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Keywords:

  • Adjunctive treatment;
  • Antiepileptic drugs;
  • Partial epilepsy;
  • Partial seizures;
  • Pediatric epilepsy;
  • Zonisamide

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

Purpose

To assess the efficacy and safety/tolerability of adjunctive zonisamide treatment in pediatric patients with partial epilepsy.

Methods

In this phase III, double-blind, randomized, placebo-controlled, multicenter trial, 207 patients (age 6–17 years) with partial epilepsy, receiving one or two antiepileptic drugs, were randomized to receive adjunctive zonisamide or placebo. Zonisamide was initiated at 1 mg/kg/day, titrated to a target dose of 8 mg/kg/day over 8 weeks (one down-titration permitted), and maintained for 12 weeks. The primary efficacy end point was the proportion of responders (≥50% seizure frequency reduction from baseline) during the 12-week maintenance period. Safety/tolerability assessments included the incidence of treatment-emergent adverse events (TEAEs).

Key Findings

In total, 93 (86.9%) of 107 patients randomized to zonisamide and 90 (90.0%) of 100 patients randomized to placebo completed the trial. Responder rates were 50% for zonisamide versus 31% for placebo (p = 0.0044; intention-to-treat population, last observation carried forward). The overall incidence of TEAEs was similar for zonisamide (55.1%) versus placebo (50.0%), with low rates of serious TEAEs with zonisamide and placebo (3.7% vs. 2.0%) and TEAEs leading to withdrawal (0.9% vs. 3.0%). TEAEs reported more frequently with zonisamide versus placebo were decreased appetite (6.5% vs. 4.0%), decreased weight (4.7% vs. 3.0%), somnolence (4.7% vs. 2.0%), vomiting (3.7% vs. 2.0%), and diarrhea (3.7% vs. 1.0%).

Significance

Adjunctive zonisamide treatment was shown to be effective and well tolerated in pediatric patients with partial epilepsy. No new or unexpected safety findings emerged.

Epilepsy is a common condition in children, partial seizures being the most frequently observed seizure type in this patient population (Berg et al., 1999; Bergin, 2003). Currently, only approximately 60% of patients achieve satisfactory seizure control with antiepileptic drug (AED) monotherapy; other patients require adjunctive AED treatment to attain adequate control (Kwan & Brodie, 2000). Five of the newer AEDs (topiramate, lamotrigine, gabapentin, oxcarbazepine, and levetiracetam) have been investigated in placebo-controlled trials as adjunctive therapy for refractory partial seizures in pediatric patients (Appleton et al., 1999; Duchowny et al., 1999; Elterman et al., 1999; Glauser et al., 2000, 2006; Piña-Garza et al., 2008). Although tolerability has improved with newer AEDs, 25–30% of children with epilepsy remain refractory to medical therapy (Verrotti et al., 2011), so the need remains for additional treatment options.

Zonisamide is a benzisoxazole derivative, chemically unrelated to other AEDs, with a variety of modes of action, including inhibition of Na+ channels and reduction of T-type Ca2+ currents (Biton, 2007). It is currently licensed in Europe and the United States for the adjunctive treatment of partial seizures (with or without secondary generalization) in adults, and in Europe as monotherapy for the treatment of partial seizures (with or without secondary generalization) in adults with newly diagnosed epilepsy (Zonegran® Summary of Product Characteristics, 2012; Zonegran® Prescribing Information, 2012). Phase II studies in pediatric patients indicate that adjunctive zonisamide has an acceptable safety profile in this population and a pharmacokinetic profile similar to that observed in adult patients (Chouette & Giorgi, 2012; Giorgi & Chouette, 2012). However, these studies were not designed to provide definitive evidence of zonisamide's efficacy in this setting.

We present the results of the Children's Add-on Therapy with Zonisamide (CATZ) study, which was designed to assess the efficacy and tolerability of adjunctive zonisamide in pediatric patients with partial epilepsy receiving one or two AEDs. This is the first randomized, controlled, phase III trial to assess the efficacy and tolerability of zonisamide in this setting.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

The CATZ study was a phase III, double-blind, randomized, placebo-controlled, multicenter trial, conducted in pediatric patients (age 6–17 years) with partial epilepsy, receiving one or two AEDs. Patients were recruited from 41 sites in Europe and India. The trial was conducted in accordance with Good Clinical Practice guidelines, and the protocol was approved by an independent ethics committee (IEC). All countries had central IEC submissions, except India and Italy, where local IEC approval was required. All patients (or their guardian or a legally authorized representative) provided written informed consent. The trial is registered with ClinicalTrials.gov, number NCT00566254.

