Abstract
Objective
This real-world retrospective observational study evaluated the efficacy and safety of clobazam as adjunctive therapy in pediatric patients with refractory epilepsy (RE) in Xinjiang to provide evidence for its rational clinical application.
Methods
Treatment efficacy was assessed according to the four-level efficacy criteria established by the First National Epilepsy Academic Conference of the Chinese Medical Association using seizure frequency recorded at the final follow-up. Changes in seizure frequency from baseline were evaluated at 3, 6, and 12 months after treatment initiation. All adverse drug reactions occurring during follow-up were recorded.
Results
The response rates to clobazam therapy were 50.7%, 50.7%, 53.8%, and 56.7% at 1, 3, 6, and 12 months, respectively. The effective group received a significantly higher daily clobazam dose than the ineffective group (P < 0.05). The proportion of pediatric patients with no reduction in seizure frequency decreased significantly from 14.7% at 1 month to 1.7% at ≥12 months (P < 0.05), while the proportion of pediatric patients with a <50% reduction in seizure frequency gradually increased over time. The highest efficacy was observed in patients with a disease duration of 3–6 years (62.5%, 10/16), while those with a duration of <1 year showed relatively lower efficacy (30.8%, 4/13). Sex and comorbidities were significant predictors of clobazam controlling seizures (P = 0.039 and P = 0.030, respectively). During the clobazam treatment period, 31 pediatric patients (41.33%) experienced at least one adverse drug reaction.
Conclusion
Clobazam demonstrated favorable efficacy, safety, and tolerability as adjunctive therapy in pediatric patients with RE. These real-world findings provide clinical evidence supporting the rational use of clobazam in pediatric RE.
Keywords: clobazam, efficacy, pediatric patients, refractory epilepsy
Introduction
Epilepsy is primarily managed through long-term administration of antiseizure medications (ASMs).1 However, more than 30% of patients fail to achieve adequate seizure control with currently available ASMs, a condition defined as refractory epilepsy (RE), in which seizures persist despite the appropriate use of two or more ASMs.2 Recurrent seizures in patients with RE increase the risk of neurological dysfunction, psychiatric disorders, and progressive cognitive decline, severely impairing quality of life and social functioning. This condition also imposes substantial economic burdens on patients, families, and society.3
Clobazam, a newer benzodiazepine derivative, is used in the treatment of epilepsy. In October 2011, the US Food and Drug Administration (FDA) approved clobazam as an adjunctive therapy for seizures associated with Lennox-Gastaut syndrome (LGS) in adults and pediatric patients aged ≥2 years.4,5 In October 2022, domestically produced clobazam was officially approved in China and became available for the treatment of refractory seizures in pediatric patients, particularly as adjunctive therapy for LGS patients aged ≥2 years. Current evidence indicates that pediatric patients with childhood-onset drug-resistant epilepsies, including LGS,6 Dravet syndrome,7 and myoclonic-atonic epilepsy,8 may benefit from clobazam treatment. However, the FDA has issued a black box warning regarding serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which may occur even at standard doses of clobazam.9
However, evidence regarding the clinical efficacy and safety of clobazam in pediatric patients with RE in China, remains limited, and appropriate treatment strategies for these patients have not yet been established in China. Especially in the Xinjiang, China, there are currently no reports on the clinical efficacy and safety of clobazam in pediatric patients with RE. Therefore, this study aimed to evaluate the efficacy and safety of clobazam in pediatric patients with RE in Xinjiang and provide evidence supporting its rational clinical use. By contributing real-world evidence from Xinjiang, China, our findings are expected to inform clinical practice and further enrich the global evidence base for clobazam in RE.
Methods
Study Design and Population
This retrospective observational study included 75 pediatric patients with RE who received treatment at two institutions in Xinjiang, China (People’s Hospital of Xinjiang Uygur Autonomous Region and the Children’s Hospital of Xinjiang Uygur Autonomous Region) between August 2023 and August 2026. All patients were diagnosed with RE by experienced clinicians and received clobazam as adjunctive therapy. Written informed consent was obtained from the guardians of all participants.
The inclusion criteria were as follows: age 4–18 years; diagnosis according to the latest seizure classification and epilepsy diagnostic criteria established by the International League Against Epilepsy (ILAE);10 All patients had previously received at least one first-line ASM without achieving adequate seizure control; consequently, clobazam was administered orally as an add-on therapy as prescribed; and availability of relatively complete clinical data related to clobazam treatment. The exclusion criteria were as follows: age < 4 years or > 18 years; loss to follow-up; withdrawal of informed consent; unclear timing of the last medication administration; incomplete or missing relevant study data; or any condition considered unsuitable for inclusion by clinicians or researchers.
The ILAE defines drug-resistant epilepsy as failure to achieve sustained seizure freedom after the appropriate selection and adequate use of at least two well-tolerated ASMs, either as monotherapy or in combination based on the patient’s epilepsy type. Specifically, seizure freedom is not achieved for a duration of three times the longest pretreatment seizure interval or 1 year, whichever was longer.11
Clobazam Dosing Regimen
For pediatric patients weighing ≤ 30 kg, clobazam was initiated at 5 mg/d, increased to 10 mg/d on day 7, and further increased to 20 mg/d on day 14. For patients weighing >30 kg, treatment was initiated at 10 mg/d, increased to 20 mg/d on day 7, and further increased to 40 mg/d on day 14. Since the plasma concentrations of clobazam and its active metabolite require approximately 5 and 9 days, respectively, to reach steady state, dose adjustments were performed at intervals of at least one week.
Clinical Data Collection
Before clobazam administration, clinicians informed the guardians of the treatment objectives and gradual dose-escalation protocol and instructed them to monitor potential adverse drug reactions. An outpatient follow-up record was established for each patient to document treatment progress and address medication- and disease-related concerns during follow-up visits. Seizure frequency was recorded at baseline (before clobazam initiation) and after 3 months of treatment. Clinical information, including age, sex, height, weight, epilepsy history, seizure types, treatment duration, clobazam dosage, number and types of concomitant ASMs, and adverse events, was collected from medical records.
