treatment for people with epilepsy (PWE) with un­
controlled focal (partial-onset) seizures have been demonstrated in 3
randomized, double-blind, placebo-controlled trials in Europe, the
United States, and Australia (Ben-Menachem et al., 2007; Chung et al.,
2010; Halász et al., 2009). In the corresponding open-label extension
(OLE) trials, efficacy was maintained for up to 8 years and lacosamide as
adjunctive therapy was generally well tolerated (Husain et al., 2012;
Rosenfeld et al., 2014; Rosenow et al., 2016).
The first trial to report the efficacy and safety of adjunctive lacosa­
mide in Chinese and Japanese PWE with uncontrolled focal seizures was
EP0008 (NCT01710657), a 27-week, double-blind, randomized,
placebo-controlled trial (Hong et al., 2016). In China, lacosamide is
indicated as adjunctive therapy for the treatment of focal seizures in
PWE ≥4 years of age. In Japan, lacosamide is indicated as adjunctive
therapy or monotherapy for the treatment of focal seizures in PWE ≥4
years of age. Considering chronic treatment with ASMs is required by
many PWE, it is important that the efficacy, tolerability, and safety of
lacosamide are maintained over the long term.
Here, we present the results of an OLE trial (EP0009; NCT01832038)
conducted to evaluate the long-term tolerability, safety, and efficacy of
adjunctive lacosamide (100–400 mg/day) in Japanese and Chinese PWE
who completed the placebo-controlled trial (EP0008).
2. Methods
2.1. Trial design
EP0009 (NCT01832038) was a Phase III, uncontrolled, flexible-dose,
open-label, multicenter extension trial in Chinese and Japanese PWE
and focal seizures with or without focal to bilateral tonic-clonic seizures
(secondary generalization). A national, regional, or institutional review
board or independent ethics committee reviewed and approved the
patient informed consent, trial protocol, and trial amendments. The trial
was conducted in accordance with local laws of the countries involved,
the Declaration of Helsinki, and the International Council for
Harmonization-Good Clinical Practice. Prior to enrollment, all PWE (or
their legal representatives) provided written informed consent.
2.2. PWE eligibility
Male and female PWE aged 16–70 years who completed a double-
blind trial (EP0008; NCT01710657) could enroll in the OLE if in the
opinion of the investigator they were expected to benefit from partici­
pation. PWE were excluded if they withdrew from the double-blind trial,
if they were receiving another trial medication or unapproved medica­
tion, using an experimental device, or were experiencing an ongoing
serious adverse event (unless approved by the sponsor). Women were
excluded if they were breastfeeding or pregnant.
Eligibility criteria for the double-blind trial included uncontrolled
focal seizures, with or without secondary generalization, and a magnetic
resonance imaging exam or a brain computed tomographic scan and
electroencephalogram consistent with a diagnosis of epilepsy with focal
seizures. Eligible PWE had experienced focal seizures for ≥2 years
(despite taking ≥2 concurrent or sequential ASMs), with an average of
2
Epilepsy Research 176 (2021) 106705
≥4 focal seizures with motor signs per 28 days and no seizure-freedom
of more than 21 days during the 8 weeks prior to Baseline, and were on a
stable daily dose regimen of 1–3 orally administered ASMs for ≥4 weeks
before Baseline (vagus nerve stimulation was not classified as an ASM).
2.3. Treatment schedule
In the double-blind trial, PWE were randomized in a ratio of 1:1:1 to
placebo, 200 mg/day lacosamide, or 400 mg/day lacosamide. PWE were
assessed over a 24-week period, including an 8-week Baseline and 16-
week Treatment period (4-week Titration and 12-week Maintenance)
plus a 3-week Taper or 2-week Transition period. Treatment was initi­
ated at 100 mg/day lacosamide or placebo and up-titrated to the target
dose in weekly increments of 100 mg/day. At the end of Titration, a 1-
step dose decrease (200 to 100 mg/day; 400 to 300 mg/day) was
permitted if required for tolerability. PWE who were unable to tolerate
the reduced dose were withdrawn from the trial, with no further dose
adjustments permitted.
The OLE was designed to enable PWE who completed the Treatment
and Transition Periods of the double-blind trial to continue lacosamide
therapy until approval in each country. After completing the double-
blind trial, all PWE who chose to enroll in the OLE were transitioned
to a lacosamide dose of 200 mg/day. In contrast to the forced up-
titration in EP0008, lacosamide doses could be flexibly adjusted dur­
ing the OLE to optimize seizure reduction and tolerability. The lacosa­
mide dose could be increased, no faster than 100 mg/day per week, up to
400 mg/day, or decreased to 100 mg/day.
