Efficacy and safety of perampanel monotherapy in Chinese patients with focal‐onset seizures: A single‐center, prospective, real‐world observational study

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 enrolled 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 perampanel dose was 4.64 ± 1.55 mg/day. The 6‐ and 12‐month retention rates of perampanel 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 significantly 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 perampanel 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 sample sizes and longer follow‐ups are needed to further evaluate the long‐term efficacy and safety of perampanel monotherapy.

Key points.

• This prospective, real‐world study assessed perampanel monotherapy in treating Chinese patients ≥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.

1. INTRODUCTION

Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures that affects 50‐70 million people worldwide. ¹ , ² , 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 monotherapy 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 , ⁷ , ⁸ However, more than 1/3 of patients with epilepsy could not achieve complete seizure freedom despite the existence of ASMs of various mechanisms of action. ¹ , ⁶ As the possibility of a patient achieving seizure freedom diminishes with each subsequent change of ASM regimen, ⁶ , ⁷ , ⁸ and about 80% of patients are treated and maintained with a single ASM monotherapy during their first year after diagnosis of epilepsy, ⁹ it is critical to choose an effective initial 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 spreading 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 receptors and inhibit AMPA receptor‐mediated EPSPs in rat hippocampal slices. ¹⁰ , ¹¹ , ¹² Perampanel demonstrated broad‐spectrum anti‐seizure activities in animal models and in patients with focal and generalized seizures. ¹⁰ , ¹¹ , 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 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 seizures (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 perampanel 4‐12 mg/day as add‐on therapy was efficacious and tolerable in treating FOS with or without FBTCS. ¹ , ² , ¹⁴ , ¹⁵ , 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 , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² In China, except 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 utilizing it for monotherapy is lacking. As real‐world studies can collect long‐term efficacy and safety data in heterogeneous populations during routine clinical practice and thus can supplement findings of randomized controlled trials (RCTs), we conducted a prospective, real‐world observational 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 different ASM regimens.

2. METHODS

2.1. Study design and patients

This is a single‐center, prospective, real‐world observational study conducted at the Epilepsy Out‐Patient Clinic of Nanjing Brain Hospital affiliated to Nanjing Medical University to evaluate the efficacy and safety of perampanel 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 consent to participate in the study, to be treated with perampanel 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 Hospital affiliated to Nanjing Medical University from January 2020 to December 2021 were eligible for this study. Inclusion criteria were as follows: (a) ≥4 years old; (b) underwent 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) classification of seizure types ²⁴ 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 intolerance, lactose deficiency, or glucose–galactose malabsorption; 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 perampanel monotherapy despite being partially responsive to perampanel; or (c) when a patient chose to withdraw from the study or was lost to follow‐up.

Before initiating perampanel monotherapy, the following data were collected from each participating patient: age, gender, medical history, duration and etiology of epilepsy, past use of ASM(s), baseline monthly seizure frequency 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 perampanel 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 perampanel was up‐titrated by 2 mg every 2‐4 weeks to a maximum 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 patients who experienced no seizure during the 12‐month treatment). The secondary endpoints were as follows: (a) seizure‐freedom rate after 6 months of perampanel treatment (the percentage of patients who experienced no seizure during the first 6‐month treatment) and (b) retention rate (the percentage of patients remaining on perampanel monotherapy) after 6 and 12 months of perampanel monotherapy.

Subgroup analyses of seizure‐freedom rate were conducted 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 assessed whether these TEAEs were related to the treatment and their severity. Additionally, patients were also told to come back if they were concerned about their discomfort between the follow‐up visits. Any withdrawals 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 perampanel 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 distribution, continuous variables with nonparametric distribution, and categorical variables, respectively. The Wilcoxon rank sum test was used for analysis of seizure frequencies. The analysis of variance (ANOVA) was used for comparison among more than two groups. All statistical analyses were conducted against a two‐sided alternative hypothesis with a significance level of 0.05.

3. RESULTS

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 characteristics 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 medium 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 other ASM treatment(s) to perampanel monotherapy. Twelve of these 13 patients had previously received sodium valproate (7), oxcarbazepine (3) or carbamazepine (2) monotherapy before the study, and the remaining 1 patient had previously received lamotrigine and phenobarbital 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.

FIGURE 1.

Study flow diagram. PER, perampanel.

TABLE 1.

Demographics and baseline clinical characteristics.