Efficacy
The frequency of epileptic seizures during the baseline period was recorded as the monthly average over the previous three months and was reassessed at the 3, 6, and 12-month follow-ups. Treatment efficacy was evaluated by comparing changes in seizure frequency at each follow-up time point with baseline values during clobazam treatment. Baseline seizure activity was defined as the seizure frequency during the three months before clobazam initiation, based on the patient’s seizure diaries. Patients with a ≥50% reduction in monthly seizure frequency compared with baseline were classified as responders. Seizure-free was defined as complete seizure control after clobazam administration. Seizure frequency was evaluated using seizure diaries maintained by patients or caregivers and inpatient medical records. To avoid potential bias in treatment decisions, the last recorded visit was required to occur before the initiation of chart review. In addition to reviewing clinical records, telephone follow-up was conducted to collect and record seizure frequency.
Efficacy was evaluated based on seizure frequency at the patient’s last follow-up using the four-level efficacy criteria established by the First National Epilepsy Academic Conference of the Chinese Medical Association. Compared with baseline seizure frequency, the percentage reduction in seizure frequency after clobazam treatment was used as a clinical efficacy indicator and categorized as follows: seizure control (100% reduction in seizure frequency), significant effect (75% ≤ reduction in seizure frequency < 100%), effective (50% ≤ reduction in seizure frequency < 75%), and ineffective (< 50% reduction in seizure frequency). The overall effective rate was calculated as follows: (number of patients with effective + significant effects + seizure control) / total number of patients × 100%.
Safety
The safety and tolerability were assessed based on the types and frequencies of adverse events occurring in pediatric patients with RE during clobazam treatment, as well as all adverse reactions recorded from clobazam initiation through follow-up. Adverse reactions leading to clobazam discontinuation were also recorded. Safety data were obtained from patients’ seizure diaries and clinical inpatient/outpatient records. These data were retrospectively reviewed and categorized to identify adverse events in pediatric patients with RE. For safety assessment, potential alternative causes were evaluated by determining whether symptoms resolved after clobazam discontinuation. Psychiatric adverse reactions in pediatric patients were diagnosed by clinical psychologists according to the Chinese Expert Consensus on Epilepsy and Depression Diagnosis and Treatment (2022 Revision) and the 2018 Guidelines for the Management of Patients with Bipolar Disorder developed by the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD). Clinical data from pediatric patients experiencing adverse reactions after clobazam treatment were collected and statistically analyzed.
Statistical Analysis
Data were analyzed using SPSS software, version 25.0 (IBM, Armonk, NY, USA). P < 0.05 was considered statistically significant. Categorical variables were compared using the chi-square (χ2) test or Fisher’s exact test, as appropriate. Data normality was assessed using the Shapiro–Wilk test, and homogeneity of variances was evaluated using Levene’s test. For comparisons between two independent groups, the independent samples t-test was performed when both groups showed normal distributions (P > 0.05) and equal variances (P > 0.05); otherwise, the Mann–Whitney U-test was applied. Before logistic regression analysis, key model assumptions were assessed. The linearity of continuous variables with the logit transformation was evaluated using the Box-Tidwell test, with P > 0.05 indicating linearity. Multivariate linear regression analysis was performed to examine the effects of age, sex, body mass index (BMI), duration of epilepsy, medication duration, seizure type, etiology, and concomitant ASMs on the efficacy of clobazam after controlling for confounding factors. Model calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test, with P > 0.05 indicating an acceptable model fit. All statistical tests were two-sided.
Results
Pediatric Patient Characteristics and Demographics
A total of 75 pediatric patients with RE who received clobazam as adjunctive therapy for ≥1 month were included. Their clinical data are presented in Table 1. The mean age of the pediatric patients was 8.0 ± 4.7 years with a nearly equal male-to-female ratio. The median duration of epilepsy was 3 years (range: 0.3–15 years). The median clobazam dose was 15 mg/d (range: 5–40 mg/d). Most pediatric patients experienced both focal and generalized seizures (61.3%), while 24.00% had focal seizures and 14.7% had generalized seizures. Neuroimaging showed structural abnormalities in 50.7% of patients, followed by unknown etiologies (24.0%), genetic etiologies (13.3%), and immune-related etiologies (12.0%). The most common comorbidities were intellectual disability (20.0%), mood disorders (10.7%), and cognitive impairment (8.0%). In this cohort, clobazam was most commonly administered in combination with valproate (30.3%), perampanel (18.0%), levetiracetam (12.4%), and lamotrigine (11.8%).
Table 1.
Baseline Demographic and Clinical Characteristics of Pediatric Patients with Rasmussen Encephalitis (Mean ± Standard Deviation)
| Clinical Characteristics | Total Population (n = 75) |
Effective Group (n = 38) |
Ineffective Group (n = 37) |
Z/χ2 | P |
|---|---|---|---|---|---|
| Age (years) | 8.0 ± 4.7 | 9.2 ± 4.6 | 6.8 ± 4.5 | −2.274 | 0.023* |
| Sex | |||||
| Male, n (%) | 41 (54.7) | 18 (47.4) | 23 (62.2) | 4.537 | 0.033* |
| Female, n (%) | 34 (45.3) | 20 (52.6) | 14 (37.8) | ||
| Body mass index (kg/m2) | 18.1 ± 5.3 | 18.7 ± 6.0 | 17.6 ± 4.6 | −0.609 | 0.542 |
| Duration of epilepsy (years) | 4.6 ± 3.7 | 5.1 ± 3.6 | 4.13 ± 3.8 | −1.649 | 0.099 |
