Psychiatry and Clinical Neurosciences 2015; 69: 640–648
doi:10.1111/pcn.12300
Regular Article
Efficacy and tolerability of levetiracetam as adjunctive therapy in Japanese patients with uncontrolled partial-onset seizures Yushi Inoue, MD,1* Kazuichi Yagi, MD,1,2 Akio Ikeda, MD,3 Mutsuo Sasagawa, MD,4 Shigenobu Ishida, MD,5 Atsushi Suzuki6 and Katsumi Yoshida6 on behalf of the Japan Levetiracetam N01221 Study Group† 1
NHO, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, 2Yaizu Hospital, Yaizu, 3Department of Epilepsy, Movement Disorders and Physiology, School of Medicine, Kyoto University, Kyoto, 4Toyosato Hospital, Tsukuba, 5 Akeno Medical Clinic, Ohita, and 6UCB Pharma, Tokyo, Japan
Aims: The aim of this study was to confirm the efficacy and safety of adjunctive levetiracetam in adult Japanese patients with uncontrolled partial-onset seizures. Methods: In a double-blind, placebo-controlled, confirmatory trial, eligible patients were randomized to receive levetiracetam 500, 1000, 2000, or 3000 mg/ day or placebo for 16 weeks. The primary end-point was percentage reduction from baseline in seizure frequency/week over a 12-week evaluation period. Tolerability assessments were also conducted. Findings of this and a previous randomized, double-blind trial were compared. Results: Of 401 patients screened, 352 were randomized and 316 completed the study. Median percentage reduction in seizure frequency/week from baseline was 12.92%, 18.00%, 11.11% and 31.67% in the levetiracetam 500, 1000, 2000 and 3000-mg groups, respectively, compared with 12.50% in the placebo group. Unlike the previous trial, the primary
PILEPSY IS A chronic neurological disorder that affects approximately 50 million people globally.1 Patients with newly diagnosed epilepsy are typically treated with a single antiepileptic drug (AED). If sei-
E
efficacy analysis between the levetiracetam 1000 and 3000-mg and placebo groups did not reach statistical significance (P = 0.067). Exploratory analyses demonstrated that the difference in seizure reduction versus placebo was 14.93% (95% confidence interval, 1.98–27.64; P = 0.025) for the levetiracetam 3000-mg group. All levetiracetam doses were well tolerated. The main difference between the two trials was a high placebo response in the present trial.
Conclusions: The primary efficacy analysis did not reach statistical significance, a finding that could be attributed to an unexpectedly high placebo response. Nonetheless, exploratory analysis suggests that levetiracetam at 3000 mg/day may, at least marginally, be beneficial for patients with uncontrolled partial-onset seizures. Key words: adjunctive therapy, antiepileptic drug, efficacy, levetiracetam, partial-onset seizures.
zures remain uncontrolled, patients can either switch their AED, or receive adjunctive treatment. In Japan, several newer AED have been available for treatment of patients with uncontrolled seizure since 2006.
*Correspondence: Yushi Inoue, MD, Shizuoka Institute of Epilepsy and Neurological Disorders, Urushiyama 886, Aoi-ku, Shizuoka 420-8688, Japan. Email: [email protected] This trial was registered with ClinicalTrials.gov (no. NCT00280696). † Members of the Japanese Levetiracetam N01221 Study Group are listed in Appendix S2. Received 31 October 2014; revised 16 March 2015; accepted 1 April 2015.
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© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
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Levetiracetam for partial-onset seizures 641
Levetiracetam (LEV) is a newer AED with a mechanism of action distinct from that of other AED. It has been shown to bind to, and modulate the activity of synaptic vesicle protein 2A (SV2A) in brain neurons.2–4 The efficacy and tolerability of LEV as adjunctive therapy for adults and children with partial-onset seizures (POS) has been demonstrated in both Caucasian and Asian patients.5–11 Comparison of LEV population pharmacokinetics in adult Caucasian and Japanese patients showed no ethnic differences in pharmacokinetics, other than those affected by bodyweight.12 In the first pivotal trial of LEV in Japanese patients with POS, two doses were evaluated, 1000 and 3000 mg/day.13 In this trial, median percentage reduction in seizure frequency/week from baseline was 19.61% (P = 0.005) and 27.72% (P = 0.007) in the levetiracetam 1000 and 3000-mg groups, respectively, compared with 6.11% in the placebo group.13 Following this trial in Japan, the objective of the present trial was to reconfirm the efficacy of LEV at 1000 and 3000 mg/day, and to evaluate the efficacy and safety of LEV at 500 and 2000 mg/day, as adjunctive therapy in Japanese patients with inadequately controlled POS.
Following randomization, the dosage for patients assigned to LEV 500 or 1000 mg/day was not up-titrated; they received three placebo tablets plus one LEV 250 mg or 500 mg tablet b.i.d., respectively. The dosage for patients randomized to LEV 2000 or 3000 mg/day was up-titrated in the following manner: all patients received LEV 1000 mg/day (500 mg tablet b.i.d.) and had their dosage increased by 1000 mg/day every 2 weeks until the target dose was reached. Patients assigned to placebo received the same four tablets.
METHODS This trial was conducted at 56 sites across Japan from November 2005 to November 2007 (NCT00280696). It was conducted in compliance with the ethical principles of the Declaration of Helsinki and consistent with the ‘Good Clinical Practice (GCP)’ provided in Articles of the Pharmaceutical Affairs Law. Institutional review board approval was obtained from each study center. All patients (or their parents/legal guardians) provided written informed consent.
Patients Male and female patients aged 16–65 years, weighing ≥ 40 kg, with a history of POS for >2 years, and confirmation on electroencephalography within 1 year prior to trial entry were eligible to participate. Patients who experienced POS ≥12 times during the baseline and at least twice every 4 weeks were able to continue the trial. Patients were taking 1−3 AED at trial entry (stable AED dosage for ≥4 weeks prior to screening). Use of select sedative, hypnotic or anxiolytic drugs and neuropsychiatric drugs (restricted non-AED) was allowed as long as the type, dosage and administration remained unchanged during the study period. Patients were excluded from the trial if they had experienced status epilepticus during the last 3 months or had undergone surgery for epilepsy within the last 2 years. Patients with progressive central nervous system disorders were also excluded, as were those with a history of mental illness or suicide attempts; alcohol or drug dependence; or history of treatment with LEV. In addition, pregnant or lactating female patients were excluded.
Trial design
Efficacy assessments
This was a double-blind, randomized, multicenter, placebo-controlled, parallel-group, trial. Patients were randomized to receive LEV at 500, 1000, 2000, or 3000 mg/day twice daily (b.i.d.) or placebo in a 1:1:1:1:1 ratio stratified by POS frequency during the baseline period. The trial consisted of a 12-week baseline period, a 4-week up-titration period, a 12-week evaluation period, and a 4-week down-titration or transition period (Fig. 1). All patients received four placebo tablets b.i.d. during the baseline period.
Seizures, recorded in a seizure diary, were classified according to the International League Against Epilepsy classification of 1981.14 The primary efficacy endpoint was the percentage reduction from baseline in POS frequency/week versus placebo for patients treated with LEV over the 12-week evaluation period. Secondary efficacy end-points included POS frequency/week over the evaluation period, 50% responder rate, and percentage of seizure-free patients over the evaluation period.
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
642 Y. Inoue et al.
Psychiatry and Clinical Neurosciences 2015; 69: 640–648
Placebo single-blind Baseline (12 weeks)
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Figure 1. Trial design.
Safety and tolerability assessments Safety and tolerability were assessed based on evaluation of treatment-emergent adverse events (TEAE), physical and neurological examination, laboratory tests (chemistry, hematology, and urinalysis), vital signs, and electrocardiography (ECG). We also recorded serious TEAE and treatment-emergent adverse drug reactions (ADR), defined as TEAE considered by the investigator as unlikely, possibly, probably or highly probably related to the study drug or as an AE with an unknown relation to the study drug.