Patients

The trial included male and female subjects, aged 6–17 years, with a clinical diagnosis of epilepsy with partial-onset seizures, with or without secondary generalization (International League Against Epilepsy, 1981). Diagnosis needed to be established by clinical history, electroencephalography, and brain computerized tomography/magnetic resonance imaging, consistent with localization-related epilepsy. Patients were required to have experienced at least four partial seizures (simple or complex; with or without secondary generalization) per month during the 8-week baseline period, with at least one seizure in each 4-week period and no 21-day period without any seizures. They also needed to be receiving a stable regimen of one or two AEDs for ≥1 month before visit 1; if using a vagus nerve stimulator, the device must have been implanted for ≥5 months and the stimulator parameters must have remained unchanged for ≥1 month before visit 1. Patients had to be in good general health. They also had to be willing to provide informed assent (written or verbal) and, if appropriate, written informed consent, and to have a parent/guardian who was willing and able to sign an approved informed consent form, accompany the subject on all study visits, and complete a seizure diary for the duration of the trial. Exclusion criteria included the following: body weight <20 kg at screening; progressive neurologic disease; history of idiopathic generalized epilepsy; psychogenic seizures; cluster seizures; history of status epilepticus within the previous year; previous treatment with zonisamide; or concomitant treatment with one or more of the following drugs: felbamate, acetazolamide, any carbonic anhydrase inhibitors (e.g. topiramate), and any drugs with anticholinergic activity. Female subjects of childbearing potential were excluded if pregnant or lactating, or if not either using or willing to use a medically acceptable form of contraception or prepared to abstain from sexual activity for the duration of the study and 1 month after last administration of study medication.

Study design

The trial comprised an 8-week baseline period, 8-week titration period, and 12-week maintenance period, after which patients either entered a long-term extension study or were down-titrated over 3–4 weeks and withdrawn (Fig. S1). Baseline comprised a 4-week screening period plus historical seizure data from the 4 weeks prior to screening, collected from seizure diaries maintained as part of standard clinical practice, so that all subjects had 8 weeks of data documenting their baseline seizure frequency. Patients continued to maintain seizure diaries throughout the trial.

Following screening, eligible patients were randomized 1:1 to zonisamide or placebo, added to one or two AEDs. Zonisamide was initiated at 1 mg/kg/day and titrated in weekly increments of 1 mg/kg over 8 weeks to a target dose of 8 mg/kg/day (maximum 500 mg/day), and then continued unchanged over a 12-week maintenance period. In the event of dose-limiting adverse events (AEs) during titration, one down-titration to a lower dose was permitted, which was titrated up again when tolerability improved. Patients not titrating up following a dose reduction continued unchanged on the lower dose during the maintenance period. Changes in concomitant AEDs were not permitted during the baseline, titration, or maintenance periods.

Assessments

Efficacy

The primary efficacy end point was the proportion of responders during the 12-week maintenance period for zonisamide versus placebo. Response was defined as ≥50% seizure frequency reduction from baseline (i.e., the 8 weeks preceding randomization). The primary efficacy analysis was performed for the intent-to-treat (ITT) population using last observation carried forward (LOCF) data.

Secondary efficacy assessments included the median percentage change from baseline in 28-day seizure frequency; the proportion of patients with seizure frequency reduction of ≥75%; and the proportion of patients with an increase in seizure frequency of ≥25% and ≥100%. Additional efficacy end points included the proportion of patients achieving seizure freedom, the percentage change from baseline in 28-day seizure frequency by seizure type, and the relationship between zonisamide plasma level and responder rate.

Safety and tolerability

Safety assessments included the incidence of treatment-emergent AEs (TEAEs), serious TEAEs, and withdrawal due to TEAEs; clinical laboratory parameters (hematology, blood chemistry, urinalysis, and immune system maturation); physical and neurologic evaluations; vital signs; height and weight; and electrocardiography. Information regarding TEAEs was collected via routine case report forms and spontaneous reporting.