| Medication time (years) | 0.9 ± 0.9 | 1.0 ± 0.7 | 0.83 ± 0.6 | −0.053 | 0.958 |
| Seizure type, n (%) | |||||
| Focal | 18 (24.0) | 11 (28.9) | 7 (18.9) | 2.741 | 0.098 |
| Generalized | 11 (14.7) | 4 (10.5) | 7 (18.9) | 2.510 | 0.113 |
| Both | 46 (61.3) | 23 (60.5) | 23 (62.2) | 0.021 | 0.884 |
| Etiology, n (%) | |||||
| Structural | 38 (50.7) | 21 (55.3) | 17 (45.9) | 1.620 | 0.203 |
| Immune | 9 (12.0) | 5 (13.2) | 4 (10.8) | 0.189 | 0.663 |
| Genetic | 10 (13.3) | 6 (15.8) | 4 (10.8) | 1.070 | 0.301 |
| Unknown etiology | 18 (24.0) | 6 (15.8) | 12 (32.4) | 7.018 | 0.008* |
| Maintain daily dose [mg/d)] | 17.6 ± 9.0 | 19.7 ± 9.7 | 15.4 ± 7.7 | −2.004 | 0.045* |
| Comorbidities, n (%) | |||||
| Intellectual disability | 17 (22.7) | 7 (18.4) | 10 (27.0) | 2.323 | 0.128 |
| Mood disorders (anxiety/depression) | 8 (10.7) | 4 (10.5) | 4 (10.8) | 0.000 | 1.000 |
| Cognitive impairment | 6 (8.0) | 3 (7.9) | 3 (8.1) | 0.000 | 1.000 |
| Autism spectrum disorder | 4 (5.3) | 0 (0) | 4 (10.8) | 11.640 | 0.001** |
| Attention-deficit/hyperactivity disorder | 2 (2.7) | 0 (0) | 2 (5.4) | 5.128 | 0.024* |
| Concomitant ASMs, n (%) # | |||||
| Valproic acid (VPA) | 54 (29.8) | 26 (29.9) | 28 (29.8) | 0.000 | 1.000 |
| Perampanel (PER) | 32 (17.7) | 17 (19.5) | 15 (16.0) | 0.542 | 0.462 |
| Levetiracetam (LEV) | 22 (12.1) | 9 (10.3) | 13 (13.8) | 0.758 | 0.384 |
| Lamotrigine (LTG) | 21 (11.6) | 13 (14.9) | 8 (8.5) | 1.705 | 0.192 |
| Topiramate (TPA) | 19 (10.5) | 6 (6.9) | 13 (13.8) | 2.607 | 0.106 |
| Lacosamide (LCM) | 16 (8.8) | 10 (11.5) | 6 (6.4) | 1.607 | 0.205 |
| Zonisamide (ZNM) | 5 (2.8) | 2 (2.3) | 3 (3.2) | 0.205 | 0.651 |
| Oxcarbazepine (OXC) | 4 (2.2) | 2 (2.3) | 2 (2.1) | 0.000 | 1.000 |
| Carbamazepine (CBZ) | 4 (2.2) | 2 (2.3) | 2 (2.1) | 0.000 | 1.000 |
| Clonazepam (CZP) | 3 (1.7) | 0 (0) | 3 (3.2) | 3.046 | 0.081 |
| Phenobarbital (PB) | 1 (0.5) | 0 (0) | 1 (1.1) | 1.005 | 0.316 |
| The number of ASMs were used before clobazam, n (%) | |||||
| One ASMs | 4 (5.3) | 4 (10.5) | 0 (0) | 11.640 | 0.001** |
| Two ASMs | 38 (50.7) | 20 (52.6) | 18 (48.6) | 0.320 | 0.572 |
| Three ASMs | 28 (37.3) | 12 (31.7) | 16 (43.2) | 2.581 | 0.108 |
| Four ASMs or more | 5 (6.7) | 2 (5.3) | 3 (8.1) | 0.740 | 0.390 |
Notes: # One patient may have two or more ASMs. Comparison between effective and ineffective group, * P < 0.05; ** P < 0.001.
Retention Rates
The duration of clobazam treatment was 0.7 years (range: 0.08–6 years). Follow-up data for at least 1 month were available for all 75 pediatric patients. The mean maintenance dose of clobazam was 8.2 mg·kg−1·d−1 (standard deviation: 2.4). During the 12-month follow-up period, 15 patients discontinued clobazam, mainly due to treatment regimen changes (n = 13) and economic reasons (n = 2) (Figure 1). To evaluate long-term treatment adherence, Kaplan-Meier analysis was performed in 75 pediatric patients receiving adjunctive clobazam therapy. The retention rates at 3, 6, and 12 months were 94.7%, 86.7%, and 80.0%, respectively. Patients who had not reached the 12-month follow-up were censored in the analysis, allowing estimation of retention despite incomplete follow-up. These findings suggest that clobazam has good tolerability and adherence, supporting its use as an adjunctive treatment for pediatric patients with RE and its potential for long-term management (Figure 2).
Figure 1.
Flowchart of patient selection and follow-up of pediatric patients with drug-resistant epilepsy receiving adjunctive clobazam therapy.
Figure 2.
Kaplan-Meier analysis of estimated retention rates for pediatric patients receiving clobazam therapy (n = 75).
Treatment Efficacy
The treatment efficacy of clobazam was evaluated in 75 pediatric patients with RE. Among patients who experienced seizures during the baseline period, the response rates for all seizure types were 50.7%, 50.7%, 53.8%, and 56.7% at 1, 3, 6, and 12 months, respectively. The seizure-free rates were 24.0%, 23.9%, 24.6%, and 26.7% at 1, 3, 6, and 12 months, respectively (Figure 3).
Figure 3.
Efficacy outcomes of adjunctive clobazam therapy in pediatric patients with refractory epilepsy.
For the analysis set, the Shapiro–Wilk test was performed to assess the normality of quantitative variables. The results of the Shapiro–Wilk test and normality histograms indicate that all clinical variables had P < 0.05, suggesting non-normal distributions. Therefore, the Mann–Whitney U-test was used for subsequent analyses.
The 75 pediatric patients were divided into two groups according to treatment response: the effective group (n = 38) and the ineffective group (n = 37). The Mann–Whitney U-test and χ2 test showed no statistically significant differences between the effective and ineffective groups in body mass index (BMI), seizure duration, treatment duration, seizure type, and concomitant ASM use (P > 0.05, Table 2). However, significant differences were observed in age, sex, etiology, daily clobazam dose, comorbidities, and the number of concomitant ASMs between the two groups (P < 0.05, Table 2). Patients in the effective group were significantly older than those in the ineffective group (9.2 ± 4.6 vs 6.8 ± 4.5 years; P < 0.05), and the daily clobazam dose was significantly higher in the effective group than in the ineffective group (19.7 ± 9.7 vs 15.4 ± 7.7 mg/d; P < 0.05). In addition, the proportion of males was higher in the ineffective group than in the effective group (62.2% vs 47.4%; P < 0.05). The proportion of pediatric patients with unknown etiology was significantly higher in the ineffective group (32.4% vs 15.8%; P < 0.01). The proportions of RE pediatric patients with autism spectrum disorder and attention-deficit/hyperactivity disorder were significantly higher in the effective group (10.8% vs 0% and 5.4% vs 0%, respectively; P < 0.01). Moreover, the proportion of patients receiving one concomitant ASM was significantly higher in the effective group than in the ineffective group (10.5% vs 0%; P < 0.01).