Statistical analysis Based on the results of the previous trial,13 the probability that the observed percentage reduction in seizure frequency/week in the placebo group would be less than that of the LEV group was estimated at
0.644. To detect a treatment effect of this size, with 80% power and a 2-sided significance level of 5%, 64 patients per group (320 in total) were required. Assuming discontinuation rates of 10% after randomization, it was calculated that 352 patients needed to be randomized. The full analysis set (FAS) was used for efficacy variable analyses, based on an intention-to-treat principle. The FAS was defined as all randomized patients who received at least one dose of trial medication and had at least one post-baseline efficacy assessment. Taking multiplicity into account, primary efficacy analysis was performed using a closed-testing procedure with the following steps: (i) comparison of the percentage reduction in POS frequency/week from baseline over the evaluation period for placebo and the LEV 1000 and 3000-mg/day groups combined using the Kruskal–Wallis test; (ii) comparison of the LEV 1000-mg and placebo groups using the Wilcoxon
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2015; 69: 640–648
rank–sum test; and (iii) comparison of the LEV 3000-mg and placebo groups using the Wilcoxon rank-sum test. If comparisons were not statistically significant at any step (P-value > 5%), no further inferential analyses were conducted. For the secondary efficacy analyses, the POS frequency/week over the evaluation period was evaluated using analysis of covariance, with treatment group as the factor and baseline seizure frequency/week as the covariate after logarithmic transformation, using the same procedure as the previous trial.13 The 50% responder rate was evaluated by logistic regression analysis and odds ratios were calculated to assess treatment differences. These secondary efficacy analyses were also performed using a closed-testing procedure as for the primary analysis. Seizure freedom was also reported by treatment group. All safety analyses were performed on the safety set (SS), defined as all patients who took at least one dose of trial medication during the trial. AE were coded using MedDRA/J version 9.0 and laboratory tests and vital signs were summarized descriptively.
Levetiracetam for partial-onset seizures 643
RESULTS Demographics and baseline characteristics Of the 401 patients screened, 352 were randomized, with one randomized patient being excluded from the SS and FAS populations due to a study drug dispensing error during baseline (Fig. 2). As a result, 351 patients comprised the FAS population. Of the 351 patients, 316 patients completed the study, and 35 discontinued. The main reasons for discontinuation were AE and protocol violation in 14 and 12 patients, respectively. Demographic and baseline characteristics were similar across the treatment groups (Table 1). The percentage of patients who took restricted concomitant non-AED over the baseline was >30% for all treatment groups.
Efficacy analyses Primary efficacy variable The median percentage reduction from baseline in POS frequency/week over the evaluation period was
Screened N = 401 49 patients excluded due to screen failure Randomized N = 352 1 patient excluded due to drug dispensing error Full analysis set and safety set N = 351
Placebo n = 70
LEV 500 mg/day n = 71
LEV 1000 mg/day n = 70
LEV 2000 mg/day n = 70
LEV 3000 mg/day n = 70
Discontinued n=3 Adverse event 1 Protocol violation 1 Consent withdrawal 1
Discontinued n=9 Adverse event 2 Protocol violation 5 Consent withdrawal 1 Other reason 1
Discontinued n=6 Adverse event 1 Protocol violation 2 Lack/loss of efficacy 2 Consent withdrawal 1
Discontinued n=7 Adverse event 4 Protocol violation 1 Lack/loss of efficacy 1 1 Lost to follow-up
Discontinued n = 10 Adverse event 6 Protocol violation 3 Lack/loss of efficacy 1
Completed 95.7% (n = 67)
Completed 85.7% (n = 62)
Completed 91.4% (n = 64)
Completed 93.0% (n = 63)
Completed 85.7% (n = 60)
Figure 2. Patient disposition. LEV, levetiracetam.
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
644 Y. Inoue et al.
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Table 1. Demographic and baseline characteristics of trial participants (FAS population) Placebo (n = 70)
LEV 500 mg (n = 71)
Age (years) Mean (SD) 34.9 (12.56) 33.2 (10.64) Min–max 16.3–64.1 16.3–58.3 Sex Female, n (%) 35 (50.0) 36 (50.7) Weight (kg) Mean (SD) 60.2 (12.5) 61.3 (12.8) Epilepsy duration (years) Mean (SD) 16.3 (11.9) 16.4 (10.9) Age at onset (years) Mean (SD) 18.6 (12.1) 16.8 (11.7) Partial-onset seizure frequency (number/week) Median 3.00 2.67 Q1, Q3 1.42, 6.5 1.50, 6.08 Intellectual disability n (%) 20 (28.6) 24 (33.8) History of epilepsy surgery n (%) 10 (14.3) 8 (11.3) Use of restricted concomitant medicines n (%) 29 (41.4) 26 (36.6) Number of concomitant AED 1, n (%) 6 (8.6) 5 (7.0) 2, n (%) 28 (40.0) 25 (35.2) 3, n (%) 36 (51.4) 41 (57.7)
LEV 1000 mg (n = 70)
LEV 2000 mg (n = 70)
LEV 3000 mg (n = 70)
32.8 (10.90) 16.5–62.2
30.4 (10.06) 16.3–60.4
33.1 (11.72) 16.3–61.7
41 (58.6)
35 (50.0)
33 (47.1)
61.8 (12.3)
62.8 (16.5)
60.1 (12.6)
61.3 (13.4)
14.5 (8.9)
13.8 (9.6)
15.2 (10.3)
15.3 (10.4)
18.3 (11.9)
16.6 (9.9)
17.9 (12.8)
17.6 (11.7)
2.65 1.33, 5.75
2.78 1.50, 5.83
2.75 1.83, 5.08
3.21 1.58, 6.83
Overall (n = 351) 32.9 (11.23) 16.3–64.1 180 (51.3)
24 (34.3)
24 (34.3)
25 (35.7)
117 (33.3)
4 (5.7)
7 (10.0)
2 (2.7)
31 (8.8)
29 (41.4)
27 (38.6)
23 (32.9)
134 (38.2)
5 (7.1) 31 (44.3) 34 (48.6)
10 (14.3) 25 (35.7) 35 (50.0)
7 (10.0) 20 (28.6) 43 (61.4)
33 (9.4) 129 (36.8) 189 (53.8)
AED, antiepileptic drugs; LEV, levetiracetam; Q1, first quartile; Q3, third quartile; SD, standard deviation.
12.92% (first quartile [Q1]: −13.56%, third quartile [Q3]: 41.89%), 18.00% (Q1: −12.25%, Q3: 39.91%), 11.11% (Q1: −19.64%, Q3: 39.09%) and 31.67% (Q1: 0.00%, Q3: 52.07%) in the 500, 1000, 2000 and 3000-mg groups, respectively, compared with 12.50% (Q1: −5.81%, Q3: 31.25%) in the placebo group. The first comparison of efficacy between the combined LEV 1000 and 3000-mg/day and placebo groups did not show a significant difference (P = 0.067); therefore, the closed-testing procedure was stopped and subsequent comparisons were exploratory. The median difference in seizure reduction versus placebo (95% confidence interval [CI]) was 2.27% (−9.2–14.4%) for the LEV 1000-mg/day group (P = 0.700) and 14.9% (1.9–27.6%) for the LEV 3000-mg/day group (P = 0.025). Corresponding differences with placebo for the LEV 500 and 2000mg/day groups were 0.43% (−12.3–13.2%) and
−2.1% (−15.3–10.3%), respectively; these results were not statistically significant. Secondary efficacy variables Results for the secondary efficacy variable using logarithmic-transformed POS frequency/week were consistent with those of the primary analysis for the comparison of the LEV 1000-mg and LEV 3000-mg/ day groups versus placebo. POS frequency/week with LEV (pooled 1000 and 3000-mg/day groups) was not significantly different than that for placebo (7.2% reduction over placebo; 95%CI: −3.9–17.1%; P = 0.197) and the closed-testing procedure was stopped. Subsequent comparisons were therefore exploratory. The percentage reduction in POS frequency/week compared with placebo (95%CI) was 3.2% (−10.2–15.0%) for the LEV 1000-mg group (P = 0.619) and 10.9% (−1.6–21.8%) for the LEV
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2015; 69: 640–648
Patients with ≥50% response (%)
40 35
33.3%
30 25 19.1%
20 15
17.6%
16.2%
statistically non-significant results (P = 0.226 and P = 0.440, respectively; Fig. 3). No patients in the placebo or LEV 500-mg/day groups became seizure-free over the evaluation period; however, two patients in each of other LEV groups (six in total) became free of any type of seizure.
