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Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multi-center, uncontrolled, open-label study
Brain & Development xxx (2015) xxx–xxx www.elsevier.com/locate/braindev
Original article
Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multi-center, uncontrolled, open-label study q Sawa Yasumoto a, Masahiro Shimizu b,⇑, Katsuaki Sato b, Atsuyo Kurata b, Yotaro Numachi b a
Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan b GlaxoSmithKline, Tokyo, Japan
Received 1 July 2015; received in revised form 9 October 2015; accepted 9 October 2015
Abstract Purpose: To evaluate the efficacy and safety of lamotrigine (LTG) monotherapy for treating Japanese and South Korean pediatric patients with newly diagnosed typical absence seizures. Methods: Twenty patients with newly diagnosed typical absence seizures aged 4–12 years were enrolled in the study and were administered LTG at an initial dose of 0.3 mg/kg/day for 2 weeks, followed by 0.6 mg/kg/day for an additional 2 weeks. Thereafter, the dose was increased by 0.6 mg/kg/day up to a maximum of 10.2 mg/kg/day or 400 mg/day (whichever was the lower dose) until patients were confirmed to be seizure free induced by hyperventilation (HV). After confirmation, the dose was increased by one level (0.6 mg/kg/day). If the patient was found to be seizure free by HV-electroencephalography (EEG) on the following two consecutive visits, the patient entered the 12-week maintenance phase. After the maintenance phase, patients could enter the extension phase if clinically indicated. Results: The seizure-free rate confirmed by HV-EEG at the end of the maintenance phase was 35.0% (7/20 patients). Most of patients who were confirmed to be seizure free during the escalation phase had maintained seizure control during the 12-week maintenance phase and the 12-week extension phase. The most frequently noted adverse events were bronchitis, headache, and rash (20% each). No serious adverse events were reported. Conclusion: Lamotrigine monotherapy in Japanese and South Korean children with typical absence seizures was well tolerated and 35.0% of patients were seizure free at the end of maintenance phase. Ó 2015 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Keywords: Lamotrigine; Monotherapy; Typical absence seizures; Children
1. Introduction q
ClinicalTrials.gov Identifier: NCT01431976.URL: https://clinicaltrials.gov/show/NCT01431976. ⇑ Corresponding author at: GlaxoSmithKline, GSK Bldg., 6-15, Sendagaya 4-chome, Shibuya-ku, Tokyo 151-8566, Japan. Tel.: +81 3 5786 5092; fax: +81 3 5786 5223. E-mail address: [email protected] (M. Shimizu).
Previous studies [1,2] have shown that lamotrigine (LTG) monotherapy is effective in the treatment of newly diagnosed typical absence seizures in the western countries. Treatment guidelines recommend ethosuximide (ESM), valproic acid (VPA), and LTG as firstline treatment for patients with absence seizures [3],
http://dx.doi.org/10.1016/j.braindev.2015.10.007 0387-7604/Ó 2015 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Please cite this article in press as: Yasumoto S et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multicenter, uncontrolled, open-label study. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.10.007
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and suggest that LTG may be effective as initial monotherapy in children with newly diagnosed or untreated absence seizures [4]. In the report by Wheless et al. on European expert opinion (2007) [5], LTG is considered to be the treatment of choice as the next option of initial treatment. In Japan, LTG was approved in 2008 as an antiepileptic drug. However, its indications are limited to adjunctive treatment for partial seizures (including secondary generalized seizures), tonic–clonic seizures, and generalized seizures of Lennox–Gastaut syndrome in adult and pediatric patients who have not responded to other antiepileptic drugs. This open-label study, therefore, was designed to evaluate the efficacy and safety of LTG monotherapy for newly diagnosed typical absence seizures in Japanese and South Korean pediatric patients. 2. Methods 2.1. Patient population Eligible criteria included patients with newly diagnosed and untreated typical absence seizures based on the International Classification of Epileptic Seizures [6]. Diagnosis of typical absence seizures was established by clinical signs of typical absence seizures (e.g., staring or impairment of consciousness) and electroencephalography (EEG) findings on one of two 4-min hyperventilation (HV) tests. A typical absence seizure was defined as a discharge of P3 s of 2.5–4.5 Hz generalized spikeand-wave or multiple spike-and-wave activity during the awake state on EEG. All patients were followed at the outpatient clinic and aged 2–15 years in Japan and 2–12 years in South Korea at the time of obtaining informed consent. Patients had to weigh at least 7 kg. Written informed consent was obtained from the legally acceptable representatives of all patients and from patients who were able to understand the concepts and procedures of the protocol. Patients were not eligible for the study if they had partial seizures or generalized seizures other than typical absence seizures; a history of rash associated with other treatments; a psychiatric disorder requiring medication, or a psychiatric condition in the past judged to be both severe and requiring hospitalization. Patients who had been taking any psychoactive drugs to treat hyperactivity disorder or attention deficit disorder were excluded from the study. 2.2. Procedures This study was conducted as a multi-center, uncontrolled open-label study to evaluate the efficacy and safety of LTG monotherapy in children and adolescents with newly diagnosed typical absence seizures. The
study consisted of a baseline phase, fixed escalation phase, escalation phase, maintenance phase, taper phase, and post-study examination. During the fixed escalation phase, patients received an LTG dose of 0.3 mg/kg/day for 2 weeks, followed by 0.6 mg/kg/day for an additional 2 weeks. Patients thereafter visited the clinic once every 1–2 weeks during the escalation phase. The dose was increased in increments of 0.6 mg/kg/day up to a maximum of 10.2 mg/kg/day or 400 mg/day (whichever was the lower dose) until the patient was confirmed to be seizure free by HV-clinical signs. The dosing regimens for the dose escalation, maintenance, and extension phases are shown in Table 1. After the patient was confirmed to be seizure free by HV-clinical signs, the dose was increased by one level (0.6 mg/kg/day) and the first HV-EEG was assessed at the next visit. If the patient was found to be seizure free by HV-EEG, the same dose was administered. Thereafter, the second HV-EEG was performed at the next visit and if the patient’s seizure-free status was confirmed again, the patient entered the 12-week maintenance phase. During the maintenance phase, patients visited the clinic once every 4 weeks. The dose could be adjusted as necessary within the range of 1.2– 10.2 mg/kg/day (maximum dose: 400 mg/day) while taking seizure status and safety into consideration. However, if a patient was not confirmed to be seizure free by HV-EEG at the LTG maximum dose of 10.2 mg/kg/day or 400 mg/day (whichever was lower), or the patient could not be confirmed to be seizure free by HV-clinical signs at the LTG dose one level lower than a maximum dose, the patient was withdrawn from the study and underwent tests at the discontinuation visit, followed by the taper phase and post-study examination. After completion of the maintenance phase, patients who had responded positively to treatment with LTG without tolerability issues were eligible to enter the extension phase of the study. Patients who entered the extension phase could continue the study either until approval of LTG monotherapy for typical absence seizures in children, or until 24 months had elapsed after the last visit in the maintenance phase, whichever came first. LTG was administered once a day in the evening. If the number of tablets was large, administration could be divided into two doses in the morning and evening. 