Table 2.
Efficacy Outcomes of Adjunctive Clobazam Therapy in Pediatric Patients with Rasmussen Encephalitis at Different Time Points
| Changes in Seizure Frequency and Clobazam Dosage | Follow-Up Time Point | |||
|---|---|---|---|---|
| 1 Month (n = 75) |
3 Month (n = 71) |
6 Month (n = 65) |
12 Month (n = 60) |
|
| Effective (n, %) | 38 (50.7) | 36 (50.7) | 35 (53.8) | 34 (56.7) |
| Seizure freedom (n, %) | 18 (24.0) | 17 (23.9) | 16 (24.6) | 16 (26.7) |
| ≥50% reduction (n, %) | 20 (26.7) | 19 (26.8) | 19 (29.2) | 18 (30.0) |
| Ineffective (n, %) | 37 (49.3) | 35 (49.3) | 30 (46.1) | 26 (43.3) |
| <50% reduction (n, %) | 26 (34.7) | 26 (36.6) | 26 (40.0) | 24 (40.0) |
| No improvement (n, %) | 11 (14.7) | 9 (12.7) | 4 (6.1) | 2 (3.3)* |
| Clobazam dosage (mg/d) | 17.6 ± 9.0 | 17.7 ± 9.1 | 18.5 ± 9.0 | 18.7 ± 9.2 |
Notes: *12 months vs 1 month, P < 0.01.
Association Between Clobazam Response and Clinical Characteristics
Different Follow-Up Times
At the 1-month follow-up, 50.7% of pediatric patients achieved a response to clobazam, with the response rate gradually increasing over time, reaching 56.7% at 12 months. No significant differences were observed in response rates among different follow-up time points (P > 0.05, Table 2). In contrast, the proportion of pediatric patients with no reduction in seizure frequency decreased from 14.7% at 1 month to 1.7% at ≥12 months (P < 0.05), while the proportion of those with a <50% reduction in seizure frequency gradually increased over time (Table 2). The daily clobazam dose increased from 17.6 ± 9.0 mg/d at 1 month to 18.5 ± 9.0 mg/d at 6 months and then remained stable.
Seizure frequency (times/month) over the treatment period for clobazam use was as follows: at baseline, the mean seizure frequency was 39.9 times/month (median: 25, range: 0.25–150); at the 1-month follow-up, the mean was 10.7 times/month (median: 1.0, range: 0–90); at the 3-month follow-up, the mean was 14.2 times/month (median: 1, range: 0–90); at the 6-month follow-up, the mean was 10.7 times/month (median: 1, range: 0–60); and at the 12-month follow-up, the mean was 8.6 times/month (median: 0.4, range: 0–60).
Different Etiologies
Analysis according to epilepsy etiology showed that pediatric patients with genetic etiologies had the highest response rate (60.0%). Pediatric patients with structural, immune, and genetic etiologies also showed relatively high response rates (55.3% and 55.5%, respectively), while those with unknown etiologies had the lowest response rate (33.3%). For complete seizure control, the immune etiology group had the highest proportion (44.4%), followed by the genetic etiology group (30.0%) and the structural etiology group (23.7%), while the unknown etiology group had the lowest proportion (18.8%). Overall, adjunctive clobazam therapy showed efficacy across all etiology groups, with patients in the immune and genetic etiology groups showing higher response and seizure control rates, whereas those in the unknown etiology group showed the lowest rates (Table 3).
Table 3.
Efficacy Outcomes of Adjunctive Clobazam Therapy According to Epilepsy Etiology
| Changes in Seizure Frequency and Clobazam Dosage | Etiology Classification | |||
|---|---|---|---|---|
| Structural (n = 38) |
Immune (n = 9) |
Genetic (n = 10) |
Unknown (n = 18) |
|
| Effective (n, %) | 21 (55.3)* | 5 (55.5)* | 6 (60.0)* | 6 (33.3) |
| Seizure freedom (n, %) | 9 (23.7)*# | 4 (44.4)* | 3 (30.0)*# | 2 (11.1) |
| ≥50% reduction (n, %) | 12 (31.6) | 1 (11.1)* | 3 (30.0)# | 4 (22.2) |
| Ineffective (n, %) | 17 (44.7)* | 4 (44.4)* | 4 (40.0)* | 12 (66.7) |
| <50% reduction (n, %) | 12 (31.6) | 3 (33.3) | 3 (30.0)* | 8 (44.4) |
| No improvement (n, %) | 5 (13.2) | 1 (11.1)* | 1 (10.0)* | 4 (22.2) |
| Clobazam dosage (mg/d) | 18.9 ± 10.3 | 15.6 ± 3.9 | 17.0 ± 10.6 | 16.1 ± 6.5 |
Notes: *Comparison with unknown etiology, P < 0.05. # Comparison with immune etiology, P < 0.05.
Statistical analysis showed that the treatment efficacy in pediatric patients with unknown etiologies was significantly lower than that in patients with structural, immune, and genetic etiologies (P < 0.05). The seizure control rate in patients with the immune etiology group was significantly higher than that in patients with structural, genetic, and unknown etiologies (P < 0.05) (Table 3).
Different Disease Durations
In the analysis stratified by epilepsy duration, pediatric patients with a disease duration of 3–6 years exhibited the highest response rate (62.5%), followed by those with a duration of > 6 years (55.00%), while pediatric patients with a duration of < 1 year showed a relatively lower response rate (30.77%). The response rate of clobazam therapy increased with longer disease duration, and the differences were statistically significant (P < 0.05, Table 4). In addition, patients with a disease duration of 3–6 years had the highest seizure-free rate with clobazam therapy (43.75%), while those with a disease duration of <1 year had the lowest seizure-free rate (7.69%). The seizure-free rate increased with disease duration but declined after a disease duration of >6 years, and the differences were statistically significant (P < 0.05, Table 4). The daily clobazam dose increased from 0.86 ± 0.28 mg/d in patients with a disease duration of ≤1 year to 9.87 ± 2.79 mg/d in those with a disease duration of >6 years, and the difference was statistically significant (P < 0.01, Table 4).
Table 4.
