Received: 27 April 2023

| Accepted: 26 August 2023

DOI: 10.1002/epi4.12823

ORIGINAL ARTICLE

Efficacy and safety of perampanel monotherapy in

Chinese patients with focal-­onset seizures: A single-­center,
prospective, real-­world observational study

Haiyan Ma | Haitao Zhu | Fangqing Chen | Yiqing Yang | Xuefeng Qu |

Honghao Xu | Lu Yang | Rui Zhang

Department of Functional Neurosurgery,

Nanjing Brain Hospital affiliated to
Nanjing Medical University, Nanjing,
China
Correspondence
Lu Yang and Rui Zhang, Department of
Functional Neurosurgery, Nanjing Brain
Hospital affiliated to Nanjing Medical
University, 264 Guangzhou Road,
Nanjing, 210029, Jiangsu, China.
Email: 776278173@qq.com;
yl198188@126.com and
neurosurgeonzr@njmu.edu.cn
Funding information
Nanjing Medical Science and Technology
Development Project, Grant/Award
Number: YKK17136 and YKK21111
Abstract
Objective: Efficacy and safety of perampanel monotherapy for treating focal-­
onset seizures (FOS) has been barely studied in China. This observational study
aimed to evaluate the efficacy and safety of perampanel monotherapy in treating
Chinese patients with FOS.
Methods: This single-­center, prospective, real-­world observational study en-
rolled patients aged ≥4 years with FOS who visited the Epilepsy Out-­Patient
Clinic of Nanjing Brain Hospital affiliated to Nanjing Medical University from
January 2020 to December 2021. All patients were treated with perampanel
monotherapy. Seizure-­freedom rates after 6 and 12 months of treatment were
calculated. Adverse events (AEs) were recorded.
Results: Seventy patients with FOS were enrolled. The mean maintenance per-
ampanel dose was 4.64 ± 1.55 mg/day. The 6-­and 12-­month retention rates of per-
ampanel monotherapy were 78.6% (55/70) and 70.0% (49/70), respectively. The
6-­and 12-­month seizure-­freedom rates were 69.84% (44/63) and 65.08% (41/63),
respectively. Patients with focal to bilateral tonic–­clonic seizures had signifi-
cantly higher 6-­month and numerically higher 12-­month seizure freedom rates
than patients with focal impaired awareness seizures (P = 0.046 and P = 0.204,
respectively). Twenty-­six (37.1%) patients experienced treatment-­emergent AEs,
and the most common AE was dizziness. Four (5.7%) patients withdrew from the
study due to AEs. No new safety concern was observed.
Significance: This is the first prospective study on the efficacy and safety of per-
ampanel monotherapy in treating Chinese patients with FOS, and perampanel
monotherapy was effective and safe in treating Chinese patients aged ≥4 years
with FOS up to 12 months. More multicenter, real-­world studies with large sam-
ple sizes and longer follow-­ups are needed to further evaluate the long-­term ef-
ficacy and safety of perampanel monotherapy.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
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© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Epilepsia Open. 2023;00:1–10.  wileyonlinelibrary.com/journal/epi4 | 1