11.6%
10
Safety and tolerability
5 0
Levetiracetam for partial-onset seizures 645
Placebo (n = 69)
500 mg (n = 68)
1000 mg 2000 mg 3000 mg (n = 68) (n = 68) (n = 69) Levetiracetam
Comparison vs placebo
Odds ratio (95%Cl)
P-value
Levetiracetam 1000+3000 mg
2.6 (1.1–6.0)
0.025*
Levetiracetam 1000 mg
1.6 (0.6–4.3)
0.319
Levetiracetam 3000 mg
3.8 (1.6–9.4)
0.003†
Levetiracetam 500 mg
1.8 (0.7–4.7)
0.226
Levetiracetam 2000 mg
1.5 (0.6–3.9)
0.440
*Significant using closed-testing analysis †
Exploratory due to non-significance of the previous step (comparison to placebo and 1000 mg group)
Figure 3. Patients with at least 50% reduction in seizure frequency (50% responder rates) during the evaluation period. Only patients with values at both baseline (values > 0) and evaluation (values ≥ 0) periods were included in the analysis.
3000-mg group (P = 0.084). Corresponding differences with placebo for the LEV 500 and 2000-mg/day groups were 2.1% (−11.6–14.0%) and −0.3% (−14.3–11.9%), respectively; these results were not statistically significant. The ≥50% responder rates over the evaluation period for the LEV 500, 1000, 2000, 3000-mg/day and placebo groups were 19.1%, 17.6%, 16.2%, 33.3% and 11.6%, respectively (Fig. 3). Logistic regression analysis showed a significant difference between the pooled LEV (1000 and 3000-mg/day) and placebo groups (P = 0.025, Fig. 3). Comparison of efficacy between the placebo and LEV 1000-mg/day groups was not significant (P = 0.319) and the closed-testing procedure was stopped. Exploratory statistical testing of the LEV 3000-mg/day group versus placebo showed a significant treatment effect (P = 0.003). Evaluations of LEV 500 and 2000 mg/day versus placebo yielded
At least one TEAE was reported by 79.2% (278/351) of patients during the titration and evaluation periods. ADR with an incidence of ≥5% in any group are presented in Table 2. The most common ADR in the LEV groups during the up-titration and evaluation period were nasopharyngitis (49 patients, 17.4%) and somnolence (36 patients, 12.8%). The majority of TEAE and ADR in each group were mild in intensity. Serious TEAE and ADR were reported by 12 (3.4%) and eight (2.3%) patients, respectively, during the titration and evaluation period; brain contusion and status epilepticus in the placebo group; convulsion in the LEV 500-mg/day group; ventricular tachycardia in the LEV 1000-mg/day group; cognitive impairment in the LEV 2000-mg/day group; and gastric cancer, contusion and insomnia/irritability/anxiety in the LEV 3000-mg/day group. One patient (LEV 3000 mg/day) died during this study due to advanced gastric cancer. The investigator judged a causal relation between the study medication and gastric cancer as unlikely. No patients showed any clinically relevant changes from baseline in hematology, vital signs, ECG variables or blood chemistry.
Adverse events leading to discontinuation Eighteen patients discontinued due to AE: two (1.4%) in the placebo group, and four (4.2%), one (1.4%), five (5.7%), and six (7.1%) in the LEV 500, 1000, 2000 and 3000-mg/day groups, respectively. AE leading to discontinuation reported by two patients were status epilepticus (placebo group), dizziness (LEV 2000 mg/day), convulsion (LEV 500 mg/ day), epilepsy (2000 mg/day), somnolence (LEV 3000 mg/day), decreased neutrophil count (LEV 500 mg/day), and decreased white blood cell count (LEV 3000 mg/day) (14 patients in total). The remaining four AE occurred in individual patients. Of the 18 patients, eight discontinued due to SAE.
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
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Psychiatry and Clinical Neurosciences 2015; 69: 640–648
Table 2. Summary of TEAE and ADR reported during the treatment period (up-titration and evaluation periods) [Safety Set]
Placebo n = 70 n (%) At least one TEAE 57 (81.4) Discontinuation due to TEAE 1 (1.4) Serious TEAE 3 (4.3) At least one ADR 41 (58.6) At least one serious ADR 2 (2.9) Number of deaths 0 ADR reported by >5% of patients in any group Nasopharyngitis 8 (11.4) Somnolence 5 (7.1) Contusion 2 (2.9) Dizziness 3 (4.3) Diarrhea 3 (4.3) Headache 9 (12.9) Neutrophil count decreased 1 (1.4) White blood cell count increased 4 (5.7) Abdominal pain 2 (2.9)
LEV 500 mg n = 71 n (%)
LEV 1000 mg n = 70 n (%)
LEV 2000 mg n = 70 n (%)
LEV 3000 mg n = 70 n (%)
56 (78.9) 3 (4.2) 2 (2.8) 43 (60.6) 1 (1.4) 0
57 (81.4) 1 (1.4) 2 (2.9) 43 (61.4) 1 (1.4) 0
53 (75.7) 4 (5.7) 1 (1.4) 41 (58.6) 1 (1.4) 0
55 (78.6) 5 (7.1) 4 (5.7) 45 (64.3) 3 (4.3) 1 (1.4)
10 (14.1) 5 (7.0) 1 (1.4) 5 (7.0) 7 (9.9) 4 (5.6) 3 (4.2) 0 4 (5.6)
13 (18.6) 7 (10.0) 0 1 (1.4) 2 (2.9) 1 (1.4) 2 (2.9) 0 0
11 (15.7) 12 (17.1) 5 (7.1) 4 (5.7) 0 2 (2.9) 1 (1.4) 0 1 (1.4)
15 (21.4) 12 (17.1) 3 (4.3) 4 (5.7) 1 (1.4) 3 (4.3) 5 (7.1) 1 (1.4) 0
ADR, adverse drug reactions; LEV, levetiracetam; TEAE, treatment-emergent adverse events.
DISCUSSION The primary goal of the present trial was to evaluate the safety and efficacy of LEV in patients with uncontrolled POS. The median percentage reduction in seizure frequency/week was 12.50% in the placebo group and 12.92%, 18.00%, 11.11% and 31.67% in the LEV 500, 1000, 2000 and 3000-mg/ day groups, respectively. The first-step comparison of the efficacy of the LEV 1000-mg/day, 3000-mg/ day, and placebo groups did not show a significant difference (P = 0.067). Secondary efficacy analysis using logarithmic-transformed POS frequency was consistent with the results of the primary analysis. POS frequency/week for LEV (pooled 1000 and 3000-mg/day groups) was not significantly different from that for placebo. As LEV (pooled 1000 and 3000 mg/day) was found to significantly reduce POS frequency compared with placebo (20.9% [95%CI: 10.2–30.4%], P < 0.001) in the previous trial,13 the results remain controversial. To identify potential reasons for the discrepancy, we looked into the differences between the trials. First, placebo responses differed substantially between the two trials. In the previous trial, the
median percentage reduction in seizure frequency reported with the LEV 1000-mg/day, 3000-mg/day and placebo groups were 19.61%, 27.72%, and 6.11%, respectively.13 In contrast, corresponding values in the present trial were 18.00%, 31.67%, and 12.50%. Although LEV efficacy was similar in these two trials, a marked difference in the placebo response was apparent. The high placebo response in this trial is the most likely explanation for the lack of significant difference between the LEV and placebo groups. However, the causes of this high placebo response in the present trial could not be identified with any post-hoc analyses we could conceive; for example, investigations of demographic factors and individual seizure statuses. A number of important differences in the population characteristics of the two trials should also be noted (Appendix S1). The proportion of patients who took restricted concomitant non-AED was 8.5% in the previous investigation and 38.2% in this trial. This suggests that the population in the present trial might have included more patients with complicated mental status, requiring non-AED to control disorders or symptoms associated with epilepsy and to maintain quality of life compared to the previous trial.