PWE entering the OLE could continue on the concomitant ASMs that
were used during the double-blind trial. Changes to concomitant ASMs
were allowed provided the person with epilepsy had taken lacosamide at
a stable dose for the previous 4 weeks, and the lacosamide dose
remained stable during changes to concomitant ASMs. PWE could
receive no more than 3 concomitant ASMs, with the exception of tem­
porary use (up to 12 weeks) of 4 ASMs while switching to a new ASM (i.
e., taper from old ASM during titration of a new ASM). Addition of a new
ASM (approved for epilepsy in the person with epilepsy’s country) was
only permitted if the person with epilepsy was not adequately or opti­
mally responding to lacosamide at the maximum tolerated dose. At the
discretion of the investigator, concomitant ASMs could be tapered or
discontinued, and monotherapy with lacosamide was permitted.
PWE who completed the Treatment Period and chose to discontinue
lacosamide, or who prematurely withdrew from the trial, entered a
Taper Period if they were taking a lacosamide dose of greater than 200
mg/day. A dose decrease of up to 200 mg/day lacosamide per week was
recommended, with a slower taper of 100 mg/day lacosamide per week
permitted if medically necessary.
2.4. Trial variables
Safety variables were treatment-emergent adverse events (TEAEs)
observed by the investigator or reported spontaneously by the person
with epilepsy, and discontinuation due to TEAEs. Other significant
TEAEs were defined as TEAEs with preferred terms from the Medical
Dictionary for Regulatory Activities related to hepatotoxicity, cardiac/
echocardiogram, suicidality, syncope, loss of consciousness, and
decreased appetite. Signs or symptoms of epilepsy (e.g., seizures) were
recorded as TEAEs (regardless of causality) if their intensity or fre­
quency increased in a manner considered clinically significant, or their
nature changed considerably. Other safety variables were vital sign
measurements (blood pressure and pulse rate), urinalysis parameters,
Y. Inoue et al.
clinical chemistry, 12-lead electrocardiograms, changes in hematology,
and body weight.
Efficacy variables were percent change in focal seizure frequency per
28 days from the Baseline of the double-blind trial, and ≥50 %
responder rate (PWE experiencing a reduction in focal seizure frequency
of ≥50 %/28 days from the Baseline of the double-blind trial). Other
efficacy variables were ≥75 % responder rate (PWE experiencing a ≥75
% reduction in focal seizure frequency/28 days from Baseline of the
double-blind trial), PWE who achieved seizure-free status, percentage of
seizure-free days, and PWE who were changed to lacosamide mono­
therapy for at least 6 and 12 months.
2.5. Statistical methods
Datasets were analyzed using SAS version 9.2 or higher, with
descriptive statistics used for safety and efficacy results. Safety was
assessed in the Safety Set (SS), which was defined as all PWE that had ≥1
lacosamide dose in the OLE. Efficacy was assessed in the Full Analysis
Set (FAS), which included all PWE in the SS who had ≥1 day with
available data in their seizure diary during the OLE.
Data are presented for all PWE, and by randomized treatment group
in the double-blind trial (placebo, 200 mg/day lacosamide, or 400 mg/
day lacosamide). For efficacy analyses, completer cohorts were defined
as subsets of PWE in the FAS who received lacosamide for a specified
period of time (6, 12, 18, 24, 30, and 36 months, where a month was
defined as 28 days), and had seizure diary data available for the duration
of the cohort. Data are presented for the duration of each cohort and by
6-month intervals.
Monotherapy was defined as lacosamide use with no other
concomitant ASMs. Benzodiazepines were not regarded as ASMs if they
were used as rescue medication for the control of seizures that were
uncountable due to clustering. PWE also qualified as being on lacosa­
mide monotherapy if they received other ASM rescue medication for ≤1
day.
Fig. 1. PWE disposition.
FAS = Full Analysis Set; PWE = people with epilepsy; SS = Safety Set.