Efficacy Outcomes of Adjunctive Clobazam Therapy According to Epilepsy Duration
| Changes in Seizure Frequency and Clobazam Dosage | Disease Duration (Years) | |||
|---|---|---|---|---|
| 0 < Duration ≤ 1 (n = 13) |
1 < Duration ≤ 3 (n = 26) |
3 < Duration ≤ 6 (n = 16) |
Duration > 6 (n = 20) |
|
| Effective (n, %) | 4 (30.8) | 13 (50.0)** | 10 (62.5)** | 11 (55.0)** |
| Seizure freedom (n, %) | 1 (7.7) | 6 (23.1)** | 7 (43.7)** | 4 (20.0)** |
| ≥50% reduction (n, %) | 3 (23.1) | 7 (26.9) | 3 (18.7)# | 7 (35.0) |
| Ineffective (n, %) | 9 (69.2) | 13 (50.0)** | 6 (37.5)** | 9 (45.0)** |
| <50% reduction (n, %) | 6 (46.1) | 10 (38.5) | 4 (25.0)** | 6 (30.0)* |
| No improvement (n, %) | 3 (23.1) | 3 (11.5)* | 2 (12.5) | 3 (15.0) |
| Clobazam dosage (mg/d) | 0.9 ± 0.3 | 2.4 ± 0.4** | 4.8 ± 0.7** | 9.9 ± 2.8** |
Notes: Comparison with 0 < duration ≤ 1 years, * P < 0.05, ** P < 0.01. Comparison with duration > 6 years, # P < 0.05.
Clobazam in Combination with Different ASMs
Among pediatric patients receiving clobazam combined with different ASMs, the response rates varied among treatment regimens. The highest response rate was observed in patients receiving clobazam combined with lacosamide (62.5%), followed by those receiving clobazam combined with lamotrigine (61.9%), perampanel (53.1%), valproate (48.1%), and levetiracetam (40.9%). The lowest response rate was observed in patients receiving clobazam combined with topiramate (31.6%).
This study compared the response and seizure-free rates of clobazam combined with individual ASMs with those of clobazam combined with other ASMs. The response rates in pediatric patients receiving clobazam combined with levetiracetam and topiramate were significantly lower than those in patients receiving clobazam combined with other ASMs (40.9% vs 54.7%, p = 0.048; 31.6% vs 57.1%, P = 0.000). In contrast, the response rates in patients receiving clobazam combined with lamotrigine and lacosamide were significantly higher than those in patients receiving clobazam combined with other ASMs (61.9% vs 46.3%, p = 0.023; 62.5% vs 47.5%, P = 0.034) (Table 5). The seizure-free rate was significantly lower in patients receiving clobazam combined with valproate than in those receiving clobazam combined with other ASMs (16.7% vs 42.9%, p = 0.000), while the seizure-free rate was significantly higher in pediatric patients receiving clobazam combined with lacosamide than in those receiving clobazam combined with other ASMs (37.5% vs 20.3%, P = 0.006) (Table 5). Among patients receiving clobazam combined with sodium valproate, 48.1% achieved a response, including 16.7% who achieved seizure freedom, with no significant difference compared with patients receiving clobazam combined with other ASMs (Table 5). Similarly, in the clobazam-perampanel group, 53.1% of patients achieved a response, including 28.1 who achieved seizure freedom, with no significant difference compared with patients receiving clobazam combined with other ASMs (Table 5).
Table 5.
Efficacy Outcomes of Adjunctive Clobazam Therapy in Pediatric Patients Receiving Different Concomitant Antiseizure Medications
| ASMs Regimen | Effective (n, %) |
Seizure Freedom (n, %) |
≥ 50% Reduction (n, %) |
Ineffective (n, %) |
< 50% Reduction (n, %) |
No Improvement (n, %) |
Clobazam Dosage (mg/d) |
|
|---|---|---|---|---|---|---|---|---|
| VPA | CLB+Others (n = 21) | 12 (57.1) | 9 (42.9) | 3 (14.3) | 9 (42.9) | 7 (33.3) | 2 (9.5) | 17.9 ± 9.6 |
| CLB+VPA (n = 54) | 26 (48.1)#$ | 9 (16.7)**$$ | 17 (31.5)** | 28 (51.8)#$ | 19 (35.2) | 9 (16.7) | 17.5 ± 8.8 | |
| PER | CLB+Others (n = 43) | 21 (48.8) | 9 (20.9) | 12 (27.9) | 22 (51.2) | 13 (30.2) | 9 (20.9) | 17.1 ± 8.9 |
| CLB+PER (n = 32) | 17 (53.1)## | 9 (28.1) | 8 (25.0)# | 15 (46.9)## | 13 (40.6)$ | 2 (6.2)**## | 18.3 ± 9.1 | |
| LEV | CLB+Others (n = 53) | 29 (54.7) | 14 (26.4) | 15 (28.3) | 24 (45.3) | 19 (35.8) | 5 (9.4) | 18.3 ± 9.4 |
| CLB+LEV (n = 22) | 9 (40.9)*$ | 4 (18.2)$$ | 5 (22.7)# | 13 (59.1)*$ | 7 (31.8)# | 6 (27.3)**$ | 15.9 ± 7.7 | |
| LTG | CLB+Others (n = 54) | 25 (46.3) | 14 (25.9) | 11 (20.4) | 29 (53.7) | 18 (33.3) | 11 (20.4) | 16.3 ± 8.7 |
| CLB+LTG (n = 21) | 13 (61.9)*## | 4 (19.0)$$ | 9 (42.9)**##$ | 8 (38.1)*## | 8 (38.1)$ | 0 (0)**##$$ | 20.9 ± 8.9* | |
| TPA | CLB+Others (n = 56) | 32 (57.1) | 14 (25.0) | 18 (32.1) | 24 (42.9) | 17 (30.4) | 7 (12.5) | 19.0 ± 9.1 |
| CLB+TPA (n = 19) | 6 (31.6)**$ | 4 (21.0)$ | 2 (10.5)** | 13 (68.4)**$ | 9 (47.4)*$$ | 4 (21.0) | 13.4 ± 7.3* | |
| LCM | CLB+Others (n = 59) | 28 (47.5) | 12 (20.3) | 16 (27.1) | 31 (52.5) | 22 (37.3) | 9 (15.2) | 17.6 ± 8.6 |
| CLB+LCM (n = 16) | 10 (62.5)*## | 6 (37.5)** | 4 (25.0)# | 6 (37.5)*## | 4 (25.0)# | 2 (12.5) | 17.5 ± 10.6 | |
Notes: Comparison with CLB+Others, *P < 0.05, **P < 0.01. Comparison with CLB+TPA, # P < 0.05, ##P < 0.01. Comparison with CLB+LCM, $P < 0.05, $P < 0.01.