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
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The proportion of patients with intellectual disability was higher in this trial (33.3%) than in the previous one (8.0%). Among individuals with intellectual disability, seizures tend to occur more frequently than in those without disability; seizures also tend to be more complex, severe and refractory to treatment;15–18 therefore, patients in this study were also considered to represent a more refractory population. Other differences between the populations included age, age at epilepsy onset and history of epilepsy surgery. In summary, patient characteristics might have differed sufficiently between the two trials to have contributed to the inconsistent efficacy results. In comparing the present with overseas trials, the population of the present trial included more refractory patients from the perspective of the number of concomitant AED. The proportion of patients treated with more than three concomitant AED at initiation of LEV was much higher in the present trial (53.8%) than in European (5%)6 and US (5–8%)5 trials. Although the population of a Taiwanese trial included a high proportion of patients who took more than three concomitant AED (34.0–44.7%),9 this proportion was still lower than that seen in our trial. Such results suggest that the population in the present trial may have been unexpectedly unique compared to those of other successful LEV trials. The efficacy of LEV 2000 mg/day was lower than that of 1000 mg/day in this trial. In contrast, Boon et al. demonstrated a dose–response effect of LEV.19 Furthermore, Shorvon et al. and Tsai et al. demonstrated significant efficacy of 2000 mg/day compared to placebo.6,9 From the results of overseas trials, LEV is highly unlikely to have a biphasic effect and the low efficacy of the 2000-mg group may be due to the influence of some unique characteristics of the trial population. The causes of the low response of LEV 2000 mg could not be identified nor for the high placebo response even after performing every conceivable post-hoc analysis. Although analysis of the primary objective did not demonstrate a statistically significant difference between the LEV 1000-mg/day, 3000-mg/day and placebo groups, in the subsequent exploratory comparisons, the median difference in seizure reduction versus placebo was 14.93% for the LEV 3000-mg/day group (P = 0.025). Furthermore, 50% responder rates in the pooled LEV (1000 and 3000 mg/day) and LEV 3000-mg/day groups were significantly higher than that observed in the placebo group (P = 0.025, P = 0.003, respectively). While the factors discussed
above could explain the difference in the efficacy findings of the two trials to a certain extent, pooling data from the two pivotal trials could also help re-evaluate the efficacy of LEV in Japanese patients with uncontrolled POS. Six patients became seizurefree in this trial, two in each of the LEV treatment groups with the exception of the LEV 500-mg/day group. In contrast, no seizure-free patients were encountered in the placebo group. All LEV doses in the present study were well tolerated. The safety profile was consistent with that of the previous trial and resembled those observed in international LEV trials. In post-marketing studies, LEV has often shown a higher incidence of behavioral abnormalities, particularly in patients with biological vulnerability.20,21 Clinical monitoring with regard to behavioral abnormalities in such high-risk patients may be required in practical settings. In conclusion, the primary efficacy end-point did not reach statistical significance for either dose of LEV in this study, a finding that was inconsistent with that of the previous trial. The high placebo effect in this trial and differences in patient populations between the two trials may have contributed to these apparently contradictory findings. In exploratory analyses, treatment with LEV 3000 mg/day clearly reduced the frequency of seizures. Furthermore, clear separation from placebo was observed on one of the secondary efficacy outcomes for LEV (≥50% responder rate; 1000 and 3000-mg/day pooled data) in this study. LEV was well tolerated, and safety findings were consistent with the known safety profile of LEV. These results suggest that adjunctive treatment with LEV at 3000 mg/day may represent a suitable option for patients with uncontrolled POS in Japan.
ACKNOWLEDGMENTS This trial was sponsored by UCB Pharma. Atsushi Suzuki and Katsumi Yoshida are employees of UCB Pharma. According to the Conflict of Interest guidelines of The Japan Epilepsy Society, Dr Inoue reports receiving writing fees from Dainippon-Sumitomo; Dr Yagi, consulting fees from UCB and honoraria and speaking fees from Dainippon-Sumitomo, Kyowa-Kirin and Otsuka; Dr Sasagawa, speaker fees from Otsuka, GSK and Kyowa-Kirin; Dr Ishida, speaker fees from Otsuka and GSK; and Dr Ikeda, grant support and speaker fees from DainipponSumitomo, Kyowa-Kirin, UCB Pharma, GSK and Otsuka. Dr Ikeda is a recipient of an endowed chair
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supported by multiple companies, including UCB Pharma, but not at the time when this trial was being conducted and data finalized. Other authors have no conflicts of interest to report. The authors thank Max Frenzel PhD (QXV Communications, Macclesfield, UK) and Azita Tofighy PhD, UCB Pharma, for assistance with writing the manuscript, and Mayumi Yamada PhD UCB Pharma, for coordinating manuscript preparation.
11. Heo K, Lee BI, Yi SD et al. Efficacy and safety of levetiracetam as adjunctive treatment of refractory partial seizures in a multicentre open-label single-arm trial in Korean patients. Seizure 2007; 16: 402–409. 12. Stockis A, Lu S, Tonner F, Otoul C. Clinical pharmacology of levetiracetam for the treatment of epilepsy. Expert Rev. Clin. Pharmacol. 2009; 2: 339–350. 13. Yagi K, Kameyama S, Kaneko S, Murasaki M, Yamauchi T. Multicenter, double-blind, randomized, placebocontrolled study of levetiracetam as add-on therapy in Japanese patients with uncontrolled partial seizures. J. Jpn. Epil. Soc. 2010; 28: 3–16 (in Japanese). 14. International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1981; 22: 489–501. 15. Bowley C, Kerr M. Epilepsy and intellectual disability. J. Intellect. Disabil. Res. 2000; 44: 529–543. 16. Martin JP, Brown SW. Best clinical and research practice in adults with an intellectual disability. Epilepsy Behav. 2009; 15 (Suppl 1): S64–S68. 17. Sillanpää M. Learning disability: Occurrence and longterm consequences in childhood-onset epilepsy. Epilepsy Behav. 2004; 5: 937–944. 18. Beavis J, Kerr M, Marson AG, Dojcinov I. Pharmacological interventions for epilepsy in people with intellectual disabilities. Cochrane Database Syst. Rev. 2007; (3)CD005399. 19. Boon P, Chauvel P, Pohlmann-Eden B, Otoul C, Wroe S. Dose-response effect of levetiracetam 1000 and 2000mg/ day in partial epilepsy. Epilepsy Res. 2002; 48: 77–89. 20. Mula M, Trimble MR, Yuen A, Liu RS, Sander JW. Psychiatric adverse events during levetiracetam therapy. Neurology 2003; 61: 704–706. 21. White JR, Walczak TS, Leppik IE et al. Discontinuation of levetiracetam because of behavioral side effects: A casecontrol study. Neurology 2003; 61: 1218–1221.