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Epilepsy Research 176 (2021) 106705
3. Results
3.1. PWE disposition and demographics
The OLE (EP0009) was conducted between February 2013 and
August 2019 at 67 sites across China and Japan. Overall, 474 PWE were
screened and 473 PWE entered the trial (Fig. 1). Of these, 350 (74.0 %)
were Chinese and 123 (26.0 %) were Japanese. All 473 enrolled PWE
were included in the SS (all had ≥1 lacosamide dose), of whom 471 PWE
had ≥1 day with an available seizure diary entry and were included in
the FAS. In all, 238/473 (50.3 %) PWE completed the trial and 235 (49.7
%) PWE discontinued. The most frequent primary reasons for discon­
tinuation were lack of efficacy (81 [17.1 %]), adverse events (55 [11.6
%]), and consent withdrawn (49 [10.4 %]).
PWE had a mean (SD) age of 32.7 (12.0) years at double-blind
Baseline and 259 (54.8 %) were male. The mean time since first epi­
lepsy diagnosis was 17.3 (range: 0.4–59.0) years (SS; Table 1). Baseline
demographics were similar across PWE enrolled in the OLE from each
randomized treatment group of the double-blind trial.
3.2. Safety variables
3.2.1. Lacosamide exposure
PWE received lacosamide for a median of 1016.0 days, with a total
exposure of 1454.8 person-years (SS). 321 (67.9 %) PWE received
lacosamide for more than 24 months, and 246 (52.0 %) PWE received
lacosamide for more than 36 months. The median modal dose of laco­
samide was 300 mg/day (range: 100–400 mg/day) for all PWE, and for
PWE from each of the randomized treatment groups of the double-blind
trial. Eighteen (3.8 %), 139 (29.4 %), 113 (23.9 %), and 201 (42.5 %)
PWE had modal doses of 100, 200, 300, and 400 mg/day lacosamide,
respectively. Two PWE did not have exposure data because they dis­
continued the trial immediately after the first visit of the OLE. For PWE
taking modal doses of 100, 200, 300, and 400 mg/day lacosamide, the
median trial duration was 557.5, 819.0, 1171.0, and 1233.0 days,
respectively.
Y. Inoue et al. Epilepsy Research 176 (2021) 106705

Table 1 Table 2
Baseline demographics and epilepsy characteristics overall (EP0009) and by Overall incidence of TEAEs that began during the EP0009 Treatment Period and
randomized treatment in the double-blind trial (SS)a. by randomized treatment in the previous double-blind trial (SS).
Randomized treatment group in EP0008 Randomized treatment group in
EP0008
Characteristic Lacosamide Lacosamide
Placebo 200 mg/day 400 mg/day All PWE Patients, n (%) Lacosamide Lacosamide
(n = 164) (n = 163) (n = 146) (N = 473) Placebo 200 mg/day 400 mg/day All PWE
(n = 164) (n = 163) (n = 146) (N = 473)
Age, mean (SD), years 32.2 (12.2) 33.6 (12.5) 32.2 (11.4) 32.7 (12.0)
Male, n (%) 91 (55.5) 84 (51.5) 84 (57.5) 259 (54.8) Any TEAEs 144 146 (89.6) 120 (82.2) 410
Racial subgroup, n (%) (87.8) (86.7)
Chinese 119 (72.6) 120 (73.6) 111 (76.0) 350 (74.0) Drug-related TEAEs 85 (51.8) 85 (52.1) 74 (50.7) 244