 |   
2 MA et al.
KEYWORDS
Chinese patients, focal to bilateral tonic–­clonic seizures, focal-­onset seizures, perampanel
monotherapy, seizure-­freedom rate
1 | I N T RO DU CT ION
Epilepsy is a common chronic neurological disorder char-
acterized by recurrent unprovoked seizures that affects
50-­70 million people worldwide.1–­3 An epileptic seizure is
an occurrence of sudden, transient symptoms induced by
hyper-­synchronous abnormal neuronal discharges in the
brain.4 The prevalence of epilepsy in China is about 4.5-­7
per 1000.3 Patients with epilepsy are primarily treated
with anti-­seizure medications (ASMs), and ASM mono-
therapy is the gold standard for treating newly diagnosed
epilepsy.1,5 Nearly half of patients become seizure free
while receiving their initial ASM monotherapy, most of
whom achieve seizure freedom at a low or moderate ASM
dose.6–­8 However, more than 1/3 of patients with epilepsy
could not achieve complete seizure freedom despite the ex-
istence of ASMs of various mechanisms of action.1,6 As the
possibility of a patient achieving seizure freedom dimin-
ishes with each subsequent change of ASM regimen,6–­8
and about 80% of patients are treated and maintained with
a single ASM monotherapy during their first year after di-
agnosis of epilepsy,9 it is critical to choose an effective ini-
tial ASM monotherapy for patients with newly diagnosed
epilepsy in order to achieve the best possible outcomes.9
Perampanel (PER) is a first-­in-­class, orally active, highly
selective, noncompetitive antagonist of alpha-­ amino-­ 3-­
hydroxy-­5-­methyl-­4-­isoxazolepropionic acid (AMPA)-­type
glutamate receptor.1,2,9 AMPA receptors are major post-­
synaptic glutamate receptors mediating the fast excitatory
synaptic transmission and the fast excitatory post-­synaptic
potentials (EPSPs) and are critical in triggering and spread-
ing epileptic seizures.6,10 AMPA receptors in hippocampal
and neocortical tissues from patients with epilepsy were
denser, upregulated and hypersensitive.6,10 In cultured
rat cortical neurons, perampanel could inhibit AMPA-­
induced increases in intracellular Ca2+ concentration
in a dose-­dependent manner.9,10 It could also selectively
block synaptic neurotransmission mediated by AMPA re-
ceptors and inhibit AMPA receptor-­mediated EPSPs in rat
hippocampal slices.10–­12 Perampanel demonstrated broad-­
spectrum anti-­seizure activities in animal models and in
patients with focal and generalized seizures.10–­12
Perampanel, as a once-­daily oral ASM, is indicated
for monotherapy and adjunctive treatment of focal-­
onset seizures (FOS) with or without focal to bilateral
tonic-­clonic seizures (FBTCS) in patients aged 4 years
or older in China.1,13 In the United States, it is indicated
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Key points
• This prospective, real-­world study assessed per-
ampanel monotherapy in treating Chinese pa-
tients ≥4 years old with focal-­onset seizures.
• Perampanel monotherapy had a 12-­ month
seizure-­
freedom rate and retention rate of
65.08% and 70%, respectively.
• Twenty-­
six (37.1%) patients experienced
treatment-­
emergent adverse events (TEAEs),
and dizziness and irritability were the most
common TEAEs.
• The most frequently used maintenance dose
was 4 and 6 mg/day perampanel seemed to be
more effective and safer than other doses.
• Perampanel monotherapy was effective and
safe in treating Chinese patients ≥4 years old
with focal-­onset seizures.
for monotherapy and adjunctive therapy for treating
FOS with or without FBTCS in patients ≥4 years old and
for adjunctive treatment of generalized tonic–­clonic sei-
zures (GTCS) in patients ≥12 years old, while in Europe,
perampanel has been approved for adjunctive treatment
of FOS with or without FBTCS in patients ≥4 years old
and GTCS in patients ≥12 years old.1,13 Numerous studies
including several phase III studies reported that peram-
panel 4-­12 mg/day as add-­on therapy was efficacious and
tolerable in treating FOS with or without FBTCS.1,2,14–­16
Several studies reported perampanel monotherapy was
effective and safe in treating adult and pediatric patients
with refractory FOS with or without FBTCS, and most of
these studies were retrospective studies.17–­22 In China, ex-
cept for one retrospective study that reported perampanel
monotherapy was efficacious and safe in eight of the
nine treated pediatric patients with epilepsy,23 there has
been no other published study on the efficacy and safety
of perampanel monotherapy in treating FOS. In China,
perampanel is currently most used as adjunctive therapy
in treating patients with epilepsy as experience in utiliz-
ing it for monotherapy is lacking. As real-­world studies
can collect long-­term efficacy and safety data in hetero-
geneous populations during routine clinical practice and