Statistics

The safety and ITT populations were defined as all randomized patients who received at least one dose of double-blind study medication. The per-protocol (PP) population was defined as all patients in the ITT population who had no major protocol deviations.

Sample size was based on the primary efficacy end point. A sample size of 91 patients in each treatment group was estimated to have 80% power to detect a difference in the proportions of responders of 20% for the placebo group and 40% for the treatment group, using previous adjunctive therapy studies as the reference. Assuming a 10% dropout rate, a sample size of 102 patients per group was calculated.

Patients were randomized 1:1 to zonisamide or placebo, stratified by site and weight-range group. The randomization scheme was computer-generated and randomization was performed centrally (ClinPhone PLC, Nottingham, United Kingdom) using a pseudorandom number generator. The investigator or designee called the interactive voice response system (IVRS) and, on inputting the subject number on the randomization visit, received a unique four-digit randomization number. The investigator/designee then called the IVRS at each dispensing visit, to be allocated the relevant medication identification number(s). Study blinding was conducted via the IVRS. Zonisamide and placebo were visually similar.

A 5% significance level was used for all statistical comparisons. Analysis of the primary efficacy end point was performed using the Pearson's chi-square test on ITT-LOCF data; p-values were obtained for the association between treatment and responder rate. Sensitivity analyses were also performed for the ITT-observed case (ITT-OC) and PP-LOCF data sets. In addition, responder rates during the combined titration + maintenance periods were compared using the ITT-OC data set.

Percentage change from baseline in 28-day seizure frequency (for total seizures and by partial seizure type) was analyzed using analysis of covariance on rank-transformed data, with baseline seizure frequency included as a covariate. Data were presented as median percentage change from baseline, a nonparametric 95% Hodges-Lehmann confidence interval (CI) and p-value. The proportions of patients achieving seizure freedom, and decreases (≥75%) and increases (≥25% and ≥100%) in seizure frequency from baseline, were analyzed using the Pearson's chi-square test.

Zonisamide plasma concentrations in patients in the zonisamide treatment group were summarized at week 12 and at final visit. The relationship between zonisamide plasma concentration and therapeutic response was analyzed using logistic regression analysis of responder rate versus log-transformed zonisamide plasma concentration, with baseline seizure frequency included as a covariate. Results for week 12 and final visit were presented as odds ratios, with 95% CIs and p-values.

Baseline and demographic data were summarized using descriptive statistics; no between-group statistical comparisons were performed. The incidence and frequency of TEAEs were summarized by treatment group using the Medical Dictionary for Regulatory Activities preferred terminology. Safety variables were described using summary statistics.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

Patient population

Between December 28, 2007 and March 1, 2011, patients (n = 242) from 41 centers in 10 European countries and India were screened, of whom 207 were randomized to receive zonisamide (n = 107) or placebo (n = 100; Fig. 1). Overall, 93 (86.9%) of 107 and 90 (90.0%) of 100 patients randomized to zonisamide and placebo, respectively, completed the study. Reasons for discontinuation were primarily lack of therapeutic efficacy (zonisamide, 5.6%; placebo, 5.0%), AEs (zonisamide, 0.9%; placebo, 3.0%), and protocol deviation (zonisamide, 2.8%; placebo, 1.0%; Fig. 1). Demographic and baseline characteristics were similar between treatment groups (Table 1). Median baseline seizure frequency was similar between groups (10.5 for zonisamide vs. 10.0 for placebo); however, mean baseline seizure frequency was lower in the zonisamide versus placebo group (32.9 vs. 43.9). Seizure types at baseline were also similar between groups.

Table 1. Patient demographics and baseline characteristics (safety population)
 PlaceboZonisamide
  1. AED, antiepileptic drug. SD, standard deviation.

  2. a

    One subject in the placebo group had no evidence of taking an AED at baseline, but started taking one AED on day 8 after randomization (this subject was excluded from the per-protocol population).

  3. b

    Patients may have had more than one seizure type.