REFERENCES 1. de Boer HM, Mula M, Sander JW. The global burden and stigma of epilepsy. Epilepsy Behav. 2008; 12: 540–546. 2. Lynch BA, Lambeng N, Nocka K et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 9861–9866. 3. Kaminski RM, Gillard M, Leclercq K et al. Proepileptic phenotype of SV2A deficient mice is associated with reduced anticonvulsant efficacy of levetiracetam. Epilepsia 2009; 50: 1729–1740. 4. Kaminski RM, Matagne A, Leclercq K et al. SV2A protein is a broad-spectrum anticonvulsant target: Functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy. Neuropharmacology 2008; 54: 715–720. 5. Cereghino JJ, Biton V, Abou-Khalil B, Dreifuss F, Gauer LJ, Leppik I. Levetiracetam for partial seizures: Results of a double-blind, randomized clinical trial. Neurology 2000; 55: 236–242. 6. Shorvon SD, Löwenthal A, Janz D, Bielen E, Loiseau P. Multicenter double-blind, randomized, placebocontrolled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group. Epilepsia 2000; 41: 1179– 1186. 7. Glauser TA, Ayala R, Elterman RD et al. Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology 2006; 66: 1654–1660. 8. Piña-Garza JE, Nordli DR Jr, Rating D, Yang H, Schiemann-Delgado J, Duncan B. Adjunctive levetiracetam in infants and young children with refractory partial-onset seizures. Epilepsia 2009; 50: 1141–1149. 9. Tsai JJ, Yen DJ, Hsih MS et al. Efficacy and safety of levetiracetam (up to 2000 mg/day) in Taiwanese patients with refractory partial seizures: A multicenter, randomized, double-blind, placebo-controlled study. Epilepsia 2006; 47: 72–81. 10. Wu XY, Hong Z, Wu X et al. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in Chinese patients with refractory partialonset seizures. Epilepsia 2009; 50: 398–405.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Appendix S1. Demographic and baseline characteristics of patients (full analysis set [FAS] population) in the first pivotal trial in Japan (N0165) evaluating the efficacy and safety of adjunctive levetiracetam in patients with partial-onset seizures (modified from Yagi K et al. J Jpn Epil Soc 2010; 28: 3–16). Appendix S2. Members of the Japanese levetiracetam N01221 Study Group
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
doi:10.1111/pcn.12300
Regular Article
Efficacy and tolerability of levetiracetam as adjunctive therapy in Japanese patients with uncontrolled partial-onset seizures Yushi Inoue, MD,1* Kazuichi Yagi, MD,1,2 Akio Ikeda, MD,3 Mutsuo Sasagawa, MD,4 Shigenobu Ishida, MD,5 Atsushi Suzuki6 and Katsumi Yoshida6 on behalf of the Japan Levetiracetam N01221 Study Group† 1
NHO, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, 2Yaizu Hospital, Yaizu, 3Department of Epilepsy, Movement Disorders and Physiology, School of Medicine, Kyoto University, Kyoto, 4Toyosato Hospital, Tsukuba, 5 Akeno Medical Clinic, Ohita, and 6UCB Pharma, Tokyo, Japan
Aims: The aim of this study was to confirm the efficacy and safety of adjunctive levetiracetam in adult Japanese patients with uncontrolled partial-onset seizures. Methods: In a double-blind, placebo-controlled, confirmatory trial, eligible patients were randomized to receive levetiracetam 500, 1000, 2000, or 3000 mg/ day or placebo for 16 weeks. The primary end-point was percentage reduction from baseline in seizure frequency/week over a 12-week evaluation period. Tolerability assessments were also conducted. Findings of this and a previous randomized, double-blind trial were compared. Results: Of 401 patients screened, 352 were randomized and 316 completed the study. Median percentage reduction in seizure frequency/week from baseline was 12.92%, 18.00%, 11.11% and 31.67% in the levetiracetam 500, 1000, 2000 and 3000-mg groups, respectively, compared with 12.50% in the placebo group. Unlike the previous trial, the primary
PILEPSY IS A chronic neurological disorder that affects approximately 50 million people globally.1 Patients with newly diagnosed epilepsy are typically treated with a single antiepileptic drug (AED). If sei-
E
efficacy analysis between the levetiracetam 1000 and 3000-mg and placebo groups did not reach statistical significance (P = 0.067). Exploratory analyses demonstrated that the difference in seizure reduction versus placebo was 14.93% (95% confidence interval, 1.98–27.64; P = 0.025) for the levetiracetam 3000-mg group. All levetiracetam doses were well tolerated. The main difference between the two trials was a high placebo response in the present trial.
Conclusions: The primary efficacy analysis did not reach statistical significance, a finding that could be attributed to an unexpectedly high placebo response. Nonetheless, exploratory analysis suggests that levetiracetam at 3000 mg/day may, at least marginally, be beneficial for patients with uncontrolled partial-onset seizures. Key words: adjunctive therapy, antiepileptic drug, efficacy, levetiracetam, partial-onset seizures.
zures remain uncontrolled, patients can either switch their AED, or receive adjunctive treatment. In Japan, several newer AED have been available for treatment of patients with uncontrolled seizure since 2006.
*Correspondence: Yushi Inoue, MD, Shizuoka Institute of Epilepsy and Neurological Disorders, Urushiyama 886, Aoi-ku, Shizuoka 420-8688, Japan. Email: [email protected] This trial was registered with ClinicalTrials.gov (no. NCT00280696). † Members of the Japanese Levetiracetam N01221 Study Group are listed in Appendix S2. Received 31 October 2014; revised 16 March 2015; accepted 1 April 2015.
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Levetiracetam (LEV) is a newer AED with a mechanism of action distinct from that of other AED. It has been shown to bind to, and modulate the activity of synaptic vesicle protein 2A (SV2A) in brain neurons.2–4 The efficacy and tolerability of LEV as adjunctive therapy for adults and children with partial-onset seizures (POS) has been demonstrated in both Caucasian and Asian patients.5–11 Comparison of LEV population pharmacokinetics in adult Caucasian and Japanese patients showed no ethnic differences in pharmacokinetics, other than those affected by bodyweight.12 In the first pivotal trial of LEV in Japanese patients with POS, two doses were evaluated, 1000 and 3000 mg/day.13 In this trial, median percentage reduction in seizure frequency/week from baseline was 19.61% (P = 0.005) and 27.72% (P = 0.007) in the levetiracetam 1000 and 3000-mg groups, respectively, compared with 6.11% in the placebo group.13 Following this trial in Japan, the objective of the present trial was to reconfirm the efficacy of LEV at 1000 and 3000 mg/day, and to evaluate the efficacy and safety of LEV at 500 and 2000 mg/day, as adjunctive therapy in Japanese patients with inadequately controlled POS.
Following randomization, the dosage for patients assigned to LEV 500 or 1000 mg/day was not up-titrated; they received three placebo tablets plus one LEV 250 mg or 500 mg tablet b.i.d., respectively. The dosage for patients randomized to LEV 2000 or 3000 mg/day was up-titrated in the following manner: all patients received LEV 1000 mg/day (500 mg tablet b.i.d.) and had their dosage increased by 1000 mg/day every 2 weeks until the target dose was reached. Patients assigned to placebo received the same four tablets.
METHODS This trial was conducted at 56 sites across Japan from November 2005 to November 2007 (NCT00280696). It was conducted in compliance with the ethical principles of the Declaration of Helsinki and consistent with the ‘Good Clinical Practice (GCP)’ provided in Articles of the Pharmaceutical Affairs Law. Institutional review board approval was obtained from each study center. All patients (or their parents/legal guardians) provided written informed consent.