Japanese 45 (27.4) 43 (26.4) 35 (24.0) 123 (26.0) (51.6)
Time since diagnosis, 17.0 (11.6) 18.4 (10.8)b 16.5 (10.7) 17.3 (11.1)c Serious TEAEs 24 (14.6) 34 (20.9) 20 (13.7) 78 (16.5)
mean (SD), years Severe TEAEs 9 (5.5) 21 (12.9) 9 (6.2) 39 (8.2)
Seizure classificationd, n (%) Discontinuations due to TEAEs 12 (7.3) 17 (10.4) 20 (13.7) 49 (10.4)
Simple partial (focal 53 (32.3) 59 (36.2) 53 (36.3) 165 (34.9) Deaths 2 (1.2) 1 (0.6) 2 (1.4) 5 (1.1)
aware) TEAEsa occurring in ≥5% of all PWE
Complex partial 54 (32.9) 42 (25.8) 40 (27.4) 136 (28.8) Nasopharyngitis 62 (37.8) 47 (28.8) 46 (31.5) 155
with simple partial (32.8)
(focal aware) onset Dizziness 53 (32.3) 36 (22.1) 36 (24.7) 125
Complex partial 110 (67.1) 109 (66.9) 100 (68.5) 319 (67.4) (26.4)
(focal impaired Upper respiratory tract 41 (25.0) 29 (17.8) 30 (20.5) 100
awareness) at onset infection (21.1)
Partial evolving to 114 (69.5) 105 (64.4) 90 (61.6) 309 (65.3) Headache 25 (15.2) 21 (12.9) 30 (20.5) 76 (16.1)
secondarily Somnolence 19 (11.6) 13 (8.0) 9 (6.2) 41 (8.7)
generalized (focal to Diarrhea 14 (8.5) 12 (7.4) 15 (10.3) 41 (8.7)
bilateral tonic-clonic) Pyrexia 21 (12.8) 9 (5.5) 11 (7.5) 41 (8.7)
Concomitant ASMs, taken by ≥15 % of all PWE, n (%) Toothache 7 (4.3) 18 (11.0) 13 (8.9) 38 (8.0)
Valproatee 82 (50.0) 83 (50.9) 74 (50.7) 239 (50.5) Vomiting 11 (6.7) 14 (8.6) 11 (7.5) 36 (7.6)
Carbamazepine 79 (48.2) 86 (52.8) 64 (43.8) 229 (48.4) Nausea 13 (7.9) 10 (6.1) 7 (4.8) 30 (6.3)
Levetiracetam 48 (29.3) 45 (27.6) 44 (30.1) 137 (29.0) Upper abdominal pain 13 (7.9) 10 (6.1) 5 (3.4) 28 (5.9)
Lamotrigine 45 (27.4) 41 (25.2) 35 (24.0) 121 (25.6) Gastroenteritis 8 (4.9) 7 (4.3) 13 (8.9) 28 (5.9)
Topiramate 40 (24.4) 27 (16.6) 26 (17.8) 93 (19.7) Cough 19 (11.6) 4 (2.5) 4 (2.7) 27 (5.7)
Oxcarbazepine 34 (20.7) 27 (16.6) 24 (16.4) 85 (18.0) Oropharyngeal pain 13 (7.9) 3 (1.8) 11 (7.5) 27 (5.7)
Number of concomitant ASMs, n (%) Contusion 14 (8.5) 4 (2.5) 8 (5.5) 26 (5.5)
1 38 (23.2) 42 (25.8) 32 (21.9) 112 (23.7) Insomnia 9 (5.5) 11 (6.7) 6 (4.1) 26 (5.5)
2 60 (36.6) 70 (42.9) 64 (43.8) 194 (41.0) Drug-related TEAEsa occurring in ≥3% of all PWE
3 66 (40.2) 51 (31.3) 50 (34.2) 167 (35.3) Dizziness 41 (25.0) 31 (19.0) 28 (19.2) 100
f
Number of historical ASMs , n (%) (21.1)
0 10 (6.1) 11 (6.7) 9 (6.2) 30 (6.3) Somnolence 9 (5.5) 12 (7.4) 9 (6.2) 30 (6.3)
1 23 (14.0) 30 (18.4) 30 (20.5) 83 (17.5) Headache 7 (4.3) 5 (3.1) 11 (7.5) 23 (4.9)
2 36 (22.0) 34 (20.9) 35 (24.0) 105 (22.2) Nausea 8 (4.9) 4 (2.5) 6 (4.1) 18 (3.8)
3 34 (20.7) 33 (20.2) 27 (18.5) 94 (19.9) Vision blurred 5 (3.0) 8 (4.9) 4 (2.7) 17 (3.6)
≥4 61 (37.2) 55 (33.7) 45 (30.8) 161 (34.0) Vomiting 5 (3.0) 5 (3.1) 6 (4.1) 16 (3.4)
Baseline seizure 11.0 11.0 10.0 10.7 Gait disturbance 5 (3.0) 4 (2.5) 5 (3.4) 14 (3.0)
frequency per 28 (3.6–707.6) (3.7–1118.0)g (2.6–221.0)h (2.6–1118.0)i
days, median (range) PWE, people with epilepsy; SS, safety set; TEAE, treatment-emergent adverse
event.