2.3. Assessments The primary endpoint was the proportion of patients confirmed to be seizure free by HV-EEG at the end of the maintenance phase. The secondary endpoints were the proportion of patients confirmed to be seizure free by HV-EEG at the two consecutive visits during the escalation phase, the proportion confirmed to be seizure free by HV-clinical signs at each visit during
Please cite this article in press as: Yasumoto S et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multicenter, uncontrolled, open-label study. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.10.007
S. Yasumoto et al. / Brain & Development xxx (2015) xxx–xxx
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Table 1 LTG dose regimens. Phase
Week
LTG dose (mg/kg/day)
Fixed escalation phase
1–2 3–4
0.3 0.6
Escalation phase
Patients visited the site until confirmed to be seizure free by HV-clinical signs Weeks 5–8: once every 1–2 weeks After Week 8: once every 1–2 weeks (maximum permissible interval of 4 weeks)
1.2 1.8 2.4 3.0 3.6 4.2 4.8 5.4 6.0 6.6 7.2 7.8 8.4 9.0 9.6 10.2 Dose at which seizure free status confirmed by HV-clinical signs +0.6 mg/kg/day Dose at which seizure-free status confirmed by the first HV-EEG
After confirmation of seizure-free status by HV-clinical signs until next visit (first HV-EEG) After confirmation of seizure-free status by the first HV-EEG until the next visit (second HV-EEG) Maintenance phase
12 weeks
Dose at which seizure-free status confirmed by the first HV-EEG
Extension phase
Either until approval of LTG monotherapy for typical absence seizures in children, or until 24 months elapsed after the last visit in the maintenance phase, whichever came first
1.2–10.2 mg/kg/day or 400 mg/day (whichever was the lower dose)
the escalation phase, the proportion confirmed to be seizure free by HV-clinical signs at each visit during the maintenance phase, and the proportion confirmed to be seizure free by HV-EEG at Week 12 of the extension phase. The number of days per week with seizures was analyzed for each study phase using a seizure diary. The following safety data were collected periodically throughout the study: adverse events, clinical laboratory data, vital signs (blood pressure and pulse rate), body weight and 12-lead ECG. Blood samples to measure plasma LTG concentration were collected at the end of the maintenance phase or at withdrawal from the study. The mean plasma LTG concentration was measured from blood samples taken within 24 h after administration of LTG. 2.4. Statistical analysis The target sample size for analysis was set at 20 patients for feasibility reasons. The seizure-free rate at the end of the maintenance phase was estimated to be 0.44 based on the results of a previous clinical trial of LTG monotherapy for newly diagnosed typical absence seizures in children. A sample size of 20 produced a 95% confidence interval, 0.23–0.65 when the estimated
seizure-free rate was 0.44. The analysis for this interim report was conducted after all patients completed Week 12 of the extension phase or withdrew. The analysis used data from the fixed escalation phase, escalation phase, maintenance phase, and up to Week 12 of the extension phase. The safety population (SP) was defined as all patients who took at least one dose of LTG. The full analysis set (FAS) was defined as all patients in the SP who provided at least one piece of efficacy data while being treated with LTG. Efficacy analyses were performed on the FAS. The primary endpoint was the seizure-free rate at the end of the maintenance phase, which was calculated along with the associated 95% confidence intervals. Seizure-free rates for the secondary endpoints were also calculated along with their associated 95% confidence intervals. The number of days per week with seizures was summarized based on the information contained in the seizure diary. Data were analyzed with the use of SAS software, version 9.1.3. The study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice and the principles of the Declaration of Helsinki.
Please cite this article in press as: Yasumoto S et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multicenter, uncontrolled, open-label study. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.10.007
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was 35.0% (7/20 patients, 95% CI 15.39–59.22%) (Table 3).
3. Results 3.1. Patients From September 2011 to December 2012, a total of 20 patients were enrolled in the study. Both the SP and FAS comprised 20 patients. Seven patients completed the maintenance phase of the study, while 13 patients had withdrawn from the study by the end of the maintenance phase. The most common reason for withdrawal was adverse events in five patients, followed by meeting withdrawal criteria defined by the protocol in four patients (Fig. 1). All four patients met the criterion for study discontinuation when seizures could not be controlled and it was difficult to continue the study, including when it could not be confirmed if patients were seizure free based on HV-clinical signs at 9.6 mg/kg/day or by HV-EEG at 10.2 mg/kg/day or 400 mg/day, whichever was the lower dose. All of the seven patients who completed the maintenance phase entered the extension phase. No patient withdrew from the study between the end of the maintenance phase and Week 12 of the extension phase. According to the epilepsy classification shown in Table 2, all patients had only absence seizures. The mean LTG actual daily dose up to Week 12 of the extension phase was 97.61 mg/day (n = 20; range, 5.0–234.6 mg/day). Furthermore, the mean LTG actual daily dose was 101.32 mg/day (n = 16; range, 5.0–234.6 mg/day) in Japanese patients and 82.77 mg/day (n = 4; range, 30.9–107.1 mg/day) in South Korean patients. In the responding patients including one patient who was withdrawn in the maintenance phase, the mean LTG modal daily dose in the maintenance phase was 6.5 mg/kg/day (n = 8; range 4.2–9.0 mg/kg/day). 3.2. Efficacy 3.2.1. Primary endpoint The proportion of patients confirmed to be seizure free by HV-EEG at the end of the maintenance phase
Enrolled patients N=20
Patients who entered the maintenance phase N=8 (40%)
Patients who completed the maintenance phase N=7 (35%) Patients who continued up to Week 12 of the extension phase N=7
Patients withdrawn during the maintenance phase N=13 (65%) Main reasons for withdrawal, n (%) Adverse events 5 (25%) Lack of efficacy 2 (10%) Meeting withdrawal criteria 4 (20%) Investigator’s judgment 1 (5%) Withdrawal of consent 1 (5%)
Fig. 1. Study flow and patient disposition.