  4. c

    All subjects with missing seizure types history had confirmatory seizures during screening period and/or double-blind phase.

  5. d

    Number of seizures per 28 days.

Total number of patients, N100107
Age, years  
Mean (SD)11.2 (3.2)11.6 (3.3)
Median (range)11.0 (6–17)11.0 (6–17)
Age group, n (%)  
6–11 years55 (55.0)55 (51.4)
12–17 years45 (45.0)52 (48.6)
Sex, n (%)  
Male55 (55.0)53 (49.5)
Female45 (45.0)54 (50.5)
Weight, kg  
Mean (SD)43.3 (17.6)42.8 (17.2)
Median (range)39.8 (20.7–108.0)40.0 (20.0–95.4)
Height, cm  
Mean (SD)148.2 (17.0)147.3 (17.8)
Median (range)149.0 (112.5–193.0)147.2 (107.0–186.1)
Body mass index, kg/m2  
Mean (SD)19.1 (4.3)19.0 (4.8)
Median (range)18.3 (9.6)18.7 (11.0)
Time since diagnosis, months  
Mean (SD)64.2 (44.6)67.4 (46.7)
Median (range)54.7 (2–205)52.4 (5–187)
Number of concomitant AEDs, n (%)  
01 (1.0)a0
139 (39.0)44 (41.1)
260 (60.0)63 (58.9)
Etiology, n (%)  
Unknown65 (65.0)60 (56.1)
Structural brain anomalies13 (13.0)21 (19.6)
Head injuries4 (4.0)5 (4.7)
Family history of epilepsy1 (1.0)1 (0.9)
Other17 (17.0)20 (18.7)
Seizure type,b n (%)  
Simple partial with motor signs34 (34.0)40 (37.4)
Simple partial without motor signs10 (10.0)11 (10.3)
Complex partial58 (58.0)59 (55.1)
Secondarily generalized tonic–clonic33 (33.0)29 (27.1)
Missingc7 (7.0)7 (6.5)
Baseline seizure frequency,d n  
Mean (SD)43.8 (126.4)32.9 (50.3)
Median (range)10.0 (4–882)10.5 (4–261)
image

Figure 1. Patient disposition. ITT, intent-to-treat. Epilepsia © ILAE

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Dosing

The target dose for zonisamide was 8 kg/mg/day, with a maximum of 500 mg/day. The protocol assigned doses based on each patient's weight band (20 to <29, 29 to <42, 42 to <56, and ≥56 kg). The weight bands allowed a minority of patients whose weight was toward the higher end of each range to be scheduled a maintenance dose of <8 mg/kg/day and those whose weight was toward the lower end of each range to be scheduled a maintenance dose of >8 mg/kg/day. Most patients received 5 to <9 mg/kg/day during the maintenance period (placebo, 83.9%; zonisamide, 92.9%). Almost all remaining patients received 9–12 mg/kg/day (placebo, 15.1%; zonisamide, 7.1%). Only one patient, from the placebo group, received <5 mg/kg/day during the maintenance period. During titration, five patients (5.0%) in the placebo group and two (1.9%) in the zonisamide group had a single dose reduction. During the maintenance period, dosing was to remain unchanged, but one patient in the placebo group had a dose reduction. The median duration of exposure was similar in each treatment group and age group (140 days).

Efficacy

Primary end point

For the ITT-LOCF population (zonisamide n = 107; placebo n = 100), responder rates during the maintenance period were 50% for zonisamide versus 31% for placebo (p = 0.0044; Fig. 2). Results of the sensitivity analyses supported the primary analysis: the ITT-OC population responder rates during the maintenance period were 48% for zonisamide versus 31% for placebo (p = 0.0143), and for the PP-LOCF population (zonisamide n = 100; placebo n = 91) they were 51% for zonisamide versus 31% for placebo (p = 0.0046; Fig. 2). Similarly, for the ITT-OC population, responder rates during the entire double-blind period (titration + maintenance periods) were 44% for zonisamide versus 18% for placebo (p < 0.0001).

image

Figure 2. Responder rates (percentage of patients with ≥50% seizure frequency reduction) during the maintenance period for the ITT-LOCF (primary analysis), ITT-OC, and PP-LOCF populations. ITT, intention-to-treat; LOCF, last observation carried forward; OC, observed case; PP, per protocol.