ASM, antiseizure medication; PWE, people with epilepsy; SD, standard devia­ a
Preferred term (Medical Dictionary for Regulatory Activities, Version 16.1).
tion; SS, safety set.
a
As reported during the Baseline Period of the double-blind trial (EP0008).
b
n = 161.
c was highest during the first 6 months of treatment (36.4 %) and
n = 471.
d
Experienced prior to enrollment into the double-blind trial. PWE could have
decreased thereafter. Overall, 49 (10.4 %) PWE discontinued due to
had more than 1 response. Seizure types are listed per the International League TEAEs. The only TEAEs leading to discontinuation in more than 2 PWE
Against Epilepsy 1981 classification (Commission on Classification and Termi­ were dizziness (8 [1.7 %]) and pregnancy (4 [0.8 %]). Analyses ac­
nology of the International League Against Epilepsy, 1981), with the newer cording to randomized treatment group in the double-blind trial
terminology (Fisher et al., 2017) in parentheses. showed no notable differences in the overall incidences of TEAEs and
e
Includes valproate magnesium, valproic acid, valproate sodium, valpromide, TEAEs considered drug-related during the OLE (Table 2). TEAEs with a
and ergenyl chrono. higher incidence in PWE who had taken placebo in the double-blind
f
Historical ASMs were defined as ASMs used by the person with epilepsy in trial compared with those who received lacosamide (≥5 % higher
the past 5 years (or >5 years if the person with epilepsy had <2 ASMs within 5 incidence with placebo than both lacosamide groups) were nasophar­
years) and stopped 28 days before Visit 1 of the double-blind trial.
g yngitis, dizziness, pyrexia, and cough.
n = 162.
h Most of the TEAEs reported were mild or moderate in intensity. A
n = 145.
i
n = 471.
total of 39 (8.2 %) PWE experienced severe TEAEs during the Treatment
Period. Severe TEAEs reported by >1 person with epilepsy were status
epilepticus (5 [1.1 %]), epilepsy (3 [0.6 %]), and dizziness (2 [0.4 %]).
3.2.2. Treatment-emergent adverse events Serious TEAEs were experienced by 78 (16.5 %) PWE, most frequently
Four-hundred and ten PWE (86.7 %) reported TEAEs during the (≥1 %) status epilepticus (10 [2.1 %]), epilepsy (10 [2.1 %]), and
Treatment Period (Table 2). The most frequent TEAEs (reported by pneumonia (6 [1.3 %]).
≥20 % of all PWE) were nasopharyngitis, dizziness, and upper respi­ Other significant TEAEs were reported by 20 PWE. Two PWE expe­
ratory tract infection. TEAEs that were deemed drug-related by the rienced TEAEs of sinus bradycardia that were mild in intensity, did not
investigator were reported by 244 (51.6 %) PWE (Table 2), most lead to trial discontinuation, and resolved; the most recent dose of
commonly dizziness (21.1 %). The incidence of drug-related TEAEs lacosamide was 200 mg/day for 1 person with epilepsy (not drug-

4
Y. Inoue et al.
related) and 300 mg/day for the other person with epilepsy (drug-
related). Three PWE reported 6 TEAEs of suicidal ideation that were
mild in intensity; the most recent dose of lacosamide was 200 mg/day
for 2 PWE and 400 mg/day for 1 person with epilepsy. Of the TEAEs of
suicidal ideation, 1 was deemed drug-related and resolved, 1 was
serious, and none led to discontinuation; 5 events resolved and 1 was
resolving at the time of reporting. One person with epilepsy taking 400
mg/day lacosamide reported a TEAE of suicide attempt, which was
serious, severe in intensity, not considered drug-related, led to trial
discontinuation, and resolved with sequelae. One person with epilepsy
on 300 mg/day lacosamide experienced a TEAE of syncope that was
mild, not drug-related, did not lead to discontinuation, and resolved.
Fourteen PWE reported 17 TEAEs of decreased appetite; all were mild or
moderate in intensity; 2 events were serious, both of which resolved; 12
were considered drug-related, with 1 event that was not resolved and 1
that was resolving; 2 events that were not considered serious or drug-
related were not resolved.
Rash was reported as a TEAE by 12 (2.5 %) PWE, and all events of
rash were mild or moderate and resolved. Two (0.4 %) PWE experienced
rash that was considered drug-related; 1 of these had a moderate TEAE
that led to discontinuation, the other person with epilepsy had mild
TEAEs that did not lead to discontinuation, and the dose of lacosamide
was not changed. Pruritus was experienced by 7 (1.5 %) PWE and was
considered drug-related in 3 (0.6 %) PWE. All events of pruritus were
mild in intensity and resolved, and none led to discontinuation.
Seven PWE died during the trial. Five (1.1 %) PWE died during the
Fig. 2. Median percent reductiona in focal seizure frequency per 28 days by completer cohort (Full Analysis Set). (A) Overall, and (B) by 6-month intervals.