MA et al.
thus can supplement findings of randomized controlled
trials (RCTs), we conducted a prospective, real-­world ob-
servational study on the efficacy and safety of perampanel
monotherapy in treating Chinese patients aged 4 years or
older with FOS, such a study could explore the feasibility
of perampanel monotherapy in treating FOS in China and
provide clinicians with some guidance on utilizing differ-
ent ASM regimens.
2 | M ET H O DS
2.1 | Study design and patients
This is a single-­center, prospective, real-­world observa-
tional study conducted at the Epilepsy Out-­Patient Clinic
of Nanjing Brain Hospital affiliated to Nanjing Medical
University to evaluate the efficacy and safety of peram-
panel monotherapy in Chinese patients with FOS. This
study was conducted in accordance with the principle of
the Declaration of Helsinki and was approved by the ethics
committee at Nanjing Brain Hospital affiliated to Nanjing
Medical University (Approval number: 2020-­KY193-­01).
All patients or their guardians gave written informed con-
sent to participate in the study, to be treated with peram-
panel monotherapy and to have subsequent scheduled
follow-­up visits.
Patients with FOS (with or without FBTCS) who visited
the Epilepsy Out-­Patient Clinic of Nanjing Brain Hospi-
tal affiliated to Nanjing Medical University from January
2020 to December 2021 were eligible for this study. In-
clusion criteria were as follows: (a) ≥4 years old; (b) un-
derwent electroencephalogram (EEG), head computed
tomography (CT) or magnetic resonance imaging (MRI)
and were diagnosed and classified as FOS according to the
2017 International League Against Epilepsy (ILAE) classi-
fication of seizure types24 based on clinical presentations
and findings from EEG; and (c) either had no history of
receiving any anti-­seizure treatment or had previously
received ASM treatment(s) but discontinued previous
treatment before enrollment. Exclusion criteria: (a) had
serious liver or renal disease(s); (b) had lactose intoler-
ance, lactose deficiency, or glucose–­galactose malabsorp-
tion; or (c) being allergic to ingredient(s) of perampanel.
Study withdrawal criteria: (a) when a patient could not
tolerate adverse reactions to perampanel or experienced
seizure aggravation, he/she would stop taking perampanel
and convert to other ASM(s); (b) when a request to convert
to polytherapy or other ASM monotherapy was made by a
patient who could not achieve seizure freedom on peram-
panel monotherapy despite being partially responsive to
perampanel; or (c) when a patient chose to withdraw from
the study or was lost to follow-­up.
|
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    3
Before initiating perampanel monotherapy, the follow-
ing data were collected from each participating patient:
age, gender, medical history, duration and etiology of ep-
ilepsy, past use of ASM(s), baseline monthly seizure fre-
quency before enrollment, findings from EEG, head CT or
MRI, and types of FOS (focal aware seizures [FAS], focal
impaired awareness seizures [FIAS], and FBTCS).
At follow-­up visits after 6 and 12 months of perampanel
monotherapy, the following data were collected from each
patient: monthly seizure frequency, dose of perampanel,
concomitant medications, and adverse events (AEs).
2.2 | Treatment
All patients enrolled in the study received oral, once-­daily
perampanel monotherapy. Each patient was initiated on
2 mg oral perampanel before bedtime every day during
the first 2 weeks of the study. If the patient tolerated the
treatment during these 2 weeks, the dose was then up-­
titrated to 4 mg/day. If the patient receiving 4 mg/day per-
ampanel could not tolerate the treatment, the patient was
encouraged to gradually reduce the dose of perampanel
to a tolerable level and maintain that dose for 2-­4 weeks
before up-­titrating the dose back to 4 mg/day. For those
patients who tolerated 4 mg/day perampanel and could
not achieve complete seizure freedom, the dose of peram-
panel was up-­titrated by 2 mg every 2-­4 weeks to a maxi-
mum tolerable dose (6, 8, 10 mg/day or the maximum dose
of 12 mg/day).
2.3 | Efficacy and safety evaluations
The primary endpoint was seizure-­ freedom rate after
12 months of perampanel treatment (the percentage of pa-
tients who experienced no seizure during the 12-­month
treatment). The secondary endpoints were as follows: (a)
seizure-­freedom rate after 6 months of perampanel treat-
ment (the percentage of patients who experienced no
seizure during the first 6-­month treatment) and (b) reten-
tion rate (the percentage of patients remaining on peram-
panel monotherapy) after 6 and 12 months of perampanel
monotherapy.
Subgroup analyses of seizure-­freedom rate were con-