Patients Male and female patients aged 16–65 years, weighing ≥ 40 kg, with a history of POS for >2 years, and confirmation on electroencephalography within 1 year prior to trial entry were eligible to participate. Patients who experienced POS ≥12 times during the baseline and at least twice every 4 weeks were able to continue the trial. Patients were taking 1−3 AED at trial entry (stable AED dosage for ≥4 weeks prior to screening). Use of select sedative, hypnotic or anxiolytic drugs and neuropsychiatric drugs (restricted non-AED) was allowed as long as the type, dosage and administration remained unchanged during the study period. Patients were excluded from the trial if they had experienced status epilepticus during the last 3 months or had undergone surgery for epilepsy within the last 2 years. Patients with progressive central nervous system disorders were also excluded, as were those with a history of mental illness or suicide attempts; alcohol or drug dependence; or history of treatment with LEV. In addition, pregnant or lactating female patients were excluded.
Trial design
Efficacy assessments
This was a double-blind, randomized, multicenter, placebo-controlled, parallel-group, trial. Patients were randomized to receive LEV at 500, 1000, 2000, or 3000 mg/day twice daily (b.i.d.) or placebo in a 1:1:1:1:1 ratio stratified by POS frequency during the baseline period. The trial consisted of a 12-week baseline period, a 4-week up-titration period, a 12-week evaluation period, and a 4-week down-titration or transition period (Fig. 1). All patients received four placebo tablets b.i.d. during the baseline period.
Seizures, recorded in a seizure diary, were classified according to the International League Against Epilepsy classification of 1981.14 The primary efficacy endpoint was the percentage reduction from baseline in POS frequency/week versus placebo for patients treated with LEV over the 12-week evaluation period. Secondary efficacy end-points included POS frequency/week over the evaluation period, 50% responder rate, and percentage of seizure-free patients over the evaluation period.
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Placebo single-blind Baseline (12 weeks)
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Figure 1. Trial design.
Safety and tolerability assessments Safety and tolerability were assessed based on evaluation of treatment-emergent adverse events (TEAE), physical and neurological examination, laboratory tests (chemistry, hematology, and urinalysis), vital signs, and electrocardiography (ECG). We also recorded serious TEAE and treatment-emergent adverse drug reactions (ADR), defined as TEAE considered by the investigator as unlikely, possibly, probably or highly probably related to the study drug or as an AE with an unknown relation to the study drug.
Statistical analysis Based on the results of the previous trial,13 the probability that the observed percentage reduction in seizure frequency/week in the placebo group would be less than that of the LEV group was estimated at
0.644. To detect a treatment effect of this size, with 80% power and a 2-sided significance level of 5%, 64 patients per group (320 in total) were required. Assuming discontinuation rates of 10% after randomization, it was calculated that 352 patients needed to be randomized. The full analysis set (FAS) was used for efficacy variable analyses, based on an intention-to-treat principle. The FAS was defined as all randomized patients who received at least one dose of trial medication and had at least one post-baseline efficacy assessment. Taking multiplicity into account, primary efficacy analysis was performed using a closed-testing procedure with the following steps: (i) comparison of the percentage reduction in POS frequency/week from baseline over the evaluation period for placebo and the LEV 1000 and 3000-mg/day groups combined using the Kruskal–Wallis test; (ii) comparison of the LEV 1000-mg and placebo groups using the Wilcoxon
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rank–sum test; and (iii) comparison of the LEV 3000-mg and placebo groups using the Wilcoxon rank-sum test. If comparisons were not statistically significant at any step (P-value > 5%), no further inferential analyses were conducted. For the secondary efficacy analyses, the POS frequency/week over the evaluation period was evaluated using analysis of covariance, with treatment group as the factor and baseline seizure frequency/week as the covariate after logarithmic transformation, using the same procedure as the previous trial.13 The 50% responder rate was evaluated by logistic regression analysis and odds ratios were calculated to assess treatment differences. These secondary efficacy analyses were also performed using a closed-testing procedure as for the primary analysis. Seizure freedom was also reported by treatment group. All safety analyses were performed on the safety set (SS), defined as all patients who took at least one dose of trial medication during the trial. AE were coded using MedDRA/J version 9.0 and laboratory tests and vital signs were summarized descriptively.
Levetiracetam for partial-onset seizures 643
RESULTS Demographics and baseline characteristics Of the 401 patients screened, 352 were randomized, with one randomized patient being excluded from the SS and FAS populations due to a study drug dispensing error during baseline (Fig. 2). As a result, 351 patients comprised the FAS population. Of the 351 patients, 316 patients completed the study, and 35 discontinued. The main reasons for discontinuation were AE and protocol violation in 14 and 12 patients, respectively. Demographic and baseline characteristics were similar across the treatment groups (Table 1). The percentage of patients who took restricted concomitant non-AED over the baseline was >30% for all treatment groups.
Efficacy analyses Primary efficacy variable The median percentage reduction from baseline in POS frequency/week over the evaluation period was
Screened N = 401 49 patients excluded due to screen failure Randomized N = 352 1 patient excluded due to drug dispensing error Full analysis set and safety set N = 351
Placebo n = 70
LEV 500 mg/day n = 71
LEV 1000 mg/day n = 70
LEV 2000 mg/day n = 70
LEV 3000 mg/day n = 70
Discontinued n=3 Adverse event 1 Protocol violation 1 Consent withdrawal 1
Discontinued n=9 Adverse event 2 Protocol violation 5 Consent withdrawal 1 Other reason 1
Discontinued n=6 Adverse event 1 Protocol violation 2 Lack/loss of efficacy 2 Consent withdrawal 1
Discontinued n=7 Adverse event 4 Protocol violation 1 Lack/loss of efficacy 1 1 Lost to follow-up
Discontinued n = 10 Adverse event 6 Protocol violation 3 Lack/loss of efficacy 1
Completed 95.7% (n = 67)
Completed 85.7% (n = 62)
Completed 91.4% (n = 64)
Completed 93.0% (n = 63)
Completed 85.7% (n = 60)
Figure 2. Patient disposition. LEV, levetiracetam.
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Table 1. Demographic and baseline characteristics of trial participants (FAS population) Placebo (n = 70)
LEV 500 mg (n = 71)
Age (years) Mean (SD) 34.9 (12.56) 33.2 (10.64) Min–max 16.3–64.1 16.3–58.3 Sex Female, n (%) 35 (50.0) 36 (50.7) Weight (kg) Mean (SD) 60.2 (12.5) 61.3 (12.8) Epilepsy duration (years) Mean (SD) 16.3 (11.9) 16.4 (10.9) Age at onset (years) Mean (SD) 18.6 (12.1) 16.8 (11.7) Partial-onset seizure frequency (number/week) Median 3.00 2.67 Q1, Q3 1.42, 6.5 1.50, 6.08 Intellectual disability n (%) 20 (28.6) 24 (33.8) History of epilepsy surgery n (%) 10 (14.3) 8 (11.3) Use of restricted concomitant medicines n (%) 29 (41.4) 26 (36.6) Number of concomitant AED 1, n (%) 6 (8.6) 5 (7.0) 2, n (%) 28 (40.0) 25 (35.2) 3, n (%) 36 (51.4) 41 (57.7)
LEV 1000 mg (n = 70)
LEV 2000 mg (n = 70)
LEV 3000 mg (n = 70)
32.8 (10.90) 16.5–62.2
30.4 (10.06) 16.3–60.4
33.1 (11.72) 16.3–61.7
41 (58.6)
35 (50.0)
33 (47.1)
61.8 (12.3)
62.8 (16.5)
60.1 (12.6)
61.3 (13.4)
14.5 (8.9)
13.8 (9.6)
15.2 (10.3)
15.3 (10.4)
18.3 (11.9)
16.6 (9.9)
17.9 (12.8)
17.6 (11.7)
2.65 1.33, 5.75
2.78 1.50, 5.83
2.75 1.83, 5.08
3.21 1.58, 6.83
Overall (n = 351) 32.9 (11.23) 16.3–64.1 180 (51.3)
24 (34.3)
24 (34.3)
25 (35.7)
117 (33.3)
4 (5.7)
7 (10.0)
2 (2.7)
31 (8.8)
29 (41.4)
27 (38.6)
23 (32.9)
134 (38.2)
5 (7.1) 31 (44.3) 34 (48.6)
10 (14.3) 25 (35.7) 35 (50.0)
7 (10.0) 20 (28.6) 43 (61.4)
33 (9.4) 129 (36.8) 189 (53.8)
AED, antiepileptic drugs; LEV, levetiracetam; Q1, first quartile; Q3, third quartile; SD, standard deviation.