Completer cohorts included people with epilepsy with at least the specified duration of lacosamide exposure.
a
From Baseline of the double-blind trial (EP0008).
5
Epilepsy Research 176 (2021) 106705
Treatment Period, due to cerebral infarction (1 person with epilepsy,
deemed possibly drug-related; prior to the trial, a magnetic resonance
imaging scan showed multiple cerebral infarctions), heat stroke (1
person with epilepsy, not deemed drug-related), sudden death (1 person
with epilepsy, not deemed drug-related), and status epilepticus (2 PWE;
1 considered drug-related, although the investigator reported that they
could not judge whether or not the fatal event was related to lacosa­
mide). One person with epilepsy had a fatal TEAE of status epilepticus
during the Post-Treatment Period (not considered drug-related) and 1
person with epilepsy completed suicide after the final trial contact and
database lock (serious, severe in intensity, and deemed drug-related by
the investigator).
There was no evidence for lacosamide to have had any clinically
relevant effect on neurological examinations, urinalysis parameters,
vital signs, hematology, body weight, clinical chemistry, or electrocar­
diogram evaluations. The incidence of TEAEs potentially related to
clinical chemistry findings or abnormal hematology was generally low.
3.3. Efficacy variables
During the Treatment Period, the overall median percent reduction
in focal seizure frequency per 28 days from Baseline of the double-blind
trial was 57.1 % (Fig. 2A). A decrease in median focal seizure frequency/
28 days was observed in the first 6 months of the OLE (51.5 %, n = 471)
and was maintained over time for PWE with data for later time intervals
(>6 to 12 months: 59.4 %, n = 419; >12 to 18 months: 65.4 %, n = 376;
Y. Inoue et al.
>18 to 24 months: 66.7 %, n = 346; >24 to 30 months: 67.6 %, n = 324;
>30 to 36 months: 69.2 %, n = 299; >36 months: 74.0 %, n = 246). By
completer cohorts, the overall median percent reductions in seizure
frequency/28 days for 12-, 24-, and 36-month completers were 58.5 %,
63.3 %, and 65.2 %, respectively (Fig. 2B). Across completer cohorts, the
reductions in seizure frequency/28 days were observed in the first 6
months of treatment and were sustained over time. Median percent re­
ductions in focal seizure frequency/28 days were similar for PWE that
were randomized to placebo (55.9 %), 200 mg/day lacosamide
Fig. 3. ≥50 % and ≥75 % responder rates for focal seizures by completer cohort (Full Analysis Set).
6
Epilepsy Research 176 (2021) 106705
(58.3 %), and 400 mg/day lacosamide (58.7 %) in the initial double-
blind trial.
Overall, the proportions of PWE with a ≥50 % and ≥75 % response
to lacosamide from Baseline in the double-blind trial to the OLE
Treatment Period were 57.1 % (269/471) and 29.7 % (140/471),
respectively. The ≥50 % responder rate was 52.0 % (245/471) in the
first 6 months of the OLE and was maintained over time for PWE with
data for later time intervals (>6 to 12 months: 61.8 % [259/419]; >12 to
18 months: 65.2 % [245/376]; >18 to 24 months: 68.5 % [237/346];
Y. Inoue et al.
>24 to 30 months: 66.4 % [215/324]; >30 to 36 months: 66.9 %
[200/299]; >36 months: 67.5 % [166/246]). The ≥75 % responder rate
was 25.7 % (121/471) in the first 6 months and was also maintained
over time (>6 to 12 months: 31.3 % [131/419]; >12 to 18 months: 37.2
% [140/376]; >18 to 24 months: 38.4 % [133/346]; >24 to 30 months:
42.0 % [136/324]; >30 to 36 months: 43.8 % [131/299]; >36 months:
49.2 % [121/246]). For the completer cohorts, ≥50 % and ≥75 %
responder rates were 62.4 % and 28.3 % (12-month completers), 67.0 %
and 33.3 % (24-month completers), and 68.0 % and 37.7 % (36-month
completers), respectively. Within each completer cohort, responses to
treatment were seen in the first 6 months of treatment and were sus­
tained over time (Fig. 3).
Overall, 3.5 % (13/375) of the 12-month completers were seizure-
free for 12 months, 3.4 % (11/321) of the 24-month completers were
seizure-free for 24 months, and 2.0 % (5/247) of the 36-month com­
pleters were seizure-free for 36 months. The median increase in the
proportion of seizure-free days from Baseline of the double-blind trial
was 12.2 %, 13.5 %, and 13.8 % in the 12-, 24-, and 36-month completer
cohorts, respectively.