3.2.2. Secondary endpoints The proportion of patients confirmed to be seizure free by HV-EEG at the two consecutive visits in the escalation phase was 40.0% (8/20 patients, 95% CI 19.12–63.95%) (Table 3). The proportion of patients confirmed to be seizure free by HV-clinical signs at each visit during the escalation phase is shown in Table 4. At both Weeks 4 and 8 of the maintenance phase, the proportion of patients confirmed to be seizure free by HV-clinical signs was 100.0% (7/7 patients, 95% CI 59.04–100.00%) (Table 3). The mean number of days with seizure episodes based on the seizure diary was 5.08 days/week for the fixed escalation phase and 2.63 days/week for the escalation phase. For patients who entered the maintenance phase, the mean was 0.06 days/week. For the seven patients who entered the extension phase, the proportion of patients confirmed to be seizure free by HV-EEG at Week 12 of the extension phase was 85.7% (6/7 patients, 95% CI 42.13–99.64%). The mean number of days with seizure episodes based on the seizure diary was 0.05 days/week averaged over the entire 12 weeks of the extension phase. 3.3. Safety Adverse events were reported in 85% of patients (17/20 patients) up to Week 12 of the extension phase (Table 5). Adverse events reported in more than one patient were bronchitis (20%, 4 patients), headache (20%, 4 patients), rash (20%, 4 patients), nasopharyngitis (15%, 3 patients), drug eruption (10%, 2 patients), stomatitis (10%, 2 patients), and upper respiratory tract infection (10%, 2 patients). There were no reports of deaths, other serious adverse events, and suiciderelated adverse events at the time of data cut-off on 14 February 2014. All reported adverse events were considered to be either mild or moderate. Thirty-five percent of patients (7/20) experienced adverse events considered to be drug related up to Week 12 of the extension phase. Rash was observed in four patients (20%), drug eruption in two patients (10%), and drug hypersensitivity in one patient (5%). These adverse events were considered to be mild or moderate, and resolved within 2–36 days of onset. In two patients with rash, two patients with drug eruption and one patient with drug hypersensitivity (25%, 5/20 patients), the adverse events related to skin rash were considered to be drug related and resulted in withdrawal from the study. Two patients with rash were not withdrawn as it was determined that the rash was not drug related, and improved in natural courses. No other patients were withdrawn from the study due to adverse events. Although rash and scarlet fever in one
Please cite this article in press as: Yasumoto S et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multicenter, uncontrolled, open-label study. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.10.007
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Table 2 Demographics and baseline characteristics. Demographics (SP) N Sex Female, n (%) Male, n (%) Age (years) Mean (SD) Median (min–max) Age group, n (%) <12 years P12 years Height (cm) Mean (SD) Median (min–max) Body weight (kg) Mean (SD) Median (min–max) Race, n (%) Asian–Japanese heritage Asian–East Asian heritage Asian–South East Asian heritage Baseline characteristics (SP) Epilepsy classification, n (%)
20 13 (65) 7 (35) 7.7 (1.95) 7.0 (4–12) 19 (95) 1 (5) 125.64 (10.307) 124.80 (104.6–140.5) 25.88 (6.389) 24.40 (14.6–35.8) 16 (80) 3 (15) 1 (5) D1: absence seizures
20 (100)
Table 3 Seizure-free rate confirmed by HV-EEG or HV-clinical signs (FAS).
Primary Seizure-free by HV-EEG at the end of the maintenance phase Secondary Seizure-free by HV-EEG at the two consecutive visits in the escalation phase Seizure-free by HV-clinical signs at Weeks 4 of the maintenance phase Seizure-free by HV-clinical signs at Weeks 8 of the maintenance phase
patient were reported as adverse events leading to withdrawal, the scarlet fever was not considered to be drug related. 3.4. LTG plasma concentration The mean plasma LTG concentration was 6.51 lg/ mL (n = 16) (range: 0.2–13.9 lg/mL) at the end of the maintenance phase or at withdrawal from the study. The mean plasma LTG concentration was 6.96 lg/mL (n = 13; daily dose, 0.3–9.6 mg/kg/day; range, 0.2–13.9 lg/mL) in Japanese patients and 4.57 lg/mL (n = 3; daily dose, 3.6–7.2 mg/kg/day; range, 3.0–6.5 lg/mL) in South Korean patients. Furthermore, in patients confirmed to be seizure free by HV-EEG at the end of the maintenance phase, the plasma LTG concentration ranged 3.0–13.9 lg/mL (n = 7; daily dose, 4.2–9.0 mg/kg/day).
N
Number of seizure-free patients
Seizure-free rate (%)
95% CI
20
7
35.0
(15.39, 59.22)
20
8
40.0
(19.12, 63.95)
7
7
100.0
(59.04, 100.00)
7
7
100.0
(59.04, 100.00)
4. Discussion The proportion of patients confirmed to be seizure free by HV-EEG at the end of maintenance phase, the primary endpoint of this study, was assumed to be 0.44 ± 0.21 (95% CI, 0.23–0.65) based on the seizurefree rate of 56% in the escalation phase and 78% at the end of maintenance phase in patients who entered the maintenance phase in a previous open-label clinical study [2]. The seizure-free rate in the present study was 35.0%, which is slightly lower than the assumed seizure-free rate of 44%. In a previous double-blind clinical study [1] employing a ‘‘responder-enriched” study design in which patients who had responded to LTG were randomized to either placebo or extended treatment with LTG, the seizure-free rate in the placebo group decreased to approximately 20% during the 4-week period when LTG was tapered and replaced by
Please cite this article in press as: Yasumoto S et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multicenter, uncontrolled, open-label study. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.10.007
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Table 4 Seizure-free rate confirmed by HV-clinical signs at each visit during the escalation phase (FAS). Dose at each visit (mg/ kg/day)
Number of patients who had received LTG
Number of patients seizure free by HVclinical signs
Seizure-free rate (%)
95% CI
0.6 1.2 1.8 2.4 3.0 3.6 4.2 4.8 5.4 6.0 6.6 7.2 7.8 8.4 9.0 9.6
17 17 16 16 16 15 15 14 14 11 11 9 9 6 6 1
1 1 2 2 2 1 0 4 1 1 0 3 0 2 1 1
5.9 5.9 12.5 12.5 12.5 6.7 – 28.6 7.1 9.1 – 33.3 – 33.3 16.7 100.0
(0.15, 28.69) (0.15, 28.69) (1.55, 38.35) (1.55, 38.35) (1.55, 38.35) (0.17, 31.95) – (8.39, 58.10) (0.18, 33.87) (0.23, 41.28) – (7.49, 70.07) – (4.33, 77.72) (0.42, 64.12) (2.50, 100.00)
–: in case of zero, the rate and its CI were not calculated.