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Secondary end points

The median percentage change from baseline in 28-day total seizure frequency during the maintenance period was −50% for zonisamide versus −24.5% for placebo (median between-group difference −25.2%; 95% CI −38.7, −12.2; p < 0.0001; ITT-LOCF; Fig. 3). Similarly, the median percentage change from baseline in 28-day total seizure frequency during the combined titration and maintenance periods was −42.2% for zonisamide versus −20.4% for placebo (median between-group difference −25.3%; 95% CI −37.3, −13.0; p < 0.0001; ITT-LOCF; Fig. 3). These findings were consistent across the ITT-OC and PP-LOCF analyses (data not shown).

image

Figure 3. Median percentage reduction from baseline in 28-day total seizure frequency during (A) maintenance period and (B) combined titration + maintenance periods (ITT-LOCF population).

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The proportion of patients demonstrating ≥75% seizure frequency reduction from baseline during the maintenance period was 27% for zonisamide versus 12% for placebo (p = 0.0064; ITT-LOCF). In addition, the proportion of patients demonstrating ≥25% increase in seizure frequency during the maintenance period was 10% for zonisamide versus 21% for placebo (p = 0.0330; ITT-LOCF), and the proportion of patients demonstrating ≥100% increase during the maintenance period was 5% for zonisamide versus 9% for placebo (p = not significant; ITT-LOCF). Similar results were observed during the combined titration + maintenance periods (data not shown).

Additional end points

The proportion of patients achieving seizure freedom during the maintenance period was significantly greater for zonisamide versus placebo (14% vs. 3%; p = 0.0049; ITT-LOCF). During the combined titration + maintenance periods, seizure freedom rates were 4% for zonisamide versus 2% for placebo (p = not significant; ITT-LOCF).

Analysis of the median percentage change from baseline in 28-day frequency by seizure type demonstrated a significantly greater reduction in simple partial seizures for zonisamide versus placebo during the combined titration + maintenance periods, and a similar trend toward significance (p = 0.0752) during the maintenance period (Table 2; ITT-LOCF). Reduction in complex partial seizures was significantly greater for zonisamide versus placebo during both the maintenance period and the combined titration + maintenance periods (Table 2; ITT-LOCF). Reduction in secondarily generalized seizures was numerically, but not significantly, greater for zonisamide versus placebo, with a trend toward significance during the combined titration + maintenance periods (p = 0.0578; Table 2; ITT-LOCF). The study was not powered to detect differences in efficacy by individual seizure type.

Table 2. Median percentage changes from baseline in seizure frequency by seizure type (ITT-LOCF population)
Seizure typePeriodMedian percentage change from baselineDifference between medians95% CIp-Value
PlaceboZonisamide
  1. CI, confidence interval; NS, not significant.

Simple partialMaintenance−43.0−61.3−16.0−34.0, 0.4NS (0.0752)
Titration + maintenance−31.9−47.1−19.1−37.3, −0.90.0278
Complex partialMaintenance−24.2−45.4−20.7−45.1, 0.00.0406
Titration + maintenance−18.6−40.2−22.9−44.3, −1.10.0210
Secondarily generalizedMaintenance−51.1−86.1−7.8−43.3, 0.0NS (0.1389)
Titration + Maintenance−40.1−69.8−20.0−45.1, 0.0NS (0.0578)

Logistic regression analysis did not reveal any statistically significant relationship between responder rate and zonisamide plasma concentration: odds ratios (95% CI; p-value) were 0.904 (0.654, 1.249; p = 0.5413) at week 12 and 1.096 (0.663, 1.810; p = 0.7216) at final visit.

Safety

The overall incidence of TEAEs was similar for zonisamide (55.1%) and placebo (50.0%); the incidence of treatment-related TEAEs was slightly higher for zonisamide (33.6%) than placebo (24.0%; Table 3). The most frequently reported TEAEs (≥5% patients in either group) were headache, decreased appetite, nasopharyngitis, and upper abdominal pain. TEAEs reported more frequently with zonisamide versus placebo were decreased appetite (6.5% vs. 4.0%), decreased weight (4.7% vs. 3.0%), somnolence (4.7% vs. 2.0%), vomiting (3.7% vs. 2.0%), and diarrhea (3.7% vs. 1.0%). Most TEAEs and treatment-related TEAEs were of mild or moderate intensity.