Among PWE exposed to lacosamide for ≥6 months, 5.0 % (21/421)
maintained continuous lacosamide monotherapy for ≥6 months, and for
PWE exposed to lacosamide for ≥12 months, 5.0 % (19/378) maintained
continuous lacosamide monotherapy for ≥12 months.
4. Discussion
In this long-term (median ~3 years) OLE trial, lacosamide (100–400
mg/day) as adjunctive treatment was safe and generally well tolerated
in Japanese and Chinese adults with uncontrolled focal seizures. In
Chinese and Japanese PWE, the efficacy and safety of adjunctive laco­
samide were reported in a double-blind, randomized, placebo-controlled
trial (Hong et al., 2016). This OLE of the double-blind, fixed-dose trial
enabled a treatment regimen that more closely reflected clinical prac­
tice, with flexible dosing of lacosamide as well as concomitant ASMs to
optimize seizure control and drug tolerability.
During the Treatment Period of the OLE, 86.7 % of PWE experienced
TEAEs and 51.6 % experienced TEAEs that were deemed drug-related by
the investigator. TEAEs related to the central nervous system such as
dizziness, headache, and somnolence were among the most commonly
reported TEAEs, consistent with those reported in previous lacosamide
trials (Ben-Menachem et al., 2007; Chung et al., 2010; Halász et al.,
2009; Hong et al., 2016; Husain et al., 2012; Rosenfeld et al., 2014;
Rosenow et al., 2016).
Dizziness was reported by 26.4 % of PWE, and was the most frequent
drug-related TEAE (21.1 %) and the most frequent TEAE leading to
discontinuation (1.7 %). PWE transitioning from placebo in the double-
blind trial had a numerically higher incidence of dizziness in this OLE
(32.3 %) than PWE who were already taking lacosamide (23.3 %).
Several trials have shown a higher incidence of dizziness during Titra­
tion than Maintenance (Biton et al., 2015; Hong et al., 2016). A post hoc
analysis of data from the fixed-titration period in the double-blind trial
compared to the initial 4 weeks of open-label lacosamide treatment
(2-week Transition Period and first 2 weeks of the OLE, representing
flexible titration) showed that in PWE initiating lacosamide with flexible
titration, the incidence of dizziness was comparable with the incidence
of dizziness when the same PWE received placebo during the
double-blind Titration period (Inoue et al., 2017). Further, the incidence
of dizziness leading to discontinuation was lower for PWE with flexible
titration compared to forced titration of lacosamide (Inoue et al., 2017).
This post hoc analysis indicated that slower and more flexible uptitra­
tion, as performed in this OLE, results in lower rates of dizziness when
starting lacosamide therapy.
For PWE taking lacosamide, rash is a TEAE of interest, particularly in
Asian PWE that have the HLA-B*1502 variant. ASMs such as carba­
mazepine, lamotrigine, and oxcarbazepine are sodium channel-blockers
that contain aromatic rings, which have been associated with an
7
Epilepsy Research 176 (2021) 106705
increase in serious skin reactions, especially in PWE with this HLA-
B*1502 allele (Cheung et al., 2013; Kaniwa et al., 2010; Wang et al.,
2012; Yang et al., 2011). In this long-term trial, 12 (2.5 %) PWE reported
a TEAE of rash. Two PWE had rash that was considered drug-related and
1 person with epilepsy discontinued due to rash. All TEAEs of rash
resolved. The incidence of rash as a TEAE in this trial (2.5 %) is com­
parable with that observed in a previous OLE trial in Caucasian PWE (3.7
%). Pruritus was experienced by 7 (1.5 %) PWE, was considered drug
related in 3 PWE, and did not lead to discontinuation for any person with
epilepsy.