ducted based on age (≤18 years old and >18 years old),
type of seizure (FAS, FIAS, and FBTCS), and perampanel
maintenance dose.
AEs and their severity were recorded at each follow-­up
visit. During follow-­up visits, patients reported possible
treatment-­emergent AEs (TEAEs) to their physicians. In
addition, their physician also inquired about commonly
known perampanel-­ related AEs. The physicians then
 |   
4 MA et al.
assessed whether these TEAEs were related to the treat-
ment and their severity. Additionally, patients were also
told to come back if they were concerned about their
discomfort between the follow-­up visits. Any withdraw-
als from the study due to AE(s) were also recorded. The
percentages of patients experiencing AEs and serious AEs
were calculated and whether the AEs were related to per-
ampanel monotherapy was assessed.
2.4 | Statistical analysis
All enrolled patients were included in the analysis for
demographics, baseline clinical characteristics and
retention rate. Efficacy analyses including subgroup
analyses were performed on all patients who received
at least one dose of perampanel and had at least one
post-­baseline efficacy assessment. Safety analysis was
performed on all patients who received at least one dose
of perampanel.
All statistical analyses in the study were performed
using SAS 9.4 (SAS Institute). Descriptive statistics
was used. Quantitative variables were expressed as
mean ± standard deviation (SD) or median (interquartile
range [IQR]), while categorical variables were expressed
as N (%). The Student t test, the Mann-­Whitney U test and
the Pearson's chi-­square test were used for between-­group
comparisons of continuous variables with normal distri-
bution, continuous variables with nonparametric distribu-
tion, and categorical variables, respectively. The Wilcoxon
rank sum test was used for analysis of seizure frequencies.
The analysis of variance (ANOVA) was used for compari-
son among more than two groups. All statistical analyses
were conducted against a two-­sided alternative hypothesis
with a significance level of 0.05.
3 | RE S U LT S
3.1 | Patient demographics and baseline
characteristics
Study flow chart was depicted in Figure 1. A total of 70
patients (35 male and 35 female) were enrolled in the
study and their demographics and baseline character-
istics were described in Table 1. Their mean age was
34.11 ± 17.19 years old, they had a medium duration of
epilepsy of 1.50 years (IQR 0.50-­7.0 years) and their me-
dium seizure frequency per month was 1.50 (IQR 0.21-­
3.0). Three (4.3%), 19 (27.1%) and 52 (74.3%) of these 70
patients had FAS, FIAS and FBTCS, respectively. Among
the enrolled 70 patients, 57 (81.4%) had never been treated
with any ASM before and 13 (18.6%) converted from
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FIGURE 1 Study flow diagram. PER, perampanel.
other ASM treatment(s) to perampanel monotherapy.
Twelve of these 13 patients had previously received so-
dium valproate (7), oxcarbazepine (3) or carbamazepine
(2) monotherapy before the study, and the remaining 1
patient had previously received lamotrigine and pheno-
barbital monotherapies. Reasons for discontinuing their
previous treatments included adverse events (5), allergic
reactions (4), poor compliance (3) and lack of efficacy
(2) (Table 1). The mean maintenance perampanel dose
was 4.64 ± 1.55 mg/day. Patients <18 years old and those
≥18 years old had comparable mean maintenance dose
(4.57 ± 1.29 vs 4.61 ± 1.69 mg/day). Among the subgroup
of patients <18 years old, patients <12, 12-­13, 14-­15, and
16-­17 years old had comparable mean maintenance doses
(Table 1). Detailed etiologies of epilepsy of these patients
were described in Table 1.
3.2 | Retention rate
The 6-­month retention rate of perampanel monotherapy
was 78.6% (55/70). Fifteen (21.4%) out of the 70 enrolled
patients discontinued the study within 6 months of treat-
ment. Among them, 7 (10%) were lost to follow-­up, 6 (8.6%)
changed their ASM regimens due to poor efficacy, and 2
(2.9%) patients discontinued the study due to AEs: 1 because
of dizziness and 1 because of seizure aggravation (Figure 1).
The 12-­month retention rate was 70.0% (49/70). Six
(8.6%) patients discontinued the study before completing
12 months of perampanel monotherapy although they did
receive the treatment for more than 6 months. Among
them, 1 (1.4%) was lost to follow-­up, 2 (2.9%) had ASM reg-
imen modification due to poor efficacy, 1 (1.4%) withdrew
from the study because the patient was pregnant, and 2
(2.9%) patients discontinued the study due to treatment-­
related AEs: 1 because of dizziness and 1 because of irri-
tability (Figure 1).
 |