12.92% (first quartile [Q1]: −13.56%, third quartile [Q3]: 41.89%), 18.00% (Q1: −12.25%, Q3: 39.91%), 11.11% (Q1: −19.64%, Q3: 39.09%) and 31.67% (Q1: 0.00%, Q3: 52.07%) in the 500, 1000, 2000 and 3000-mg groups, respectively, compared with 12.50% (Q1: −5.81%, Q3: 31.25%) in the placebo group. The first comparison of efficacy between the combined LEV 1000 and 3000-mg/day and placebo groups did not show a significant difference (P = 0.067); therefore, the closed-testing procedure was stopped and subsequent comparisons were exploratory. The median difference in seizure reduction versus placebo (95% confidence interval [CI]) was 2.27% (−9.2–14.4%) for the LEV 1000-mg/day group (P = 0.700) and 14.9% (1.9–27.6%) for the LEV 3000-mg/day group (P = 0.025). Corresponding differences with placebo for the LEV 500 and 2000mg/day groups were 0.43% (−12.3–13.2%) and
−2.1% (−15.3–10.3%), respectively; these results were not statistically significant. Secondary efficacy variables Results for the secondary efficacy variable using logarithmic-transformed POS frequency/week were consistent with those of the primary analysis for the comparison of the LEV 1000-mg and LEV 3000-mg/ day groups versus placebo. POS frequency/week with LEV (pooled 1000 and 3000-mg/day groups) was not significantly different than that for placebo (7.2% reduction over placebo; 95%CI: −3.9–17.1%; P = 0.197) and the closed-testing procedure was stopped. Subsequent comparisons were therefore exploratory. The percentage reduction in POS frequency/week compared with placebo (95%CI) was 3.2% (−10.2–15.0%) for the LEV 1000-mg group (P = 0.619) and 10.9% (−1.6–21.8%) for the LEV
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Patients with ≥50% response (%)
40 35
33.3%
30 25 19.1%
20 15
17.6%
16.2%
statistically non-significant results (P = 0.226 and P = 0.440, respectively; Fig. 3). No patients in the placebo or LEV 500-mg/day groups became seizure-free over the evaluation period; however, two patients in each of other LEV groups (six in total) became free of any type of seizure.
11.6%
10
Safety and tolerability
5 0
Levetiracetam for partial-onset seizures 645
Placebo (n = 69)
500 mg (n = 68)
1000 mg 2000 mg 3000 mg (n = 68) (n = 68) (n = 69) Levetiracetam
Comparison vs placebo
Odds ratio (95%Cl)
P-value
Levetiracetam 1000+3000 mg
2.6 (1.1–6.0)
0.025*
Levetiracetam 1000 mg
1.6 (0.6–4.3)
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Levetiracetam 3000 mg
3.8 (1.6–9.4)
0.003†
Levetiracetam 500 mg
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Levetiracetam 2000 mg
1.5 (0.6–3.9)
0.440
*Significant using closed-testing analysis †
Exploratory due to non-significance of the previous step (comparison to placebo and 1000 mg group)
Figure 3. Patients with at least 50% reduction in seizure frequency (50% responder rates) during the evaluation period. Only patients with values at both baseline (values > 0) and evaluation (values ≥ 0) periods were included in the analysis.
3000-mg group (P = 0.084). Corresponding differences with placebo for the LEV 500 and 2000-mg/day groups were 2.1% (−11.6–14.0%) and −0.3% (−14.3–11.9%), respectively; these results were not statistically significant. The ≥50% responder rates over the evaluation period for the LEV 500, 1000, 2000, 3000-mg/day and placebo groups were 19.1%, 17.6%, 16.2%, 33.3% and 11.6%, respectively (Fig. 3). Logistic regression analysis showed a significant difference between the pooled LEV (1000 and 3000-mg/day) and placebo groups (P = 0.025, Fig. 3). Comparison of efficacy between the placebo and LEV 1000-mg/day groups was not significant (P = 0.319) and the closed-testing procedure was stopped. Exploratory statistical testing of the LEV 3000-mg/day group versus placebo showed a significant treatment effect (P = 0.003). Evaluations of LEV 500 and 2000 mg/day versus placebo yielded
At least one TEAE was reported by 79.2% (278/351) of patients during the titration and evaluation periods. ADR with an incidence of ≥5% in any group are presented in Table 2. The most common ADR in the LEV groups during the up-titration and evaluation period were nasopharyngitis (49 patients, 17.4%) and somnolence (36 patients, 12.8%). The majority of TEAE and ADR in each group were mild in intensity. Serious TEAE and ADR were reported by 12 (3.4%) and eight (2.3%) patients, respectively, during the titration and evaluation period; brain contusion and status epilepticus in the placebo group; convulsion in the LEV 500-mg/day group; ventricular tachycardia in the LEV 1000-mg/day group; cognitive impairment in the LEV 2000-mg/day group; and gastric cancer, contusion and insomnia/irritability/anxiety in the LEV 3000-mg/day group. One patient (LEV 3000 mg/day) died during this study due to advanced gastric cancer. The investigator judged a causal relation between the study medication and gastric cancer as unlikely. No patients showed any clinically relevant changes from baseline in hematology, vital signs, ECG variables or blood chemistry.
Adverse events leading to discontinuation Eighteen patients discontinued due to AE: two (1.4%) in the placebo group, and four (4.2%), one (1.4%), five (5.7%), and six (7.1%) in the LEV 500, 1000, 2000 and 3000-mg/day groups, respectively. AE leading to discontinuation reported by two patients were status epilepticus (placebo group), dizziness (LEV 2000 mg/day), convulsion (LEV 500 mg/ day), epilepsy (2000 mg/day), somnolence (LEV 3000 mg/day), decreased neutrophil count (LEV 500 mg/day), and decreased white blood cell count (LEV 3000 mg/day) (14 patients in total). The remaining four AE occurred in individual patients. Of the 18 patients, eight discontinued due to SAE.
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Table 2. Summary of TEAE and ADR reported during the treatment period (up-titration and evaluation periods) [Safety Set]
Placebo n = 70 n (%) At least one TEAE 57 (81.4) Discontinuation due to TEAE 1 (1.4) Serious TEAE 3 (4.3) At least one ADR 41 (58.6) At least one serious ADR 2 (2.9) Number of deaths 0 ADR reported by >5% of patients in any group Nasopharyngitis 8 (11.4) Somnolence 5 (7.1) Contusion 2 (2.9) Dizziness 3 (4.3) Diarrhea 3 (4.3) Headache 9 (12.9) Neutrophil count decreased 1 (1.4) White blood cell count increased 4 (5.7) Abdominal pain 2 (2.9)
LEV 500 mg n = 71 n (%)
LEV 1000 mg n = 70 n (%)
LEV 2000 mg n = 70 n (%)
LEV 3000 mg n = 70 n (%)
56 (78.9) 3 (4.2) 2 (2.8) 43 (60.6) 1 (1.4) 0
57 (81.4) 1 (1.4) 2 (2.9) 43 (61.4) 1 (1.4) 0
53 (75.7) 4 (5.7) 1 (1.4) 41 (58.6) 1 (1.4) 0
55 (78.6) 5 (7.1) 4 (5.7) 45 (64.3) 3 (4.3) 1 (1.4)
10 (14.1) 5 (7.0) 1 (1.4) 5 (7.0) 7 (9.9) 4 (5.6) 3 (4.2) 0 4 (5.6)
13 (18.6) 7 (10.0) 0 1 (1.4) 2 (2.9) 1 (1.4) 2 (2.9) 0 0
11 (15.7) 12 (17.1) 5 (7.1) 4 (5.7) 0 2 (2.9) 1 (1.4) 0 1 (1.4)
15 (21.4) 12 (17.1) 3 (4.3) 4 (5.7) 1 (1.4) 3 (4.3) 5 (7.1) 1 (1.4) 0
ADR, adverse drug reactions; LEV, levetiracetam; TEAE, treatment-emergent adverse events.