Table 3. Summary of TEAEs (safety population)
 PlaceboZonisamide
N = 100N = 107
  1. TEAE, treatment-emergent adverse event.

  2. a

    Some patients reported >1 serious TEAE.

Patients with TEAEs, n (%)50 (50.0)59 (55.1)
TEAEs reported by ≥3% patients in either group, n (%)  
Headache7 (7.0)7 (6.5)
Decreased appetite4 (4.0)7 (6.5)
Nasopharyngitis9 (9.0)6 (5.6)
Weight decreased3 (3.0)5 (4.7)
Somnolence2 (2.0)5 (4.7)
Viral upper respiratory tract infection3 (3.0)4 (3.7)
Pharyngitis3 (3.0)4 (3.7)
Vomiting2 (2.0)4 (3.7)
Diarrhea1 (1.0)4 (3.7)
Abdominal pain upper6 (6.0)2 (1.9)
Nausea4 (4.0)2 (1.9)
Abdominal pain3 (3.0)2 (1.9)
Pyrexia3 (3.0)2 (1.9)
Fatigue3 (3.0)0
Patients with TEAEs by severity, n (%)  
Mild29 (29.0)38 (35.5)
Moderate16 (16.0)18 (16.8)
Severe5 (5.0)3 (2.8)
Patients with treatment-related TEAEs, n (%)24 (24.0)36 (33.6)
Patients with treatment-related TEAEs by severity, n (%)  
Mild12 (12.0)22 (20.6)
Moderate9 (9.0)11 (10.3)
Severe3 (3.0)3 (2.8)
Patients with serious TEAEs,a n (%)2 (2.0)4 (3.7)
Patients with serious treatment-related TEAEs,a n (%)1 (1.0)2 (1.9)
Patients with TEAEs leading to withdrawal, n (%)3 (3.0)1 (0.9)
Patients with TEAEs leading to dose reduction, n (%)5 (5.0)3 (2.8)

Serious TEAEs were reported by four (3.7%) zonisamide patients and two (2.0%) placebo patients (Table 3). Two patients receiving zonisamide reported a total of four serious treatment-related TEAEs: one patient died due to de novo status epilepticus (considered possibly related to study treatment); another experienced severe weight loss (possibly related), moderately decreased blood glucose (possibly related), and moderate dehydration (possibly related). One patient receiving placebo reported two serious treatment-related TEAEs: severe vomiting (possibly related) and moderate somnolence (probably related).

There was only one withdrawal due to a TEAE with zonisamide (0.9%), versus three (3.0%) with placebo (Table 3). The TEAE leading to withdrawal of zonisamide was allergic dermatitis of moderate intensity, considered probably related to study treatment. In the placebo group, one patient discontinued due to upper abdominal pain of moderate intensity (possibly related); one discontinued due to aggressive behavior of moderate intensity (possibly related) and sleep disorder of mild intensity (possibly related); and one discontinued due to complex partial seizures of severe intensity (not related). TEAEs leading to dose reduction were fewer with zonisamide (2.8%) than with placebo (5.0%).

There were no clinically significant treatment-emergent laboratory abnormalities, and no clinically important changes in mean vital signs from baseline to final visit, in either treatment group. Bicarbonate levels decreased from baseline to final visit in the zonisamide group. These decreases were generally small to moderate, the mean decrease being −3.3 mm. The proportion of patients with a ≥3.5 mm decrease from baseline in bicarbonate levels was 50.5% for zonisamide versus 16.0% for placebo. Six zonisamide-treated patients (5.6%) and no placebo-treated patients had a bicarbonate value of ≤16 mm and a decrease from baseline of ≥6 mm. Decreased bicarbonate was reported as a TEAE in one zonisamide-treated patient. There were no reports of metabolic acidosis. There were no clinically significant electrocardiography abnormalities in any patients, at baseline or the final visit. Weight loss was reported as a TEAE by 4.7% of zonisamide-treated patients and 3.0% of placebo-treated subjects. Decreased body weight (>10%) was reported as a serious TEAE by one patient treated with zonisamide; their dose was unchanged and the event resolved without treatment. There were no notable differences between groups in physical or neurologic examination findings.