Table 5 Summary of common adverse events (P10%). N = 20 n (%) Patients with any adverse event(s) Bronchitis Headache Rash Nasopharyngitis Drug eruption Stomatitis Upper respiratory tract infection
17 (85) 4 (20) 4 (20) 4 (20) 3 (15) 2 (10) 2 (10) 2 (10)
Adverse events reported in P10% of patients are listed.
placebo. Based on these data, the historical seizure-free rate for placebo was assumed to be 20% in the clinical study [2] on which the present study was based. The actual seizure-free rate of 35.0% in the present study was higher than the seizure-free rate for placebo of 20% in the previous studies. In the present study, all of the responding patients entered the maintenance phase and most of these patients continued the study during the extension phase. The results of the secondary endpoints suggest that these patients were almost seizure free by Week 12 of the extension phase. Specifically, the seizure-free rate confirmed by HV-EEG at Week 12 in the extension phase was 85.7% and the mean number of days with seizure episodes based on the seizure diary was 0.06 and 0.05 days/week for the maintenance and extension phases, respectively. These results suggest that LTG monotherapy appears to be an effective treatment for typical absence seizures in children. The observed decrease in the seizure-free rate in the 4-week period with tapering of LTG to placebo in the above-mentioned double-blind clinical study [1]
indicates that seizures may recur soon after cessation of LTG administration. In the present study, responding patients remained seizure free during the extension phase, suggesting that LTG therapy is effective against typical absence seizures. The data on dose levels at visits when patients were first confirmed to be seizure free by HV-clinical signs in the escalation phase indicate that LTG was effective in a dose range as wide as 0.6–9.6 mg/kg/day. The mean daily dose of LTG in the maintenance phase was 6.5 mg/ kg/day (range, 4.2–9.0 mg/kg/day) and the observed range overlapped with the effective dose (range, 2– 15 mg/kg/day) reported by Frank et al. [1]. The mean LTG actual daily dose was similar in Japanese patients and South Korean patients. Although LTG had effect in a wide range of the plasma LTG concentration in the responding patients, there was no association between plasma level and the response rate. The adverse events reported in the present study were similar to those observed in previous studies [1,2] except for rash. In the present study, rash, unless a causal relationship with the investigational product could be unequivocally ruled out, was included in the withdrawal criteria and five patients were withdrawn from the study due to rash. There were no withdrawals due to rash reported in previous studies [1,2]. However, no severe or serious skin disorders were reported in the present study. The study requirement, which any patient with rash had to be promptly evaluated by a dermatologist and the study treatment had to be discontinued unless the rash was clearly not drug related, may have been responsible for the prompt medical treatment for skin disorders to prevent any increase in severity. This was a small-scale, open-label, uncontrolled study and may not provide sufficient data for an efficacy
Please cite this article in press as: Yasumoto S et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multicenter, uncontrolled, open-label study. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.10.007
S. Yasumoto et al. / Brain & Development xxx (2015) xxx–xxx
and safety assessment. However, considering with the following previous studies, our results suggest that LTG monotherapy may be an effective treatment for typical absence seizures in Japanese and Korean pediatric patients. Glauser et al. [7] reported that LTG was less effective compared with ethosuximide and valproic acid, while Coppola et al. [8] compared LTG and valproic acid in a small-scale study and reported similar seizure-free rates for both drugs after 12 month’s treatment. Thus, LTG may be effective as initial monotherapy in children with newly diagnosed or untreated typical absence seizures although it is slightly less effective compared with ethosuximide and valproic acid. Glauser et al. [7] stated that ethosuximide is the treatment of choice but there is still significant room to improve treatment options, since even the best empirical initial monotherapy fails in 55% of children over the first 12 months of treatment. This comment indicates that alternative options including LTG or valproic acid are required. It has also been reported that generalized tonic-clonic seizures often occur 5–10 years after the onset of typical absence seizures in children or adolescents and sometimes beyond 20 and even 30 years of age. [9]. Because of the higher teratogenic risk of valproic acid, use of LTG should be considered in pubescent girls. LTG is also recommended for patients who do not respond to or who cannot tolerate ethosuximide or valproic acid [3,4] and could be one of the monotherapy options for treating typical absence seizures. Conflicts of interest Sawa Yasumoto has declared no conflicts of interest. Masahiro Shimizu, Katsuaki Sato and Atsuyo Kurata are employees of GSK. Yotaro Numachi is an employee and shareholder of GSK.
Acknowledgments The study was sponsored and funded by GlaxoSmithKline (GSK). The GSK clinical study identifier is LAM115377. Sawa Yasumoto participated as investigator for this study. Appendix A Members of the lamotrigine monotherapy study group included the following investigators. For each site, the principal investigator is listed first, followed by sub-investigators. Japan: S. Yasumoto, H. Ideguchi, T. Inoue, T. Fujita, Y. Ihara, Y. Tomonou, S. Ninomiya, K. Noda (Fukuoka University Hospital), H. Shiraishi, Y. Ueda, K. Otsuka, M. Nakajima (Hokkaido University
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Hospital), K. Kuwabara, Y. Takaishi (Nippon Medical School Hospital), H. Osaka, M. Iai, T. Wada, K. Takano, Y. Tsuyusaki (Kanagawa Children’s Medical Center-Kanagawa), J. Tohyama, N. Akasaka (NishiNiigata Chuo National Hospital), H. Enoki, T. Yokota, T. Matsubayashi (Seirei Hamamatsu General Hospital), S. Itomi, T. Nakata, T. Ikuta (Japanese Red Cross Nagoya Daiichi Hospital), Y. Ohtsuka, Y. Harumi, K. Kobayashi, F. Endo, T. Akiyama, T. Inoue, Y. Hayashi, M. Akiyama (Okayama University Hospital), K. Iyoda, K. Ogawa, S. Itamura, O. Mitani (Hiroshima City Hospital), M. Fukuda, N. Nakano, S. Kawakami, C. Kikuchi, M. Kawabe (Ehime University Hospital), M. Shimono, T. Sato, Y. Honda, M. Ishii (University Hospital of Occupational and Environmental Health), S. Maniwa, N. Kodani, K. Nakano (Matsuyama Red Cross Hospital), K. Minagawa, T. Watanabe, S. Fukumura (Hokkaido Medical Center for Child Health and Rehabilitation). South Korea: H.D. Kim, R. Yu, H.C. Kang, J.R. Yoon, Y.Y. Yi (Severance Hospital, YUCM). References [1] Frank LM, Enlow T, Holmes GL, Manasco P, Concannon S, Chen C, et al. Lamictal (lamotrigine) monotherapy for typical absence seizures in children. Epilepsia 1999;40:973–9. [2] Holmes GL, Frank LM, Sheth RD, Philbrook B, Wooten JD, Vuong A, et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children. Epilepsy Res 2008;82: 124–32. [3] National Institute for Health and Care Excellence (NICE). The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. NICE clinical guideline 137, 2012. Available from: [issued January 2012; last modified December 2013]. [4] Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Guerreiro C, Ka¨lvia¨inen R, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013;54:551–63. [5] Wheless JW, Clarke DF, Arzimanoglou A, Carpenter D. Treatment of pediatric epilepsy: European expert opinion, 2007. Epileptic Disord 2007;9:353–412. [6] Commission on Classification and Terminology of the International League against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489–501. [7] Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months. Epilepsia 2013;54:141–55. [8] Coppola G, Auricchio G, Federico R, Carotenuto M, Pascotto A. Lamotrigine versus valproic acid as first-line monotherapy in newly diagnosed typical absence seizures: an open-label, randomized, parallel-group study. Epilepsia 2004;45:1049–53. [9] Hirsch E, Panayiotopoulos CP. Childhood absence epilepsy and related syndromes. In: Roger J, Bureau M, Dravet C, Genton P, Tassinari CA, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence. Montrouge: John Libbey Eurotext Ltd; 2005. p. 315–35.