Abbreviations: CLB, Clobazam; VPA, valproate; PER, perampanel; LEV, levetiracetam; LTG, lamotrigine; TPA, topiramate; LCM, lacosamide.
This study compared the response and seizure-free rates of clobazam combined with different ASMs in pediatric patients with epilepsy. The response rate in patients receiving clobazam combined with topiramate was significantly lower than that in patients receiving clobazam combined with valproate, perampanel, lamotrigine, or lacosamide (31.6% vs 48.1%, 53.1%, 61.9%, and 62.5%, respectively; P < 0.05). In contrast, patients receiving clobazam combined with lacosamide showed a higher response rate than those receiving clobazam combined with valproate, levetiracetam, or topiramate (62.5% vs 48.1%, 40.9%, and 31.6%, respectively; P < 0.05). In addition, the seizure-free rate was significantly higher among patients receiving clobazam combined with lacosamide than among those receiving clobazam combined with valproate, levetiracetam, lamotrigine, or topiramate (37.5% vs 16.7%, 18.2%, 19.0%, and 21.0%, respectively; P < 0.05).
Meanwhile, the daily clobazam dose was significantly higher in patients receiving clobazam combined with lamotrigine than in those receiving clobazam combined with other ASMs (20.9 ± 8.9 mg/d vs 16.3 ± 8.7 mg/d, P = 0.040). Conversely, the daily clobazam dose was significantly lower in patients receiving clobazam combined with topiramate than in those receiving clobazam combined with other ASMs (13.4 ± 7.3 mg/d vs 19.0 ± 9.1 mg/d, P = 0.038).
Predictive Factors for Effective of Clobazam Treatment
To evaluate the factors affecting the efficacy of clobazam, a multivariable logistic regression analysis was performed. Age, sex, body mass index (BMI), duration of epilepsy, medication duration, seizure type, etiology, and concomitant ASMs were included as covariates. The results showed that sex and comorbidities were significant predictors of seizure control with clobazam (P = 0.039 and P = 0.030, respectively; Table 6).
Table 6.
Multivariate Logistic Regression Model to Identify Independent Predictors of Effective Seizure Outcome after Taking Clobazam
| Variables | Odds Ratio | 95% CI | P |
|---|---|---|---|
| Age | 1.047 | 0.861–1.272 | 0.647 |
| Sex | 3.192 | 1.058–9.636 | 0.039* |
| Body mass index | 1.068 | 0.951–1.199 | 0.264 |
| Duration of epilepsy | 1.039 | 0.825–1.308 | 0.747 |
| Medication time | 1.248 | 0.678–2.294 | 0.477 |
| Etiology | 0.786 | 0.515–1.200 | 0.265 |
| Maintain daily dose | 1.044 | 0.958–1.137 | 0.326 |
| Comorbidities | 0.532 | 0.301–0.939 | 0.030* |
| Concomitant valproate | 0.696 | 0.252–1.923 | 0.485 |
| Concomitant perampanel | 1.187 | 0.475–2.968 | 0.713 |
| Concomitant levetiracetam | 0.573 | 0.209–1.569 | 0.279 |
| Concomitant lamotrigine | 1.885 | 0.673–5.282 | 0.228 |
| Concomitant topiramate | 0.346 | 0.115–1.043 | 0.059 |
| Concomitant lacosamide | 1.845 | 0.594–5.734 | 0.290 |
Note: * P < 0.05.
Abbreviations: CI, confidence interval; ASMs, antiseizure medications.
Adverse Events
During adjunctive clobazam treatment, 31 pediatric patients with RE (41.33%) experienced at least one adverse event, and some patients experienced multiple adverse events. The most common events were drowsiness and fatigue (13.33%, 10/75), followed by dizziness (9.33%, 7/75), nausea/vomiting (8.00%, 6/75), and decreased appetite (5.33%, 4/75). Adverse events led to clobazam discontinuation in only two pediatric patients. The incidence of adverse events among patients receiving clobazam combined with valproate, perampanel, levetiracetam, lamotrigine, topiramate, and lacosamide was 28.00% (21/75), 20.00% (15/75), 14.67% (11/75), 25.33% (19/75), 20.00% (15/75), and 16.00% (12/75), respectively. The incidence of adverse events was significantly higher in patients receiving clobazam combined with valproate than in those receiving clobazam combined with levetiracetam or lacosamide (28.00% vs 14.67% and 16.00%; P = 0.025 and 0.041, respectively). Overall, clobazam was well tolerated, with most adverse events being mild to moderate in severity and primarily involving the central nervous system. No deaths or serious adverse events were reported (Table 7).
Table 7.
Adverse Events Associated with Adjunctive Clobazam Therapy
| Adverse Drug Reactions | n, % |
|---|---|
| Somnolence and mental fatigue | 10 (13.3) |
| Dizziness | 7 (9.3) |
| Nausea/vomiting | 6 (8.0) |
| Poor appetite | 4 (5.3) |
| Irritability | 2 (2.7) |
| Blurred vision | 1 (1.3) |
| Rash | 1 (1.3) |
Discussion
In October 2022, clobazam (10 mg × 28 tablets), manufactured by Yichang Renfu Co., Ltd., was officially approved by the China National Medical Products Administration, providing patients with RE in China with a legally available and more affordable treatment option. Following its introduction into clinical practice, clobazam has been increasingly used as an adjunctive ASM for pediatric patients with epilepsy. This retrospective study was conducted in the neurology departments of two tertiary hospitals in Xinjiang to evaluate the efficacy and safety of clobazam as an adjunctive therapy in pediatric patients with RE. Our results showed that adjunctive clobazam therapy significantly reduced seizure frequency in pediatric patients with RE, and the response rate increased gradually during long-term follow-up with dose optimization. At the final follow-up (≥12 months), 56.67% of pediatric patients achieved a ≥50% reduction in seizure frequency compared with baseline, 26.67% achieved seizure freedom, and no serious adverse events were observed. These findings suggest that clobazam is an effective and well-tolerated adjunctive treatment option for pediatric patients with RE.