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MA et al.     5

TABLE 1 Demographics and baseline clinical characteristics. TABLE 1 (Continued)

All patients All patients

Characteristics (N = 70) Characteristics (N = 70)
Age (years), mean ± SD 34.11 ± 17.19 Stroke 6 (8.6%)
<18 years, n (%) 21 (30.0%) Vascular Malformations of the Brain 2 (2.9%)
<12 years, n (%) 3 (4.3%) Unknown 30 (42.9%)
12-­13 years, n (%) 3 (4.3%) Note: Continuous variables were expressed as mean ± SD or medium (IQR)
14-­15 years, n (%) 4 (5.7%) and categorical variables were expressed as n (%).
Abbreviations: ASM(s), anti-­seizure medication(s); CNS, central nervous
16-­17 years, n (%) 11 (15.7%)
system; FAS, focal aware seizures; FBTCS, focal to bilateral tonic–­clonic
≥18 years, n (%) 49 (70.0%) seizures; FIAS, focal impaired awareness seizures; IQR, interquartile range;
Gender, n (%) PER, perampanel; SD, standard deviations.
a
One patients had previous received both phenobarbital monotherapy and
Male 35 (50.0%)
lamotrigine monotherapy.
Female 35 (50.0%)
Duration of epilepsy, years, median (IQR) 1.50 (0.50-­7.0) 3.3 | Efficacy
Seizure frequency per month, medium (IQR) 1.50 (0.21-­3.0)
PER monotherapy, n (%) Sixty-­three patients were included in efficacy analyses as
Primary (ASM-­naive) 57 (81.4%) seven patients lost to follow-­up and did not have any post-­
Secondary (had been treated with ASM 13 (18.6%) baseline efficacy assessment (Figure 1).
before) The 6-­and 12-­ month seizure-­ freedom rates were
Previous ASM(s), n (%)a 69.84% and 65.08%, respectively (Figure 2), suggest-
Sodium valproate 7 (10.0%)
ing that most patients who achieved seizure freedom
for 6 months could remain seizure free for at least
Oxcarbazepine 3 (4.3%)
12 months.
Carbamazepine 2 (2.9%)
Seizure type-­based subgroup analyses revealed that
Lamotrigine 1 (1.4%) patients with FBTCS had significantly higher 6-­month
Phenobarbital 1 (1.4%) seizure-­freedom rate than patients with FIAS (73.33% vs
Reason(s) for discontinuing previous ASM, n (%) 47.37%, P = 0.046). Patients with FBTCS also had numeri-
Adverse events 5 (7.1%) cally higher 12-­month seizure-­freedom rate than patients
Allergic reactions 4 (5.7%) with FIAS, although the difference did not reach statisti-
cal significance (P = 0.204; Figure 2).
Lack of efficacy 2 (2.9%)
Age-­based subgroup analysis showed that compared
Poor compliance 3 (4.3%)
to patients > 18 years old, patients ≤ 18 years old had nu-
Dosage of perampanel, mg/day, mean ± SD 4.64 ± 1.55
merically higher 6-­and 12-­month seizure freedom rates,
<18 years old 4.57 ± 1.29 though the differences did not reach statistical signifi-
<12 years old 4.67 ± 1.15 cance (P = 0.102 and 0.270, respectively; Figure 3A).
12-­13 years old 4.67 ± 1.15 Maintenance perampanel dose-­based subgroup analy-
14-­15 years old 4.50 ± 1.00 sis revealed that 4 mg/day was the most frequently used
16-­17 years old 4.55 ± 1.57 maintenance dose, it was used in 39 patients (Figure 3B).
Compared to patients receiving 4 or 8 mg/day peram-
≥18 years old 4.61 ± 1.69
panel treatment, patients receiving 6 mg/day perampanel
Type of seizures at baseline, n (%)
monotherapy had numerically though statistically insig-
FAS 3 (4.3%) nificantly higher 6-­and 12-­month seizure-­freedom rates
FIAS 19 (27.1%) (P = 0.907 and 0.913, respectively; Figure 3B).
FBTCS 52 (74.3%)
Etiology, n (%)
Cerebral neoplasm 4 (5.7%) 3.4 | Safety
CNS infection 3 (4.3%)
All of the 70 enrolled patients were included in the safety
Cortical dysplasia 9 (12.9%)
analysis. Among them, 26 (37.1%) patients experienced
Head injury/cranial trauma 5 (7.1%)
TEAEs during the 12-­ month perampanel monother-
Hippocampal sclerosis/atrophy 11 (15.7%) apy. Twenty-­five of the 26 TEAEs were judged by our
 |   
6 MA et al.
investigators to be perampanel-­related AEs, the remain-
ing 1 TAEA (gastroesophageal reflux) was judged by our
investigator to be unrelated to the treatment. Dizziness
was the most common TEAE (16 [22.9%]), followed by
irritability (6 [8.6%]), somnolence (3 [4.3%]) and seizure
aggravation (1 [1.4%]) (Table 2). Most of the TEAEs were
mild to moderate and tolerable. A total of 4 (5.7%) patients
withdrew from the study due to TEAEs: 2 due to dizziness
(1 on 2 mg/day and 1 on 4 mg/day perampanel), 1 due to
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F I G U R E 2 Seizures-­freedom
rates in all patients, patients with FIAS
and patients with FBTCS after they
received 6 and 12 months of perampanel
monotherapy. FBTCS, focal to bilateral
tonic–­clonic seizures; FIAS, focal
impaired awareness seizures.
F I G U R E 3 Age-­based (A) and
Dosage-­based (B) subgroup analyses
of seizure freedom rates in patients
after they received 6 and 12 months of
perampanel monotherapy.
seizure aggravation (on 4 mg/day perampanel) and 1 due
to irritability (on 8 mg/day perampanel). No new safety
concern was observed.
The most frequently used maintenance dose in the
study was 4 mg/day (42/70 [60%]), followed by 6 mg/day
(14/70 [20%]). Patients in the 2, 4, 6, and 8 mg groups all
reported TEAEs. The 6 mg/day group had the lowest prev-
alence of AEs (14.1% [2/14]), and the 8 mg group had the
highest prevalence (57.1% [4/7]) (Table 2).