Please cite this article in press as: Yasumoto S et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multicenter, uncontrolled, open-label study. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.10.007
Original article
Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multi-center, uncontrolled, open-label study q Sawa Yasumoto a, Masahiro Shimizu b,⇑, Katsuaki Sato b, Atsuyo Kurata b, Yotaro Numachi b a
Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan b GlaxoSmithKline, Tokyo, Japan
Received 1 July 2015; received in revised form 9 October 2015; accepted 9 October 2015
Abstract Purpose: To evaluate the efficacy and safety of lamotrigine (LTG) monotherapy for treating Japanese and South Korean pediatric patients with newly diagnosed typical absence seizures. Methods: Twenty patients with newly diagnosed typical absence seizures aged 4–12 years were enrolled in the study and were administered LTG at an initial dose of 0.3 mg/kg/day for 2 weeks, followed by 0.6 mg/kg/day for an additional 2 weeks. Thereafter, the dose was increased by 0.6 mg/kg/day up to a maximum of 10.2 mg/kg/day or 400 mg/day (whichever was the lower dose) until patients were confirmed to be seizure free induced by hyperventilation (HV). After confirmation, the dose was increased by one level (0.6 mg/kg/day). If the patient was found to be seizure free by HV-electroencephalography (EEG) on the following two consecutive visits, the patient entered the 12-week maintenance phase. After the maintenance phase, patients could enter the extension phase if clinically indicated. Results: The seizure-free rate confirmed by HV-EEG at the end of the maintenance phase was 35.0% (7/20 patients). Most of patients who were confirmed to be seizure free during the escalation phase had maintained seizure control during the 12-week maintenance phase and the 12-week extension phase. The most frequently noted adverse events were bronchitis, headache, and rash (20% each). No serious adverse events were reported. Conclusion: Lamotrigine monotherapy in Japanese and South Korean children with typical absence seizures was well tolerated and 35.0% of patients were seizure free at the end of maintenance phase. Ó 2015 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Keywords: Lamotrigine; Monotherapy; Typical absence seizures; Children
1. Introduction q
ClinicalTrials.gov Identifier: NCT01431976.URL: https://clinicaltrials.gov/show/NCT01431976. ⇑ Corresponding author at: GlaxoSmithKline, GSK Bldg., 6-15, Sendagaya 4-chome, Shibuya-ku, Tokyo 151-8566, Japan. Tel.: +81 3 5786 5092; fax: +81 3 5786 5223. E-mail address: [email protected] (M. Shimizu).
Previous studies [1,2] have shown that lamotrigine (LTG) monotherapy is effective in the treatment of newly diagnosed typical absence seizures in the western countries. Treatment guidelines recommend ethosuximide (ESM), valproic acid (VPA), and LTG as firstline treatment for patients with absence seizures [3],
http://dx.doi.org/10.1016/j.braindev.2015.10.007 0387-7604/Ó 2015 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology.
Please cite this article in press as: Yasumoto S et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multicenter, uncontrolled, open-label study. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.10.007
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and suggest that LTG may be effective as initial monotherapy in children with newly diagnosed or untreated absence seizures [4]. In the report by Wheless et al. on European expert opinion (2007) [5], LTG is considered to be the treatment of choice as the next option of initial treatment. In Japan, LTG was approved in 2008 as an antiepileptic drug. However, its indications are limited to adjunctive treatment for partial seizures (including secondary generalized seizures), tonic–clonic seizures, and generalized seizures of Lennox–Gastaut syndrome in adult and pediatric patients who have not responded to other antiepileptic drugs. This open-label study, therefore, was designed to evaluate the efficacy and safety of LTG monotherapy for newly diagnosed typical absence seizures in Japanese and South Korean pediatric patients. 2. Methods 2.1. Patient population Eligible criteria included patients with newly diagnosed and untreated typical absence seizures based on the International Classification of Epileptic Seizures [6]. Diagnosis of typical absence seizures was established by clinical signs of typical absence seizures (e.g., staring or impairment of consciousness) and electroencephalography (EEG) findings on one of two 4-min hyperventilation (HV) tests. A typical absence seizure was defined as a discharge of P3 s of 2.5–4.5 Hz generalized spikeand-wave or multiple spike-and-wave activity during the awake state on EEG. All patients were followed at the outpatient clinic and aged 2–15 years in Japan and 2–12 years in South Korea at the time of obtaining informed consent. Patients had to weigh at least 7 kg. Written informed consent was obtained from the legally acceptable representatives of all patients and from patients who were able to understand the concepts and procedures of the protocol. Patients were not eligible for the study if they had partial seizures or generalized seizures other than typical absence seizures; a history of rash associated with other treatments; a psychiatric disorder requiring medication, or a psychiatric condition in the past judged to be both severe and requiring hospitalization. Patients who had been taking any psychoactive drugs to treat hyperactivity disorder or attention deficit disorder were excluded from the study. 2.2. Procedures This study was conducted as a multi-center, uncontrolled open-label study to evaluate the efficacy and safety of LTG monotherapy in children and adolescents with newly diagnosed typical absence seizures. The
study consisted of a baseline phase, fixed escalation phase, escalation phase, maintenance phase, taper phase, and post-study examination. During the fixed escalation phase, patients received an LTG dose of 0.3 mg/kg/day for 2 weeks, followed by 0.6 mg/kg/day for an additional 2 weeks. Patients thereafter visited the clinic once every 1–2 weeks during the escalation phase. The dose was increased in increments of 0.6 mg/kg/day up to a maximum of 10.2 mg/kg/day or 400 mg/day (whichever was the lower dose) until the patient was confirmed to be seizure free by HV-clinical signs. The dosing regimens for the dose escalation, maintenance, and extension phases are shown in Table 1. After the patient was confirmed to be seizure free by HV-clinical signs, the dose was increased by one level (0.6 mg/kg/day) and the first HV-EEG was assessed at the next visit. If the patient was found to be seizure free by HV-EEG, the same dose was administered. Thereafter, the second HV-EEG was performed at the next visit and if the patient’s seizure-free status was confirmed again, the patient entered the 12-week maintenance phase. During the maintenance phase, patients visited the clinic once every 4 weeks. The dose could be adjusted as necessary within the range of 1.2– 10.2 mg/kg/day (maximum dose: 400 mg/day) while taking seizure status and safety into consideration. However, if a patient was not confirmed to be seizure free by HV-EEG at the LTG maximum dose of 10.2 mg/kg/day or 400 mg/day (whichever was lower), or the patient could not be confirmed to be seizure free by HV-clinical signs at the LTG dose one level lower than a maximum dose, the patient was withdrawn from the study and underwent tests at the discontinuation visit, followed by the taper phase and post-study examination. After completion of the maintenance phase, patients who had responded positively to treatment with LTG without tolerability issues were eligible to enter the extension phase of the study. Patients who entered the extension phase could continue the study either until approval of LTG monotherapy for typical absence seizures in children, or until 24 months had elapsed after the last visit in the maintenance phase, whichever came first. LTG was administered once a day in the evening. If the number of tablets was large, administration could be divided into two doses in the morning and evening. 