Previous randomized controlled trials and retrospective studies have reported that more than 50% of patients with RE achieved a ≥50% reduction in seizure frequency after the addition of clobazam,12–14 and approximately 40–70% achieved seizure freedom during follow-up periods exceeding one year.14,15 Zhang et al4 demonstrated that adjunctive clobazam therapy significantly reduced seizure frequency in patients with RE, with higher doses, longer treatment durations, and concomitant use of oxcarbazepine being associated with improved outcomes. Clobazam also showed favorable effectiveness, applicability across different patient populations, and acceptable safety profiles. Fang et al16 reported that 62 patients (38.8%) achieved seizure freedom, and clobazam was well-tolerated, with only 5% of patients discontinuing treatment due to adverse reactions. Das et al17 found that, in patients with generalized tonic-clonic seizures inadequately controlled with valproate monotherapy, adjunctive clobazam therapy reduced seizure frequency and improved cognitive function and overall quality of life.
In addition, the efficacy of clobazam in pediatric patients with epilepsy has been evaluated in several retrospective studies.18–20 Uzunhan et al18 reported that 37.5% of pediatric patients with RE achieved seizure freedom with clobazam, while 40% achieved a ≥50% reduction in seizure frequency. A large retrospective cohort study further showed that 28% of RE achieved seizure freedom after clobazam treatment, while 67.7% achieved a ≥50% reduction in seizure frequency.19 Yu et al20 demonstrated that adjunctive clobazam therapy was effective, safe, and well tolerated in children with drug-resistant epilepsy. In their study, the response rates at 6 and 12 months were 58.99% (82/139) and 62.41% (83/133), respectively, with seizure-free rates of 36.69% (51/139) and 35.34% (47/133). Compared with the study by Yu et al,20 our study included additional analytical perspectives, including an examination of how the efficacy of clobazam varies across different follow-up times, epilepsy durations, and combinations with different ASMs.
The results of this study further support the efficacy of adjunctive clobazam therapy in pediatric patients with RE. At the initial follow-up, 50.67% of pediatric patients achieved a ≥50% reduction in seizure frequency, and 24.00% achieved seizure freedom. At the final follow-up (≥12 months), the response rate and seizure-free rate increased to 56.67% and 26.67%, respectively, which was accompanied by an increase in the daily clobazam dose. The daily dose of clobazam increased from 17.60 ± 8.98 mg/d at 1 month to 18.46 ± 8.97 mg/d at 6 months and then remained stable.
Ciullo et al13 reported a 12-month retention rate of 83.1% for adjunctive clobazam therapy in adults with drug-resistant epilepsy. Satishchandra et al15 observed a 12-month retention rate of 88.5% in patients with uncontrolled epilepsy receiving adjunctive clobazam treatment. Yu et al20 reported 6-month and 12-month retention rates of 87.67% and 81.51%, respectively, among pediatric patients with drug-resistant epilepsy treated with adjunctive clobazam. In the present study, the retention rates of clobazam therapy at 3, 6, and 12 months were 94.67%, 86.67%, and 80.00%, respectively, which were comparable to previous reports.13,15,20
A subgroup analysis stratified by epilepsy etiology showed that pediatric patients with genetic etiology had the highest response rates and seizure-free rates, while those with unknown etiology had relatively lower rates. The treatment efficacy in the unknown etiology group was significantly lower than that in pediatric patients with structural, immune, or genetic etiologies (P < 0.05). However, the overall findings indicate that adjunctive clobazam therapy may be effective across different epilepsy etiologies. Yu et al20 also reported that clobazam showed favorable efficacy in patients with genetic epilepsy (60.42%, 29/48), with significantly higher efficacy observed in patients with the SCN1A genotype than in those with other genotypes (P = 0.048). Consistently, our study found a comparable response rate among pediatric patients with genetic epilepsy (60.00%). However, the small subgroup sample size and multiple comparisons limit the strength of the evidence this study provides regarding epilepsy etiology. In future research, we will continue to collect more samples to further verify these findings.
Immunotherapy for epilepsy has shifted from traditional “symptomatic control” to a precise immunomodulatory strategy of “etiological intervention”, centered on stratified treatment according to autoantibody type. For epilepsy associated with neuronal surface antigens, first-line immunotherapy (corticosteroids, plasma exchange, and intravenous immunoglobulin) often achieves significant seizure control and may even lead to seizure freedom. In contrast, for chronic RE associated with intracellular antigens, the response to immunotherapy is often limited and transient, requiring consideration of second-line and emerging targeted agents such as rituximab, cyclophosphamide, or tocilizumab.21–23 Uchida et al24 reported that in two patients with autoimmune encephalitis, passive transfer of thyroid autoantibodies via intravenous immunoglobulin might lead to misleading thyroid autoantibody positivity. Early identification of immune etiology and timely initiation of immunotherapy are crucial.
Previous studies have not specifically evaluated the combination of clobazam with levetiracetam and topiramate as a distinct polytherapy regimen. Preclinical isobolographic studies have shown that topiramate combined with levetiracetam or clobazam generally produces additive or synergistic anticonvulsant effects in animal models.25 In our cohort, however, the combination of clobazam with levetiracetam and topiramate was associated with lower efficacy. One possible explanation relates to the pharmacodynamic profiles of these agents: topiramate and levetiracetam act primarily through non-GABAergic mechanisms, whereas clobazam acts via GABA-A receptor potentiation.26 A comparative efficacy study of unique ASM regimens in focal epilepsy found that clobazam/levetiracetam/lamotrigine approached statistical significance for ≥6 months of seizure freedom.27 Margolis et al28 demonstrated that ASM combinations with different mechanisms of action had greater treatment persistence and lower risks of hospitalization than same-mechanism combinations. Lacosamide and lamotrigine both act on sodium channels, whereas clobazam enhances GABAergic inhibition; these complementary mechanisms may underlie the enhanced efficacy observed.