MA et al.
TABLE 2 Prevalence of treatment-­emergent adverse event (TEAEs).
Overall (N = 70), 2 mg/day (N = 6),
n (%) n (%)
Any TEAEs 26 (37.1%) 2 (33.3%)
Perampanel-­related AEs 25 (35.7%) 2 (33.3%)
Study discontinuation due 4 (5.7%) 1 (16.7%)
to AEs
Individual AEs
Dizziness 16 (22.9%) 2 (33.3%)
Irritability 6 (8.6%) 0 4 (9.5%)
Somnolence 3 (4.3%) 0 2 (4.8%)
Seizure aggravation 1 (1.4%) 0 1 (2.4%)
Abbreviation: AE, adverse events.
a
One patient experienced both somnolence and irritability.
4 | DI S C USSION
In this single-­center, prospective, real-­world observational
study, we evaluated the efficacy and safety of perampanel
monotherapy in 70 Chinese patients aged 4 years or older
with FOS. To the best of our knowledge, this is the first
prospective study on the efficacy and safety of peram-
panel monotherapy in treating Chinese patients with FOS.
We found that these patients' 6-­and 12-­month seizure-­
freedom rates were 69.84% and 65.08%, respectively, and
their respective 6-­and 12-­ month retention rates were
78.6% and 70.0%. These findings were consistent with pre-
vious studies.17,18,20–­22 The single-­arm, open-­label, phase
III Study 342 (FREEDOM Study) conducted in Japan and
South Korea found that seizure-­freedom rates of patients
≥12 years old with FOS receiving perampanel monother-
apy during a 6-­month 4 mg/day maintenance period and
last evaluated dose (4 or 8 mg/day) were 63.0% and 74.0%,
respectively.21 Another retrospective study of patients
≥15 years with treatment-­naive newly onset FOS with or
without FBTCS receiving perampanel monotherapy found
that their 6-­and 12-­month seizure-­freedom rates were 80%,
and 76%, respectively, that their respective 6-­and 12-­month
retention rates were 73%, and 61%, and their medium per-
ampanel dose was 4 mg/day.20 In yet another multicenter,
retrospective study conducted in Europe and Russia, pa-
tients with epilepsy treated with perampanel monotherapy
had a 3-­month seizure freedom rate and retention rate of
55% and 82%, respectively.17 Other studies on perampanel
monotherapy in treating patients with FOS had similar
findings.18,22 Additionally, Patients in our study had a good
retention rate over 12 months, further confirming the effec-
tiveness and safety of perampanel monotherapy in treating
Chinese patients with FOS, as retention rate was a com-
bined indicator of effective and tolerability.19
Type(s) of seizures could play a role in a patient's re-
sponse to perampanel.1,25–­28 Our study found that patients
|
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    7
4 mg/day (N = 42), 6 mg/day 8 mg/day
n (%) (N = 14), n (%) (N = 7), n (%)
16 (38.1%) 3 (21.4%) 5 (71.4%)
16 (38.1%) 2 (14.3%) 5 (71.4%)
2 (4.8%) 0 1 (14.3%)
9 (21.4%) 1 (7.1%) 4 (57.1%)
a
1 (7.1%) 1 (14.3%)
1 (7.1%)a 0
0 0
with FBTCS had significantly higher 6-­month and numer-
ically higher 12-­month seizure freedom rates than patient
with FIAS, this finding was consistent with Study 342
(FREEDOM Study) reporting that patients with FBTCS on
perampanel monotherapy had a higher 6-­month seizure-­
freedom rate than patients with FIAS (64.6% vs 58.5%),21
as well as with previous studies on adjunctive perampanel
treatment reporting that patients with FOS with FBTCS re-
sponded better to perampanel than patients with FOS with-
out FBTCS.1,25–­28 The fact that perampanel was a selective
AMPA receptor antagonist might contribute to the addi-
tional efficacy of perampanel for treating FBTCS, as AMPA
receptors were involved in neuronal over-­excitation related
disorders, and tonic–­clonic seizures are characterized by
abnormal cortical hyper-­excitability which is affected by
ASMs.25,29 As one of the most important risk factors of sud-
den unexpected death in epilepsy (SUDEP) was the pres-
ence of FBTCS,29,30 this finding could potentially be helpful
in determining the proper ASM(s) for patients with FBTCS.
Age could also be relevant in a patient's response to
perampanel. Our study found that patients aged ≤18 years
had statistically insignificantly higher 6-­and 12-­month
seizure freedom rates than patients aged >18 years. In
one retrospective study of adjunctive perampanel ther-
apy in treating children and adolescents with refractory
seizures, patients ≥6 years old had a better treatment re-
sponse than patients aged 7-­17 years,31 and another simi-
lar study found that children aged 12-­18 years were more
responsive to perampanel treatment than younger chil-
dren.32 On the other hand, a prospective, post-­marketing,
observational study of combination treatment with per-
ampanel in treating Japanese adults with epilepsy found
patients >65 years old responded better than younger pa-
tients.27 Large-­scale studies including enough children,
adolescents and adult patients with epilepsy are needed
to further elucidate whether and how a patient's age
might affect his/her response to perampanel.
 |   
8 MA et al.
Choosing an optimal dose is important in achieving the
best possible efficacy and safety. The mean perampanel
dose in our study was 4.64 ± 1.55 mg, and 4 mg/day was
the most frequently used maintenance dose, followed by
6 mg/day. This was similar to Toledano Delgado et al,19 a
retrospective study of perampanel monotherapy for treat-
ing patients with FOS or GTCS, in which 4 mg/day was
the most frequently used, followed by 6 mg/day. We also