Characteristics	All patients (N = 70)
Age (years), mean ± SD	34.11 ± 17.19
<18 years, n (%)	21 (30.0%)
<12 years, n (%)	3 (4.3%)
12‐13 years, n (%)	3 (4.3%)
14‐15 years, n (%)	4 (5.7%)
16‐17 years, n (%)	11 (15.7%)
≥18 years, n (%)	49 (70.0%)
Gender, n (%)
Male	35 (50.0%)
Female	35 (50.0%)
Duration of epilepsy, years, median (IQR)	1.50 (0.50‐7.0)
Seizure frequency per month, medium (IQR)	1.50 (0.21‐3.0)
PER monotherapy, n (%)
Primary (ASM‐naive)	57 (81.4%)
Secondary (had been treated with ASM before)	13 (18.6%)
Previous ASM(s), n (%) a
Sodium valproate	7 (10.0%)
Oxcarbazepine	3 (4.3%)
Carbamazepine	2 (2.9%)
Lamotrigine	1 (1.4%)
Phenobarbital	1 (1.4%)
Reason(s) for discontinuing previous ASM, n (%)
Adverse events	5 (7.1%)
Allergic reactions	4 (5.7%)
Lack of efficacy	2 (2.9%)
Poor compliance	3 (4.3%)
Dosage of perampanel, mg/day, mean ± SD	4.64 ± 1.55
<18 years old	4.57 ± 1.29
<12 years old	4.67 ± 1.15
12‐13 years old	4.67 ± 1.15
14‐15 years old	4.50 ± 1.00
16‐17 years old	4.55 ± 1.57
≥18 years old	4.61 ± 1.69
Type of seizures at baseline, n (%)
FAS	3 (4.3%)
FIAS	19 (27.1%)
FBTCS	52 (74.3%)
Etiology, n (%)
Cerebral neoplasm	4 (5.7%)
CNS infection	3 (4.3%)
Cortical dysplasia	9 (12.9%)
Head injury/cranial trauma	5 (7.1%)
Hippocampal sclerosis/atrophy	11 (15.7%)
Stroke	6 (8.6%)
Vascular Malformations of the Brain	2 (2.9%)
Unknown	30 (42.9%)

Note: Continuous variables were expressed as mean ± SD or medium (IQR) and categorical variables were expressed as n (%).

Abbreviations: ASM(s), anti‐seizure medication(s); CNS, central nervous system; FAS, focal aware seizures; FBTCS, focal to bilateral tonic–clonic seizures; FIAS, focal impaired awareness seizures; IQR, interquartile range; PER, perampanel; SD, standard deviations.

^a One patients had previous received both phenobarbital monotherapy and lamotrigine monotherapy.

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 treatment. 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 regimen 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 irritability (Figure 1).

3.3. Efficacy

Sixty‐three patients were included in efficacy analyses as seven patients lost to follow‐up and did not have any post‐baseline efficacy assessment (Figure 1).

The 6‐ and 12‐month seizure‐freedom rates were 69.84% and 65.08%, respectively (Figure 2), suggesting that most patients who achieved seizure freedom for 6 months could remain seizure free for at least 12 months.

FIGURE 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.

Seizure type‐based subgroup analyses revealed that patients with FBTCS had significantly higher 6‐month seizure‐freedom rate than patients with FIAS (73.33% vs 47.37%, P = 0.046). Patients with FBTCS also had numerically higher 12‐month seizure‐freedom rate than patients with FIAS, although the difference did not reach statistical significance (P = 0.204; Figure 2).

Age‐based subgroup analysis showed that compared to patients > 18 years old, patients ≤ 18 years old had numerically higher 6‐ and 12‐month seizure freedom rates, though the differences did not reach statistical significance (P = 0.102 and 0.270, respectively; Figure 3A).

FIGURE 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.

Maintenance perampanel dose‐based subgroup analysis revealed that 4 mg/day was the most frequently used maintenance dose, it was used in 39 patients (Figure 3B). Compared to patients receiving 4 or 8 mg/day perampanel treatment, patients receiving 6 mg/day perampanel monotherapy had numerically though statistically insignificantly higher 6‐ and 12‐month seizure‐freedom rates (P = 0.907 and 0.913, respectively; Figure 3B).

3.4. Safety

All of the 70 enrolled patients were included in the safety analysis. Among them, 26 (37.1%) patients experienced TEAEs during the 12‐month perampanel monotherapy. Twenty‐five of the 26 TEAEs were judged by our investigators to be perampanel‐related AEs, the remaining 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 seizure aggravation (on 4 mg/day perampanel) and 1 due to irritability (on 8 mg/day perampanel). No new safety concern was observed.