2.3. Assessments The primary endpoint was the proportion of patients confirmed to be seizure free by HV-EEG at the end of the maintenance phase. The secondary endpoints were the proportion of patients confirmed to be seizure free by HV-EEG at the two consecutive visits during the escalation phase, the proportion confirmed to be seizure free by HV-clinical signs at each visit during
Please cite this article in press as: Yasumoto S et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multicenter, uncontrolled, open-label study. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.10.007
S. Yasumoto et al. / Brain & Development xxx (2015) xxx–xxx
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Table 1 LTG dose regimens. Phase
Week
LTG dose (mg/kg/day)
Fixed escalation phase
1–2 3–4
0.3 0.6
Escalation phase
Patients visited the site until confirmed to be seizure free by HV-clinical signs Weeks 5–8: once every 1–2 weeks After Week 8: once every 1–2 weeks (maximum permissible interval of 4 weeks)
1.2 1.8 2.4 3.0 3.6 4.2 4.8 5.4 6.0 6.6 7.2 7.8 8.4 9.0 9.6 10.2 Dose at which seizure free status confirmed by HV-clinical signs +0.6 mg/kg/day Dose at which seizure-free status confirmed by the first HV-EEG
After confirmation of seizure-free status by HV-clinical signs until next visit (first HV-EEG) After confirmation of seizure-free status by the first HV-EEG until the next visit (second HV-EEG) Maintenance phase
12 weeks
Dose at which seizure-free status confirmed by the first HV-EEG
Extension phase
Either until approval of LTG monotherapy for typical absence seizures in children, or until 24 months elapsed after the last visit in the maintenance phase, whichever came first
1.2–10.2 mg/kg/day or 400 mg/day (whichever was the lower dose)
the escalation phase, the proportion confirmed to be seizure free by HV-clinical signs at each visit during the maintenance phase, and the proportion confirmed to be seizure free by HV-EEG at Week 12 of the extension phase. The number of days per week with seizures was analyzed for each study phase using a seizure diary. The following safety data were collected periodically throughout the study: adverse events, clinical laboratory data, vital signs (blood pressure and pulse rate), body weight and 12-lead ECG. Blood samples to measure plasma LTG concentration were collected at the end of the maintenance phase or at withdrawal from the study. The mean plasma LTG concentration was measured from blood samples taken within 24 h after administration of LTG. 2.4. Statistical analysis The target sample size for analysis was set at 20 patients for feasibility reasons. The seizure-free rate at the end of the maintenance phase was estimated to be 0.44 based on the results of a previous clinical trial of LTG monotherapy for newly diagnosed typical absence seizures in children. A sample size of 20 produced a 95% confidence interval, 0.23–0.65 when the estimated
seizure-free rate was 0.44. The analysis for this interim report was conducted after all patients completed Week 12 of the extension phase or withdrew. The analysis used data from the fixed escalation phase, escalation phase, maintenance phase, and up to Week 12 of the extension phase. The safety population (SP) was defined as all patients who took at least one dose of LTG. The full analysis set (FAS) was defined as all patients in the SP who provided at least one piece of efficacy data while being treated with LTG. Efficacy analyses were performed on the FAS. The primary endpoint was the seizure-free rate at the end of the maintenance phase, which was calculated along with the associated 95% confidence intervals. Seizure-free rates for the secondary endpoints were also calculated along with their associated 95% confidence intervals. The number of days per week with seizures was summarized based on the information contained in the seizure diary. Data were analyzed with the use of SAS software, version 9.1.3. The study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice and the principles of the Declaration of Helsinki.
Please cite this article in press as: Yasumoto S et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multicenter, uncontrolled, open-label study. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.10.007
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was 35.0% (7/20 patients, 95% CI 15.39–59.22%) (Table 3).
3. Results 3.1. Patients From September 2011 to December 2012, a total of 20 patients were enrolled in the study. Both the SP and FAS comprised 20 patients. Seven patients completed the maintenance phase of the study, while 13 patients had withdrawn from the study by the end of the maintenance phase. The most common reason for withdrawal was adverse events in five patients, followed by meeting withdrawal criteria defined by the protocol in four patients (Fig. 1). All four patients met the criterion for study discontinuation when seizures could not be controlled and it was difficult to continue the study, including when it could not be confirmed if patients were seizure free based on HV-clinical signs at 9.6 mg/kg/day or by HV-EEG at 10.2 mg/kg/day or 400 mg/day, whichever was the lower dose. All of the seven patients who completed the maintenance phase entered the extension phase. No patient withdrew from the study between the end of the maintenance phase and Week 12 of the extension phase. According to the epilepsy classification shown in Table 2, all patients had only absence seizures. The mean LTG actual daily dose up to Week 12 of the extension phase was 97.61 mg/day (n = 20; range, 5.0–234.6 mg/day). Furthermore, the mean LTG actual daily dose was 101.32 mg/day (n = 16; range, 5.0–234.6 mg/day) in Japanese patients and 82.77 mg/day (n = 4; range, 30.9–107.1 mg/day) in South Korean patients. In the responding patients including one patient who was withdrawn in the maintenance phase, the mean LTG modal daily dose in the maintenance phase was 6.5 mg/kg/day (n = 8; range 4.2–9.0 mg/kg/day). 3.2. Efficacy 3.2.1. Primary endpoint The proportion of patients confirmed to be seizure free by HV-EEG at the end of the maintenance phase
Enrolled patients N=20
Patients who entered the maintenance phase N=8 (40%)
Patients who completed the maintenance phase N=7 (35%) Patients who continued up to Week 12 of the extension phase N=7
Patients withdrawn during the maintenance phase N=13 (65%) Main reasons for withdrawal, n (%) Adverse events 5 (25%) Lack of efficacy 2 (10%) Meeting withdrawal criteria 4 (20%) Investigator’s judgment 1 (5%) Withdrawal of consent 1 (5%)
Fig. 1. Study flow and patient disposition.