observed that pediatric patients and adult patients in our
study had comparable mean maintenance dose, and mean
maintenance doses for pediatric patients of different ages
were similar. Such comparable dosing between pediatric
and adult patients was in line with the perampanel pre-
scribing information issued by the US Food and Drug
Administration (FDA) stating that perampanel dosing
for pediatric and adult patients with FOS are the same,
both as monotherapy and as adjunctive therapy.33 In addi-
tion, studies have found that perampanel as monotherapy
or first add-­on at 6 mg/day had good efficacy and safety
in treating patients with epilepsy.17,34,35 Our study found
that patients on 6 mg/day perampanel had a numerically
higher seizure-­ freedom rate with a significantly lower
prevalence of AEs than patients on other doses, suggest-
ing that 6 mg/day might be an optimal perampanel main-
tenance dose. However, as ours is a single-­center study
with a modest sample size, multicenter studies with larger
sample sizes with longer follow-­ups are needed to further
explore the optimal dose of perampanel monotherapy.
37.1% of patients experienced TEAEs during the study.
Dizziness was the most common TEAEs, followed by irri-
tability, somnolence and seizure aggravation, all of which
were previously reported perampanel-­ related AEs.9,17,19
Most of the TEAEs were mild to moderate and tolerable.
Four (5.7%) patients withdrew from the study due to AEs.
Our findings were consistent with several previous studies
on perampanel monotherapy, in which the percentage of
patients reporting TEAEs ranged from 20.0% to 45.9%.9,17,19
Additionally, the most commonly reported TEAEs in these
studies were dizziness, somnolence and irritability.9,17,19 A
pooled analysis of three Phase III RCTs on perampanel ad-
junctive therapy found that 15.3% of 1038 enrolled patients
developed psychiatric TEAEs, among them, insomnia and
aggression were the most common psychiatric TEAEs.36
Another retrospective study on adjunctive perampanel
therapy found a significantly higher risk of developing
psychiatric TEAEs in patients with psychiatric comorbidi-
ties than those without psychiatric comorbidities.37 In our
study, 6 (8.6%) patients developed irritability, one of these
six patients withdrew from the study due to irritability.
However, we did not record whether these patients who
developed irritability had a history of psychiatric disorders.
As glutamate is involved in aggression and other psychiatric
issues,37 and psychiatric TEAEs occurred most frequently
24709239, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/epi4.12823 by Nat Prov Indonesia, Wiley Online Library on [14/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
during titration, especially at higher dose,36 it is important
to monitor patients' mental state during perampanel treat-
ment especially during titration and at high dose.36,37 Extra
caution should be exercised for those patients with a his-
tory of psychiatric disorders.37 Timely intervention for psy-
chiatric TEAEs is critical. AEs in our study were collected
by patients telling their physicians about possible TEAEs
combined with their physicians' inquiries about common
perampanel-­related AEs during follow-­up visits. It has been
reported that clinicians tend to downgrade the severity of
AEs and miss symptoms that would later develop into AEs,
while self-­reports by patients tend to be more sensitive and
they tend to notice symptoms earlier during a treatment.38,39
Supplementing clinician-­reported AEs with direct patients-­
reported AEs has been regarded as useful and valuable,39
and is worth further exploration and optimization.
5 | LIMITATIONS AND
STRENGTH
This study has several limitations. First, this is a single-­
center, prospective, observational study with a modest
sample size and as such, factors influencing treatment
response could not be properly analyzed. Secondly, as
follow-­up visits in the study were set to be after 6 and
12 months of treatment, treatment efficacy and TEAEs
could not be more closely and frequently monitored. Fi-
nally, as our follow-­up period was 1 year, longer follow-­
ups might be needed to better assess treatment efficacy in
those patients with low baseline frequency. On the other
hand, as a real-­world observational study, our study has
the advantage of being able to obtain data from large het-
erogeneous populations of patients outside RCTs.40 Find-
ings from real-­world observational studies such as ours
mirror routine clinical practice more closely and could
supplement findings from RCTs.
6 | CONC LUSIONS
In this first prospective, real-­world observational study of
the efficacy and safety of perampanel monotherapy in treat-
ing Chinese patients ≥4 years old with FOS, we found that
perampanel monotherapy was effective and safe in treat-
ing patients with FOS, as reflected by its seizure-­freedom
rate and retention rate. Patients with FBTCS had a better
response to perampanel monotherapy than patients with
FIAS. Our study provided experience and guidance on uti-
lizing perampanel monotherapy in treating FOS. However,
multicenter, real-­world studies with large sample sizes and
longer follow-­ups are needed to further evaluate the long-­
term efficacy and safety of perampanel monotherapy.