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

Results of this phase III, multicenter, randomized, double-blind, placebo-controlled trial clearly demonstrate that adjunctive zonisamide therapy at a target dose of 8 mg/kg/day is significantly more effective than placebo in treating children with partial epilepsy who are on a stable regimen of one or two AEDs. The primary analysis of efficacy was shown to be clinically relevant, the proportion of responders during the maintenance period being significantly higher with zonisamide versus placebo (50% vs. 31%; p = 0.0044; ITT-LOCF). The superior efficacy of zonisamide over placebo was confirmed by the responder rates observed during the entire double-blind period and by all secondary end points. These findings were further supported by an exploratory subgroup analysis of patients with clinically challenging complex partial seizures, for whom the median percentage reduction from baseline was significantly greater for zonisamide versus placebo during both the maintenance period and the entire double-blind period.

These results are similar to those of placebo-controlled trials of adjunctive levetiracetam and topiramate in refractory pediatric partial epilepsy (Elterman et al., 1999; Glauser et al., 2006). For example, ≥50% responder rates were 44.6% for levetiracetam versus 19.6% for placebo (p = 0.0002) (Glauser et al., 2006) and 39% for topiramate versus 20% for placebo (p = 0.080) (Elterman et al., 1999). Similarly, median percentage reductions from baseline in seizure frequency were 43.8% for levetiracetam versus 23.3% for placebo (p < 0.01) (Glauser et al., 2006) and 33.1% for topiramate versus 10.5% for placebo (p = 0.034) (Elterman et al., 1999). The seizure freedom rates observed during the maintenance period of the current trial (14% for zonisamide vs. 3% for placebo) were also similar to those reported for the maintenance period of the topiramate trial (10% for topiramate vs. 5% for placebo) (Elterman et al., 1999), whereas the seizure freedom rates observed during the entire double-blind period (4% for zonisamide vs. 2% for placebo) were similar to those reported for the entire double-blind periods of the levetiracetam trial (6.9% for levetiracetam vs. 1.0% for placebo) and the topiramate trial (5% for topiramate vs. 0% for placebo) (Elterman et al., 1999; Glauser et al., 2006).

Zonisamide was well tolerated compared with placebo in this study, with similar rates of TEAEs and low rates of serious TEAEs and TEAEs leading to discontinuation. One patient died due to de novo status epilepticus that appeared during zonisamide treatment. Decreased weight was reported as a TEAE more frequently with zonisamide than placebo (4.7% vs. 3.0%), as was decreased appetite (6.5% vs. 4.0%). These findings are consistent with previous reports from adjunctive studies in adult patients (Wellmer et al., 2009; Zonegran® Summary of Product Characteristics, 2012). The observed mean decrease in bicarbonate levels (−3.3 mm) was also similar to that previously reported (Zonegran® Summary of Product Characteristics, 2012). Zonisamide has an inhibitory effect on carbonic anhydrase that may lead to renal bicarbonate loss and metabolic acidosis (Zonegran® Summary of Product Characteristics, 2012). In the present trial, there were no reports of metabolic acidosis. Overall, no new or unexpected safety findings emerged from this trial, the safety profile of adjunctive zonisamide in pediatric patients being consistent with that observed in adult adjunctive zonisamide studies.

A potential limitation of the trial might have been the placebo response rate, which was higher than that observed in other trials (the ≥50% responder rate with placebo being 31% in the present trial, compared with approximately 20% in the levetiracetam and topiramate trials) (Elterman et al., 1999; Glauser et al., 2006). Pediatric patients with drug-resistant partial epilepsy who receive placebo in double-blind randomized controlled trials demonstrate significantly higher 50% response rates than adult patients, whereas response rates on active treatment do not differ significantly between pediatric and adult patients, and this has been suggested as a possible cause of falsely negative outcomes in pediatric placebo-controlled trials (Rheims et al., 2008). However, the relatively high placebo response rate in the present trial did not appear to affect the overall outcome, since zonisamide demonstrated clear and significant separation from placebo, with robust evidence of efficacy across the entire treatment period. In addition, the differential between responder rates achieved with active treatment versus placebo in the current trial (21%) was similar to those observed in the topiramate and levetiracetam trials (19% and 25%, respectively), as were the aforementioned seizure freedom rates observed in the three trials (Elterman et al., 1999; Glauser et al., 2006), indicating that the three patient populations are likely to have been broadly similar in terms of treatment refractoriness. Regional variations, which can influence outcomes in multinational, multicenter trials (Marschner, 2010), did not appear to affect the robustness of the current trial's findings.