During this long-term trial (median duration of ~3 years), 7 PWE
died. Five deaths occurred during the Treatment Period, most of which
were not considered drug-related (2 of the 5 deaths during the Treat­
ment Period were deemed possibly related to lacosamide). No deaths
were reported in the preceding double-blind trial (EP0008) (Hong et al.,
2016). Compared with the previous double-blind trial, the difference in
the number of deaths seen in the current trial may be explained by the
length of time for each trial; the duration of the previous trial was 24
weeks vs a median of ~3 years for this long-term extension. Thus, the
long-term extension allowed for more time for such instances to be
captured. It is noted that PWE enrolled in this OLE had a high Baseline
seizure frequency (median of 10.7 focal seizures/28 days), and 34.0 % of
PWE had taken ≥4 historical ASMs, suggesting that these PWE may have
represented a more treatment-resistant population. PWE with
drug-resistant epilepsy may be at higher risk of increased mortality over
time (Laxer et al., 2014). Finally, the proportion of deaths during the
Treatment Period in this long-term, OLE trial (5/473 [1.1 %]) is com­
parable with the proportion of deaths in PWE and focal seizures during a
long-term extension trial of lacosamide (5/370 [1.4 %]) (Rosenfeld
et al., 2014).
In this OLE, efficacy of lacosamide as adjunctive treatment was
maintained in the long term from the initial double-label trial. The
overall median percent reduction in focal seizure frequency (57.1 %)
was higher than in the previous OLE trials conducted in mainly Cauca­
sian PWE (48.5–50.8 %) (Husain et al., 2012; Rosenfeld et al., 2014;
Rosenow et al., 2016). The ≥50 % and ≥75 % responder rates (57.1 %
and 29.7 %, respectively) were also greater than in the previous OLE
trials (≥50 % responder rates: 48.2–51.2 % (Husain et al., 2012; Rose­
nfeld et al., 2014; Rosenow et al., 2016); ≥75 % responder rate: 23.7 %
(Rosenow et al., 2016)).
The open-label, uncontrolled design of this trial limits the interpre­
tation of the efficacy results; 17.1 % of PWE discontinued due to a lack of
efficacy throughout the trial, which could have resulted in increased
efficacy over time. This potential bias was counteracted by assessing the
efficacy of lacosamide by completer cohorts, which included PWE who
completed lacosamide therapy for certain periods of time. In the
completer cohorts, the percent reduction in seizure frequency as well as
≥50 % and ≥75 % responder rates were generally maintained over time.
Seizure-freedom and percentage of seizure-free days were also similar
across the completer cohorts.
5. Conclusions
Overall, the safety, tolerability, and efficacy results from this long-
term trial of lacosamide are consistent with previous long-term effi­
cacy and safety data from trials conducted in the predominantly Western
population of PWE (Husain et al., 2012; Rosenfeld et al., 2014; Rosenow
et al., 2016). The results of this trial support the long-term effectiveness
and safety of adjunctive lacosamide up to 400 mg/day for the treatment
of Japanese and Chinese adults with uncontrolled focal seizures.
Funding
This trial was funded by UCB Pharma. UCB Pharma was responsible
for the trial design, and collection and analysis of the data. The authors,
some of whom are UCB Pharma employees, were responsible for data
Y. Inoue et al.
interpretation, revising the manuscript for intellectual content, and
approving of the manuscript for submission.
Data statement
Underlying data from this manuscript may be requested by qualified
researchers 6 months after product approval in the United States and/or
Europe, or global development is discontinued, and 18 months after trial
completion. Investigators may request access to anonymized individual
patient-level data and redacted trial documents, which may include:
analysis-ready datasets, study protocol, annotated case report form,
statistical analysis plan, dataset specifications, and clinical study report.
Prior to use of the data, proposals need to be approved by an indepen­
dent review panel at www.Vivli.org and a signed data-sharing agree­
ment will need to be executed. All documents are available in English
only, for a pre-specified time, typically 12 months, on a password-
protected portal.
Declaration of Competing Interest
Naoki Hoshii, Hiroshi Sasamoto, Toru Osakabe, Frank Tennigkeit,
and Nancy Yuen are employees of UCB Pharma. Xinlu Du was an
employee of UCB Pharma at the time this trial was conducted, and is
currently affiliated with Takeda Development Center Asia, Pte. Ltd.
Yushi Inoue, Zhen Hong, Weiping Liao, and Xuefeng Wang have no
conflicts of interest to declare.
Acknowledgements
The authors thank the patients and their caregivers in addition to the
investigators and their teams who contributed to this trial (co-investi­
gator appendix). The authors acknowledge Kyoko Hirano, CMPP (UCB
Pharma, Tokyo, Japan) for publication coordination, and Ciara Duffy,
PhD (Evidence Scientific Solutions, London, UK) for writing assistance,
which was funded by UCB Pharma.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi: https://doi.org/10.1016/j.eplepsyres.2021.10
6705.
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