MA et al.
AUTHOR CONTRIBUTIONS
HM, RZ, and LY developed the concept of the study and
designed study; HZ, FC, YY, XQ, and HX collected and
analyzed samples and clinical data; HM, RZ, and LY wrote
the first draft of manuscript, and all authors reviewed and
made critical revisions to the manuscript with intellectual
contents. All authors approved the submitted version of
the manuscript.
ACKNOWLEDGMENTS
We are deeply grateful to participating patients and their
families. We also want to thank the clinicians who partici-
pated in this work.
FUNDING INFORMATION
This study was supported by two grants from the Nanjing
Medical Science and Technology Development Project
(Grant Numbers: YKK21111, YKK17136).
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose.
We confirm that we have read the Journal's position on
issues involved in ethical publication and affirm that this
report is consistent with those guidelines.
DATA AVAILABILITY STATEMENT
The datasets analyzed during the current study are availa-
ble from the corresponding authors on reasonable request.
ETHICS STATE MENT
This study was conducted in accordance with the princi-
ple of the Declaration of Helsinki and was approved by
the ethics committee at Nanjing Brain Hospital affili-
ated to Nanjing Medical University (Approval number:
2020-­KY193-­01).
PATIENT CONSENT STATEMENT
All patients or their guardians gave written informed con-
sent to participate in the study, to be treated with peram-
panel monotherapy and to have subsequent scheduled
follow-­up visits.
PERMISSION TO REPRODUCE MATERIAL
FROM OTHER SOURCES
Not Applicable.
CLINICAL TRIAL REGISTRATION
Not applicable.
ORCID
Haiyan Ma https://orcid.org/0000-0003-3208-3739
Lu Yang https://orcid.org/0000-0002-5033-0505
Rui Zhang https://orcid.org/0000-0002-1360-2452
|
24709239, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/epi4.12823 by Nat Prov Indonesia, Wiley Online Library on [14/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
    9
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How to cite this article: Ma H, Zhu H, Chen F,
Yang Y, Qu X, Xu H, et al. Efficacy and safety of
perampanel monotherapy in Chinese patients with
focal-­onset seizures: A single-­center, prospective,
real-­world observational study. Epilepsia Open.
2023;00:1–10. https://doi.org/10.1002/epi4.12823