3.2.2. Secondary endpoints The proportion of patients confirmed to be seizure free by HV-EEG at the two consecutive visits in the escalation phase was 40.0% (8/20 patients, 95% CI 19.12–63.95%) (Table 3). The proportion of patients confirmed to be seizure free by HV-clinical signs at each visit during the escalation phase is shown in Table 4. At both Weeks 4 and 8 of the maintenance phase, the proportion of patients confirmed to be seizure free by HV-clinical signs was 100.0% (7/7 patients, 95% CI 59.04–100.00%) (Table 3). The mean number of days with seizure episodes based on the seizure diary was 5.08 days/week for the fixed escalation phase and 2.63 days/week for the escalation phase. For patients who entered the maintenance phase, the mean was 0.06 days/week. For the seven patients who entered the extension phase, the proportion of patients confirmed to be seizure free by HV-EEG at Week 12 of the extension phase was 85.7% (6/7 patients, 95% CI 42.13–99.64%). The mean number of days with seizure episodes based on the seizure diary was 0.05 days/week averaged over the entire 12 weeks of the extension phase. 3.3. Safety Adverse events were reported in 85% of patients (17/20 patients) up to Week 12 of the extension phase (Table 5). Adverse events reported in more than one patient were bronchitis (20%, 4 patients), headache (20%, 4 patients), rash (20%, 4 patients), nasopharyngitis (15%, 3 patients), drug eruption (10%, 2 patients), stomatitis (10%, 2 patients), and upper respiratory tract infection (10%, 2 patients). There were no reports of deaths, other serious adverse events, and suiciderelated adverse events at the time of data cut-off on 14 February 2014. All reported adverse events were considered to be either mild or moderate. Thirty-five percent of patients (7/20) experienced adverse events considered to be drug related up to Week 12 of the extension phase. Rash was observed in four patients (20%), drug eruption in two patients (10%), and drug hypersensitivity in one patient (5%). These adverse events were considered to be mild or moderate, and resolved within 2–36 days of onset. In two patients with rash, two patients with drug eruption and one patient with drug hypersensitivity (25%, 5/20 patients), the adverse events related to skin rash were considered to be drug related and resulted in withdrawal from the study. Two patients with rash were not withdrawn as it was determined that the rash was not drug related, and improved in natural courses. No other patients were withdrawn from the study due to adverse events. Although rash and scarlet fever in one
Please cite this article in press as: Yasumoto S et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multicenter, uncontrolled, open-label study. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.10.007
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Table 2 Demographics and baseline characteristics. Demographics (SP) N Sex Female, n (%) Male, n (%) Age (years) Mean (SD) Median (min–max) Age group, n (%) <12 years P12 years Height (cm) Mean (SD) Median (min–max) Body weight (kg) Mean (SD) Median (min–max) Race, n (%) Asian–Japanese heritage Asian–East Asian heritage Asian–South East Asian heritage Baseline characteristics (SP) Epilepsy classification, n (%)
20 13 (65) 7 (35) 7.7 (1.95) 7.0 (4–12) 19 (95) 1 (5) 125.64 (10.307) 124.80 (104.6–140.5) 25.88 (6.389) 24.40 (14.6–35.8) 16 (80) 3 (15) 1 (5) D1: absence seizures
20 (100)
Table 3 Seizure-free rate confirmed by HV-EEG or HV-clinical signs (FAS).
Primary Seizure-free by HV-EEG at the end of the maintenance phase Secondary Seizure-free by HV-EEG at the two consecutive visits in the escalation phase Seizure-free by HV-clinical signs at Weeks 4 of the maintenance phase Seizure-free by HV-clinical signs at Weeks 8 of the maintenance phase
patient were reported as adverse events leading to withdrawal, the scarlet fever was not considered to be drug related. 3.4. LTG plasma concentration The mean plasma LTG concentration was 6.51 lg/ mL (n = 16) (range: 0.2–13.9 lg/mL) at the end of the maintenance phase or at withdrawal from the study. The mean plasma LTG concentration was 6.96 lg/mL (n = 13; daily dose, 0.3–9.6 mg/kg/day; range, 0.2–13.9 lg/mL) in Japanese patients and 4.57 lg/mL (n = 3; daily dose, 3.6–7.2 mg/kg/day; range, 3.0–6.5 lg/mL) in South Korean patients. Furthermore, in patients confirmed to be seizure free by HV-EEG at the end of the maintenance phase, the plasma LTG concentration ranged 3.0–13.9 lg/mL (n = 7; daily dose, 4.2–9.0 mg/kg/day).
N
Number of seizure-free patients
Seizure-free rate (%)
95% CI
20
7
35.0
(15.39, 59.22)
20
8
40.0
(19.12, 63.95)
7
7
100.0
(59.04, 100.00)
7
7
100.0
(59.04, 100.00)
4. Discussion The proportion of patients confirmed to be seizure free by HV-EEG at the end of maintenance phase, the primary endpoint of this study, was assumed to be 0.44 ± 0.21 (95% CI, 0.23–0.65) based on the seizurefree rate of 56% in the escalation phase and 78% at the end of maintenance phase in patients who entered the maintenance phase in a previous open-label clinical study [2]. The seizure-free rate in the present study was 35.0%, which is slightly lower than the assumed seizure-free rate of 44%. In a previous double-blind clinical study [1] employing a ‘‘responder-enriched” study design in which patients who had responded to LTG were randomized to either placebo or extended treatment with LTG, the seizure-free rate in the placebo group decreased to approximately 20% during the 4-week period when LTG was tapered and replaced by
Please cite this article in press as: Yasumoto S et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multicenter, uncontrolled, open-label study. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.10.007
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Table 4 Seizure-free rate confirmed by HV-clinical signs at each visit during the escalation phase (FAS). Dose at each visit (mg/ kg/day)
Number of patients who had received LTG
Number of patients seizure free by HVclinical signs
Seizure-free rate (%)
95% CI
0.6 1.2 1.8 2.4 3.0 3.6 4.2 4.8 5.4 6.0 6.6 7.2 7.8 8.4 9.0 9.6
17 17 16 16 16 15 15 14 14 11 11 9 9 6 6 1
1 1 2 2 2 1 0 4 1 1 0 3 0 2 1 1
5.9 5.9 12.5 12.5 12.5 6.7 – 28.6 7.1 9.1 – 33.3 – 33.3 16.7 100.0
(0.15, 28.69) (0.15, 28.69) (1.55, 38.35) (1.55, 38.35) (1.55, 38.35) (0.17, 31.95) – (8.39, 58.10) (0.18, 33.87) (0.23, 41.28) – (7.49, 70.07) – (4.33, 77.72) (0.42, 64.12) (2.50, 100.00)
–: in case of zero, the rate and its CI were not calculated.