In this study, the most commonly used concomitant ASMs included valproate, perampanel, levetiracetam, lamotrigine, and topiramate. Among different clobazam combination regimens, patients receiving clobazam combined with lacosamide showed the highest response rate (62.5%), while those receiving clobazam combined with topiramate showed the lowest response rate (31.6%). Interestingly, the response rate in pediatric patients receiving clobazam combined with levetiracetam was significantly lower than that in patients receiving clobazam combined with other ASMs. This difference may be related to the higher proportion of patients with genetic etiology in the clobazam-levetiracetam group, as these patients may have more complex disease characteristics and greater treatment resistance, potentially limiting therapeutic response.
The response rates in pediatric patients receiving clobazam combined with levetiracetam and topiramate were significantly lower than those in patients receiving clobazam combined with other ASMs (40.9% vs 54.7%, P = 0.048; 31.6% vs 57.1%, P = 0.000). In contrast, the response rates in patients receiving clobazam combined with lamotrigine and lacosamide were significantly higher than those in patients receiving clobazam combined with other ASMs (61.9% vs 46.3%, P = 0.023; 62.5% vs 47.5%, P = 0.034) (Table 5). The multivariable logistic regression analysis showed that concomitant ASMs were not a significant predictor of seizure control with clobazam (P > 0.05). However, the small subgroup sample size and multiple comparisons limit the evidence this study can provide regarding differences in the effectiveness and safety of clobazam when used concomitantly with other ASMs. We will continue to collect more samples to further verify these results.
Regarding safety, Uzunhan et al18 reported that 45% of patients with epilepsy experienced adverse events after the addition of clobazam, leading to treatment discontinuation in six patients (15%) and dose reduction in four patients (10%). The most common adverse events were hyperactivity and persistent sedation. Yu et al19 found that adjunctive clobazam therapy was generally safe and well tolerated in children with refractory epilepsy, with only 16.64% (24/146) of pediatric patients experiencing adverse reactions. Excessive drooling (2.74%) and decreased appetite (2.74%) were the most frequently reported events. Klehm et al20 reported that treatment discontinuation was attributed to adverse reactions in 59.3% of patients, lack of efficacy in 37%, and both factors in 3.7%. The most common adverse events were fatigue (14.6%) and mood or behavioral changes (7.7%). In the present study, clobazam is generally well tolerated. During the treatment period, 41.33% of RE pediatric patients (31/75) experienced at least one adverse event, with the most common being drowsiness and fatigue (13.33%), followed by dizziness (9.33%), nausea/vomiting (8.00%), and decreased appetite (5.33%). Adverse events led to clobazam discontinuation in only two pediatric patients. These adverse events may be related to the pharmacological action of clobazam as a 1,5-benzodiazepine derivative, which enhances GABA-mediated inhibitory neurotransmission and reduces neuronal excitability. Although these mechanisms contribute to seizure control, they may also result in central nervous system-related effects such as sedation and fatigue.29
Clobazam is effective as an add-on therapy for seizures in severe RE. Borrell-Pichot et al30 reported a 28-year-old man with creatine transporter deficiency who continued to have severe developmental delays and frequent seizures after multiple medications; however, after starting clobazam, he remained seizure-free for one year. Besag et al31 suggested that clobazam is partially effective as an add-on therapy for seizures in Lennox-Gastaut syndrome. In addition, ketogenic dietary therapies are an alternative treatment to ASMs and have been used for RE in children since the 1920s.32 Stiripentol, an orphan drug designated for Dravet syndrome with refractory partial seizures, enhances GABAergic activity by prolonging the opening duration of GABAA receptor channels and has an indirect metabolic effect on co-administered ASMs.33 Previous studies have reported the potential benefits of stiripentol and the ketogenic diet in refractory status epilepticus. Uchida et al34 reported a case in which the combination of a ketogenic diet and stiripentol successfully controlled super-refractory status epilepticus. Uchida et al35 suggested that cross-sensitivity between ASMs is common in adults with super-refractory status epilepticus and that stiripentol may be useful for treating super-refractory status epilepticus with cross-sensitivity. Therefore, alternative or adjunctive therapeutic strategies such as stiripentol and ketogenic dietary therapies may have potential benefits in RE, offering more options for comprehensive treatment.
In this study, some patients who failed to achieve adequate seizure control during the initial phase subsequently responded at later follow-up, suggesting that early non-response should not be regarded as a definitive predictor of ultimate treatment failure. However, given the retrospective design and limited sample size, we cannot establish a specific time point beyond which a lack of response should be considered final. We suggest that the decision to continue or withdraw clobazam be individualized, taking into account the trajectory of response over time, tolerability, and the availability of alternative therapeutic options.
However, this study has several limitations. First, this is a retrospective study, which may limited the generalizability of the findings. Second, the relatively small sample sizes in some subgroups may have reduced the statistical power of subgroup analyses. In addition, variations in medication adherence among pediatric patients may have resulted in incomplete seizure frequency records. Furthermore, pharmacokinetic data were not systematically collected. Future studies should further explore personalized combination strategies based on complementary mechanisms and individual patient characteristics to optimize therapeutic outcomes. Prospective, multicenter, randomized, double-blind studies are needed to confirm these observations and clarify potential pharmacokinetic and pharmacodynamic interactions.
Conclusion
Overall, adjunctive clobazam therapy demonstrates favorable efficacy, safety, and tolerability in pediatric patients with RE. This real-world study provides additional evidence supporting the clinical application of clobazam in RE treatment. Future multicenter prospective studies with larger sample sizes are warranted to further validate these findings.
Funding Statement
This work was supported by the National Natural Science Foundation of China (No. 82560709), and Youth Talent Support Project of Tianshan Talents Training Program of Xinjiang Uygur Autonomous Region (No. 2024TSYCQNTJ0046).
Data Sharing Statement
The datasets generated and/or analyzed during the current study are not publicly available due to privacy and ethical restrictions. De-identified data may be made available from the corresponding author upon reasonable request and subject to institutional and ethical approval.
Ethics Statement
This study was conducted in accordance with the Declaration of Helsinki’s principles. This study was authorized by the Medical Ethics Committee of People’s Hospital of Xinjiang Uygur Autonomous Region (No. KY2022041245), and informed consent was obtained from individual participants and their parents.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
None of the authors have any conflict of interest to disclose. The authors confirm that they have read the Journal’s policy on issues involved in ethical publication, and affirm that this study is consistent with those guidelines.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and/or analyzed during the current study are not publicly available due to privacy and ethical restrictions. De-identified data may be made available from the corresponding author upon reasonable request and subject to institutional and ethical approval.