TABLE 2.

Prevalence of treatment‐emergent adverse event (TEAEs).

	Overall (N = 70), n (%)	2 mg/day (N = 6), n (%)	4 mg/day (N = 42), n (%)	6 mg/day (N = 14), n (%)	8 mg/day (N = 7), n (%)
Any TEAEs	26 (37.1%)	2 (33.3%)	16 (38.1%)	3 (21.4%)	5 (71.4%)
Perampanel‐related AEs	25 (35.7%)	2 (33.3%)	16 (38.1%)	2 (14.3%)	5 (71.4%)
Study discontinuation due to AEs	4 (5.7%)	1 (16.7%)	2 (4.8%)	0	1 (14.3%)
Individual AEs
Dizziness	16 (22.9%)	2 (33.3%)	9 (21.4%)	1 (7.1%)	4 (57.1%)
Irritability	6 (8.6%)	0	4 (9.5%)	1 (7.1%) a	1 (14.3%)
Somnolence	3 (4.3%)	0	2 (4.8%)	1 (7.1%) a	0
Seizure aggravation	1 (1.4%)	0	1 (2.4%)	0	0

Abbreviation: AE, adverse events.

^a One patient experienced both somnolence and irritability.

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 prevalence of AEs (14.1% [2/14]), and the 8 mg group had the highest prevalence (57.1% [4/7]) (Table 2).

4. DISCUSSION

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 perampanel 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 previous studies. ¹⁷ , ¹⁸ , ²⁰ , ²¹ , 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 monotherapy 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 perampanel dose was 4 mg/day. ²⁰ In yet another multicenter, retrospective study conducted in Europe and Russia, patients 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 effectiveness and safety of perampanel monotherapy in treating Chinese patients with FOS, as retention rate was a combined indicator of effective and tolerability. ¹⁹

Type(s) of seizures could play a role in a patient's response to perampanel. ¹ , ²⁵ , ²⁶ , ²⁷ , ²⁸ Our study found that patients with FBTCS had significantly higher 6‐month and numerically 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 responded better to perampanel than patients with FOS without FBTCS. ¹ , ²⁵ , ²⁶ , ²⁷ , ²⁸ The fact that perampanel was a selective AMPA receptor antagonist might contribute to the additional 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 sudden unexpected death in epilepsy (SUDEP) was the presence 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 therapy in treating children and adolescents with refractory seizures, patients ≥6 years old had a better treatment response than patients aged 7‐17 years, ³¹ and another similar study found that children aged 12‐18 years were more responsive to perampanel treatment than younger children. ³² On the other hand, a prospective, post‐marketing, observational study of combination treatment with perampanel in treating Japanese adults with epilepsy found patients >65 years old responded better than younger patients. 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.

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 treating 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 prescribing 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 addition, 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, suggesting that 6 mg/day might be an optimal perampanel maintenance 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 irritability, 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 adjunctive 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 comorbidities 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 during titration, especially at higher dose, ³⁶ it is important to monitor patients' mental state during perampanel treatment especially during titration and at high dose. ³⁶ , ³⁷ Extra caution should be exercised for those patients with a history of psychiatric disorders. ³⁷ Timely intervention for psychiatric 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. Finally, 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 heterogeneous populations of patients outside RCTs. ⁴⁰ Findings from real‐world observational studies such as ours mirror routine clinical practice more closely and could supplement findings from RCTs.

6. CONCLUSIONS

In this first prospective, real‐world observational study of the efficacy and safety of perampanel monotherapy in treating Chinese patients ≥4 years old with FOS, we found that perampanel monotherapy was effective and safe in treating 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 utilizing 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.

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.

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.

ETHICS STATEMENT

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).

PATIENT CONSENT STATEMENT

All patients or their guardians gave written informed consent to participate in the study, to be treated with perampanel monotherapy and to have subsequent scheduled follow‐up visits.

PERMISSION TO REPRODUCE MATERIAL FROM OTHER SOURCES

Not Applicable.

CLINICAL TRIAL REGISTRATION

Not applicable.

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;8:1474–1483. 10.1002/epi4.12823

DATA AVAILABILITY STATEMENT

The datasets analyzed during the current study are available from the corresponding authors on reasonable request.