Table 5 Summary of common adverse events (P10%). N = 20 n (%) Patients with any adverse event(s) Bronchitis Headache Rash Nasopharyngitis Drug eruption Stomatitis Upper respiratory tract infection
17 (85) 4 (20) 4 (20) 4 (20) 3 (15) 2 (10) 2 (10) 2 (10)
Adverse events reported in P10% of patients are listed.
placebo. Based on these data, the historical seizure-free rate for placebo was assumed to be 20% in the clinical study [2] on which the present study was based. The actual seizure-free rate of 35.0% in the present study was higher than the seizure-free rate for placebo of 20% in the previous studies. In the present study, all of the responding patients entered the maintenance phase and most of these patients continued the study during the extension phase. The results of the secondary endpoints suggest that these patients were almost seizure free by Week 12 of the extension phase. Specifically, the seizure-free rate confirmed by HV-EEG at Week 12 in the extension phase was 85.7% and the mean number of days with seizure episodes based on the seizure diary was 0.06 and 0.05 days/week for the maintenance and extension phases, respectively. These results suggest that LTG monotherapy appears to be an effective treatment for typical absence seizures in children. The observed decrease in the seizure-free rate in the 4-week period with tapering of LTG to placebo in the above-mentioned double-blind clinical study [1]
indicates that seizures may recur soon after cessation of LTG administration. In the present study, responding patients remained seizure free during the extension phase, suggesting that LTG therapy is effective against typical absence seizures. The data on dose levels at visits when patients were first confirmed to be seizure free by HV-clinical signs in the escalation phase indicate that LTG was effective in a dose range as wide as 0.6–9.6 mg/kg/day. The mean daily dose of LTG in the maintenance phase was 6.5 mg/ kg/day (range, 4.2–9.0 mg/kg/day) and the observed range overlapped with the effective dose (range, 2– 15 mg/kg/day) reported by Frank et al. [1]. The mean LTG actual daily dose was similar in Japanese patients and South Korean patients. Although LTG had effect in a wide range of the plasma LTG concentration in the responding patients, there was no association between plasma level and the response rate. The adverse events reported in the present study were similar to those observed in previous studies [1,2] except for rash. In the present study, rash, unless a causal relationship with the investigational product could be unequivocally ruled out, was included in the withdrawal criteria and five patients were withdrawn from the study due to rash. There were no withdrawals due to rash reported in previous studies [1,2]. However, no severe or serious skin disorders were reported in the present study. The study requirement, which any patient with rash had to be promptly evaluated by a dermatologist and the study treatment had to be discontinued unless the rash was clearly not drug related, may have been responsible for the prompt medical treatment for skin disorders to prevent any increase in severity. This was a small-scale, open-label, uncontrolled study and may not provide sufficient data for an efficacy
Please cite this article in press as: Yasumoto S et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multicenter, uncontrolled, open-label study. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.10.007
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and safety assessment. However, considering with the following previous studies, our results suggest that LTG monotherapy may be an effective treatment for typical absence seizures in Japanese and Korean pediatric patients. Glauser et al. [7] reported that LTG was less effective compared with ethosuximide and valproic acid, while Coppola et al. [8] compared LTG and valproic acid in a small-scale study and reported similar seizure-free rates for both drugs after 12 month’s treatment. Thus, LTG may be effective as initial monotherapy in children with newly diagnosed or untreated typical absence seizures although it is slightly less effective compared with ethosuximide and valproic acid. Glauser et al. [7] stated that ethosuximide is the treatment of choice but there is still significant room to improve treatment options, since even the best empirical initial monotherapy fails in 55% of children over the first 12 months of treatment. This comment indicates that alternative options including LTG or valproic acid are required. It has also been reported that generalized tonic-clonic seizures often occur 5–10 years after the onset of typical absence seizures in children or adolescents and sometimes beyond 20 and even 30 years of age. [9]. Because of the higher teratogenic risk of valproic acid, use of LTG should be considered in pubescent girls. LTG is also recommended for patients who do not respond to or who cannot tolerate ethosuximide or valproic acid [3,4] and could be one of the monotherapy options for treating typical absence seizures. Conflicts of interest Sawa Yasumoto has declared no conflicts of interest. Masahiro Shimizu, Katsuaki Sato and Atsuyo Kurata are employees of GSK. Yotaro Numachi is an employee and shareholder of GSK.
Acknowledgments The study was sponsored and funded by GlaxoSmithKline (GSK). The GSK clinical study identifier is LAM115377. Sawa Yasumoto participated as investigator for this study. Appendix A Members of the lamotrigine monotherapy study group included the following investigators. For each site, the principal investigator is listed first, followed by sub-investigators. Japan: S. Yasumoto, H. Ideguchi, T. Inoue, T. Fujita, Y. Ihara, Y. Tomonou, S. Ninomiya, K. Noda (Fukuoka University Hospital), H. Shiraishi, Y. Ueda, K. Otsuka, M. Nakajima (Hokkaido University
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Hospital), K. Kuwabara, Y. Takaishi (Nippon Medical School Hospital), H. Osaka, M. Iai, T. Wada, K. Takano, Y. Tsuyusaki (Kanagawa Children’s Medical Center-Kanagawa), J. Tohyama, N. Akasaka (NishiNiigata Chuo National Hospital), H. Enoki, T. Yokota, T. Matsubayashi (Seirei Hamamatsu General Hospital), S. Itomi, T. Nakata, T. Ikuta (Japanese Red Cross Nagoya Daiichi Hospital), Y. Ohtsuka, Y. Harumi, K. Kobayashi, F. Endo, T. Akiyama, T. Inoue, Y. Hayashi, M. Akiyama (Okayama University Hospital), K. Iyoda, K. Ogawa, S. Itamura, O. Mitani (Hiroshima City Hospital), M. Fukuda, N. Nakano, S. Kawakami, C. Kikuchi, M. Kawabe (Ehime University Hospital), M. Shimono, T. Sato, Y. Honda, M. Ishii (University Hospital of Occupational and Environmental Health), S. Maniwa, N. Kodani, K. Nakano (Matsuyama Red Cross Hospital), K. Minagawa, T. Watanabe, S. Fukumura (Hokkaido Medical Center for Child Health and Rehabilitation). South Korea: H.D. Kim, R. Yu, H.C. Kang, J.R. Yoon, Y.Y. Yi (Severance Hospital, YUCM). References [1] Frank LM, Enlow T, Holmes GL, Manasco P, Concannon S, Chen C, et al. Lamictal (lamotrigine) monotherapy for typical absence seizures in children. Epilepsia 1999;40:973–9. [2] Holmes GL, Frank LM, Sheth RD, Philbrook B, Wooten JD, Vuong A, et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children. Epilepsy Res 2008;82: 124–32. [3] National Institute for Health and Care Excellence (NICE). The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. NICE clinical guideline 137, 2012. Available from:
Please cite this article in press as: Yasumoto S et al. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children: A multicenter, uncontrolled, open-label study. Brain Dev (2015), http://dx.doi.org/10.1016/j.braindev.2015.10.007