DISCUSSION The primary goal of the present trial was to evaluate the safety and efficacy of LEV in patients with uncontrolled POS. The median percentage reduction in seizure frequency/week was 12.50% in the placebo group and 12.92%, 18.00%, 11.11% and 31.67% in the LEV 500, 1000, 2000 and 3000-mg/ day groups, respectively. The first-step comparison of the efficacy of the LEV 1000-mg/day, 3000-mg/ day, and placebo groups did not show a significant difference (P = 0.067). Secondary efficacy analysis using logarithmic-transformed POS frequency was consistent with the results of the primary analysis. POS frequency/week for LEV (pooled 1000 and 3000-mg/day groups) was not significantly different from that for placebo. As LEV (pooled 1000 and 3000 mg/day) was found to significantly reduce POS frequency compared with placebo (20.9% [95%CI: 10.2–30.4%], P < 0.001) in the previous trial,13 the results remain controversial. To identify potential reasons for the discrepancy, we looked into the differences between the trials. First, placebo responses differed substantially between the two trials. In the previous trial, the
median percentage reduction in seizure frequency reported with the LEV 1000-mg/day, 3000-mg/day and placebo groups were 19.61%, 27.72%, and 6.11%, respectively.13 In contrast, corresponding values in the present trial were 18.00%, 31.67%, and 12.50%. Although LEV efficacy was similar in these two trials, a marked difference in the placebo response was apparent. The high placebo response in this trial is the most likely explanation for the lack of significant difference between the LEV and placebo groups. However, the causes of this high placebo response in the present trial could not be identified with any post-hoc analyses we could conceive; for example, investigations of demographic factors and individual seizure statuses. A number of important differences in the population characteristics of the two trials should also be noted (Appendix S1). The proportion of patients who took restricted concomitant non-AED was 8.5% in the previous investigation and 38.2% in this trial. This suggests that the population in the present trial might have included more patients with complicated mental status, requiring non-AED to control disorders or symptoms associated with epilepsy and to maintain quality of life compared to the previous trial.
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2015; 69: 640–648
Levetiracetam for partial-onset seizures 647
The proportion of patients with intellectual disability was higher in this trial (33.3%) than in the previous one (8.0%). Among individuals with intellectual disability, seizures tend to occur more frequently than in those without disability; seizures also tend to be more complex, severe and refractory to treatment;15–18 therefore, patients in this study were also considered to represent a more refractory population. Other differences between the populations included age, age at epilepsy onset and history of epilepsy surgery. In summary, patient characteristics might have differed sufficiently between the two trials to have contributed to the inconsistent efficacy results. In comparing the present with overseas trials, the population of the present trial included more refractory patients from the perspective of the number of concomitant AED. The proportion of patients treated with more than three concomitant AED at initiation of LEV was much higher in the present trial (53.8%) than in European (5%)6 and US (5–8%)5 trials. Although the population of a Taiwanese trial included a high proportion of patients who took more than three concomitant AED (34.0–44.7%),9 this proportion was still lower than that seen in our trial. Such results suggest that the population in the present trial may have been unexpectedly unique compared to those of other successful LEV trials. The efficacy of LEV 2000 mg/day was lower than that of 1000 mg/day in this trial. In contrast, Boon et al. demonstrated a dose–response effect of LEV.19 Furthermore, Shorvon et al. and Tsai et al. demonstrated significant efficacy of 2000 mg/day compared to placebo.6,9 From the results of overseas trials, LEV is highly unlikely to have a biphasic effect and the low efficacy of the 2000-mg group may be due to the influence of some unique characteristics of the trial population. The causes of the low response of LEV 2000 mg could not be identified nor for the high placebo response even after performing every conceivable post-hoc analysis. Although analysis of the primary objective did not demonstrate a statistically significant difference between the LEV 1000-mg/day, 3000-mg/day and placebo groups, in the subsequent exploratory comparisons, the median difference in seizure reduction versus placebo was 14.93% for the LEV 3000-mg/day group (P = 0.025). Furthermore, 50% responder rates in the pooled LEV (1000 and 3000 mg/day) and LEV 3000-mg/day groups were significantly higher than that observed in the placebo group (P = 0.025, P = 0.003, respectively). While the factors discussed
above could explain the difference in the efficacy findings of the two trials to a certain extent, pooling data from the two pivotal trials could also help re-evaluate the efficacy of LEV in Japanese patients with uncontrolled POS. Six patients became seizurefree in this trial, two in each of the LEV treatment groups with the exception of the LEV 500-mg/day group. In contrast, no seizure-free patients were encountered in the placebo group. All LEV doses in the present study were well tolerated. The safety profile was consistent with that of the previous trial and resembled those observed in international LEV trials. In post-marketing studies, LEV has often shown a higher incidence of behavioral abnormalities, particularly in patients with biological vulnerability.20,21 Clinical monitoring with regard to behavioral abnormalities in such high-risk patients may be required in practical settings. In conclusion, the primary efficacy end-point did not reach statistical significance for either dose of LEV in this study, a finding that was inconsistent with that of the previous trial. The high placebo effect in this trial and differences in patient populations between the two trials may have contributed to these apparently contradictory findings. In exploratory analyses, treatment with LEV 3000 mg/day clearly reduced the frequency of seizures. Furthermore, clear separation from placebo was observed on one of the secondary efficacy outcomes for LEV (≥50% responder rate; 1000 and 3000-mg/day pooled data) in this study. LEV was well tolerated, and safety findings were consistent with the known safety profile of LEV. These results suggest that adjunctive treatment with LEV at 3000 mg/day may represent a suitable option for patients with uncontrolled POS in Japan.
ACKNOWLEDGMENTS This trial was sponsored by UCB Pharma. Atsushi Suzuki and Katsumi Yoshida are employees of UCB Pharma. According to the Conflict of Interest guidelines of The Japan Epilepsy Society, Dr Inoue reports receiving writing fees from Dainippon-Sumitomo; Dr Yagi, consulting fees from UCB and honoraria and speaking fees from Dainippon-Sumitomo, Kyowa-Kirin and Otsuka; Dr Sasagawa, speaker fees from Otsuka, GSK and Kyowa-Kirin; Dr Ishida, speaker fees from Otsuka and GSK; and Dr Ikeda, grant support and speaker fees from DainipponSumitomo, Kyowa-Kirin, UCB Pharma, GSK and Otsuka. Dr Ikeda is a recipient of an endowed chair
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
648 Y. Inoue et al.
Psychiatry and Clinical Neurosciences 2015; 69: 640–648
supported by multiple companies, including UCB Pharma, but not at the time when this trial was being conducted and data finalized. Other authors have no conflicts of interest to report. The authors thank Max Frenzel PhD (QXV Communications, Macclesfield, UK) and Azita Tofighy PhD, UCB Pharma, for assistance with writing the manuscript, and Mayumi Yamada PhD UCB Pharma, for coordinating manuscript preparation.
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SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Appendix S1. Demographic and baseline characteristics of patients (full analysis set [FAS] population) in the first pivotal trial in Japan (N0165) evaluating the efficacy and safety of adjunctive levetiracetam in patients with partial-onset seizures (modified from Yagi K et al. J Jpn Epil Soc 2010; 28: 3–16). Appendix S2. Members of the Japanese levetiracetam N01221 Study Group
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