This study demonstrated that adjunctive zonisamide therapy is effective and well tolerated in pediatric patients with refractory partial epilepsy, and could therefore prove to be a useful new treatment option for this patient population.

Acknowledgments

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

This study was funded by Eisai Ltd. Editorial support (checking of data, technical editing, copyediting, and preparation of tables and figures) was provided by Harjinder Chahal of mXm Medical Communications and funded by Eisai Ltd.

The trial's Principal Investigators were the following: Atul Agarwal (India), Mykola Aryayev (Ukraine), Stéphane Auvin (France), Jolanta Bielicka-Cymerman (Poland), Jaime Campistol (Spain), Jaime Campos Castello (Spain), Giuseppe Capovilla (Italy), Nicolas Deconinck (Belgium), Linda De Meirleir (Belgium), Ferenc Dicso (Hungary), Olivier Dulac (France), Ewa Emich-Widera (Poland), Guiseppe Gobbi (Italy), Jayaprakash Gosalakkal (United Kingdom), Tiziana Granata (Italy), Renzo Guerrini (Italy), Vineet Gupta (India), Anaita Udwadia Hegde (India), José Luis Herranz (Spain), Katalin Hollódy (Hungary), Shaik Afshan Jabeen (India), Sergiusz Jóźwiak (Poland), Rozália Kálmánchey (Hungary), Mária Kassay (Hungary), Anna Kelemen (Hungary), Katalin Kollar (Hungary), Lieven Lagae (Belgium), Andrew Lux (United Kingdom), Irina Makedonskaya (Ukraine), Josette Mancini (France), Elżbieta Marszał (Poland), Grazyna Martynowska (Poland), Lydiya Maryenko (Ukraine), Maria Mazurkiewicz-Bełdzińska (Poland), Chandrashekhar Meshram (India), Sergii Moskovko (Ukraine), Krysztof Musiatowicz (Poland), Shankara Nellikunja (India), Magda Neuwirth (Hungary), Dominique Parain (France), Jean-Michel Pedespan (France), Jean-Marc Pinard (France), Mykola Pityk (Ukraine), Tetyana Proskurina (Ukraine), Sangeeta H. Ravat (India), Guntis Rozentals (Latvia), Valentin Sander (Estonia), Wojciech Służewski (Poland), Barbara Steinborn (Poland), Inga Talvik (Estonia), Alessandra Tiberti (Italy), Baiba Uskane (Latvia), Louis Vallee (France), Pierangelo Veggiotti (Italy), Imre Velkey (Hungary), Helene Verhelst (Belgium), Vishwanathan (India), Petro Voloshyn (Ukraine), Stanislawa Watrobska (Poland), and Nandan Yardi (India).

Disclosure

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information

Dr. Guerrini has received honoraria from Biocodex, UCB, Eisai Inc, ValueBox, and EMA (European Medicines Agency). He has received research support from the Italian Ministry of Health, the European Community Sixth Framework Thematic Priority Life Sciences, Genomics and Biotechnology for Health, the Italian Ministry of Education, University and Research, the Tuscany Region, the Telethon Foundation, and the Mariani Foundation. Dr. Rosati reports no disclosures. Dr. Segieth is a former employee of Eisai Ltd. She was an employee of Eisai Ltd during the time when the trial was conducted and the current report was generated. Dr. Pellacani reports no disclosures. Ms. Bradshaw and Dr. Giorgi are employees of Eisai Ltd. 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.

References

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  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information
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Supporting Information

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure
  8. References
  9. Supporting Information
FilenameFormatSizeDescription
epi12233-sup-0001-FigS1.tifimage/tif386KFigure S1. Study design.

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