Abstract
Objective: To compare the safety and efficacy of add-on lamotrigine and placebo in the treatment of children and adolescents with partial seizures.
Background: Add-on and monotherapy lamotrigine is safe and effective in adults with partial seizures, and reports of preliminary uncontrolled trials suggest similar benefits in children.
Methods: We studied 201 children with diagnoses of partial seizures of any subtype currently receiving stable conventional regimens of antiepileptic therapy at 40 study sites in the United States and France. After a baseline observation period (to confirm that more than four seizures occurred in each of two consecutive 4-week periods), patients were randomized to add-on lamotrigine or placebo therapy. A 6-week dose-escalation period was followed by a 12-week maintenance period.
Results: Compared with placebo, lamotrigine significantly reduced the frequency of all partial seizures and the frequency of secondarily generalized partial seizures in these treatment-resistant patients. The most commonly reported adverse events in the lamotrigine-treated patients were vomiting, somnolence, and infection; the frequency of these and other adverse events was similar to that in the placebo-treated group, with the exception of ataxia, dizziness, tremor, and nausea, which were more frequent in the lamotrigine-treated group. The frequency of withdrawals for adverse events was similar between groups. Two patients were hospitalized for skin rash, which resolved after discontinuation of lamotrigine therapy.
Conclusions: Lamotrigine was effective for the adjunctive treatment of partial seizures in children and demonstrated an acceptable safety profile.
Most patients with epilepsy experience partial seizures (with or without secondary generalization). The diagnosis of epilepsy is typically made during childhood,1-3 and antiepileptic drug (AED) therapy often includes phenytoin, carbamazepine, or valproate (VPA). However, these drugs are not effective for all patients with partial seizures, and their use has been associated with the risk of certain side effects, including neurotoxicity, hepatotoxicity, gastrointestinal effects, hematopoietic effects, and fetal abnormalities.4-8 There are few reports of controlled clinical studies in children for these drugs or newer therapies. An AED with efficacy for children with all types of partial seizures and well established tolerability would offer advantages over these traditional drugs.
Lamotrigine (Lamictal; Glaxo Wellcome, Inc., Research Triangle Park, NC) is chemically unrelated to any marketed AED and is effective in many types of epilepsy.9-13 In vitro pharmacologic studies suggest that lamotrigine blocks use- and voltage-dependent sodium channels, although with nonuniform sensitivity because rapidly and repetitively firing neurons are most susceptible to the action of the drug. Blockade of sodium channels reduces the release of excitatory amino acids such as glutamate, which are associated with seizure activity.14,15
Add-on and monotherapy treatment with lamotrigine is effective and well tolerated in adults with partial seizures.11,16,17 Because of the available evidence indicating the benefits of lamotrigine treatment in adults and the need for further treatment options for children with partial seizures, we designed this placebo-controlled study (Protocol 105-040) to investigate the efficacy and safety of lamotrigine when added to the current AED regimen in children and adolescents with partial seizures.
Methods.
Patients.
Eligible patients were 2 to 16 years of age in the United States or 2 to 12 years of age in France, weighed at least 10 kg (unless AED therapy was limited to enzyme-inducing AEDs [EIAEDs]), had a confirmed diagnosis of epilepsy limited to partial seizures classified according to the International Classification of Epileptic Seizures (simple, complex, and secondarily generalized), and were receiving AED therapy. A screening EEG was used to refine or confirm the diagnosis. Patients were eligible for the study if they were incompletely controlled by existing therapy (were judged likely to experience at least four seizures during each of two consecutive 4-week periods during the baseline phase) and if a complete and accurate record of seizures could be obtained throughout the study. Postpubescent girls were required to use an appropriate contraceptive method and (in the United States) to provide signed intent to avoid pregnancy during the study.
Patients were excluded if they 1) had previously been exposed to lamotrigine; 2) were using corticosteroid therapy for the treatment of asthma; 3) had primary generalized, pseudo-, drug-induced, or metabolic seizures; 4) had intracerebral, structural lesions, or history of status epilepticus within the previous 12 weeks; 5) demonstrated medical noncompliance, drug abuse (prescribed, legal, or illicit), psychiatric disorders, or progressive neurologic disorders; 6) had any clinically significant chronic cardiac, renal, or hepatic condition; 7) used vagal stimulation or the ketogenic diet or were likely to undergo surgical treatment for epilepsy during the study; or 8) were pregnant.
Study design and treatments.
The study used a multicenter, double-blinded, placebo-controlled, parallel-group design and consisted of four phases: screening, baseline (8 weeks), treatment (18 weeks), and taper and follow-up (1 to 6 weeks). Current therapy included any stable regimen (unchanged ≥ 2 weeks before baseline) of up to two AEDs, excluding felbamate and gabapentin. The simultaneous use of other investigational or psychoactive drugs was prohibited except for methylphenidate, dextroamphetamine, or clonidine to treat attention deficit-hyperactivity disorder.
The study was conducted in the United States and France, in compliance with the U.S. Code of Federal Regulations, the European Good Clinical Practice guidelines, and the current amendment of the Declaration of Helsinki. Institutional Review Board or Ethics Committee approval was obtained at each site. Written informed consent was provided by the parent or guardian of each patient (often with written concurrence from the patient, when he or she was competent to do so).
After the baseline phase, patients were randomized (1 : 1) with a blocked randomization scheme to treatment with add-on lamotrigine (dose scaled by body weight and rounded to the nearest 5 mg) or matched placebo in bottles labeled with pregenerated patient numbers. Treatment assignments were unknown to all study site personnel, patients, and sponsors. Lamotrigine and matching placebo were provided as berry-flavored chewable/dispersible caplets or tablets in strengths of 5, 25, and 100 mg.
The treatment phase consisted of a 6-week dose escalation period followed by a 12-week period of maintenance therapy. Dose escalation and minimum/maximum maintenance doses depended on concurrent therapy (table 1). If intolerance developed at any time during dose escalation or maintenance, the dose could be decreased down to the minimum maintenance dose. Patients unable to tolerate these doses were discontinued from the study.
Lamotrigine dosing
Procedures.
Conformity with the inclusion and exclusion criteria was documented during the screening phase of the study. Patients entered the 8-week baseline phase of the study within 4 weeks of screening, during which the patient’s seizure frequency, seizure type, and tolerability of the current therapeutic regimen were recorded. During the treatment phase, patients had clinic visits every 2 weeks during dose escalation (weeks 1 to 6) and every 4 weeks during maintenance (weeks 7 to 18). Daily records of 1) the number and type of seizures, 2) study drug and AED dosing, and 3) adverse events were maintained throughout the study. Clinical laboratory tests and neurologic examinations were performed at baseline and each visit during treatment. A 12-lead EKG was performed at the end of the baseline phase and at week 10 of treatment. Adverse events were reported from daily diaries, a verbal probe at each clinic visit, and review of neurologic examinations.
The taper and follow-up phase of the study was conducted in a double-blinded fashion. This phase took 1 to 6 weeks, depending on the dose used during the treatment stage of the study. A follow-up visit was conducted 1 week after the study drug taper was completed. All patients who discontinued treatment during the treatment phase followed the same taper and follow-up procedures.
An open-label protocol (United States only) or compassionate use (France only) was available after the current placebo-controlled study for qualified patients for whom the investigator and caregiver recommended further lamotrigine therapy. Patients were simultaneously tapered off the double-blinded study medication and began dose escalation for the continuation study. The total daily study drug dose was maintained (lamotrigine-treated patients) or was begun by appropriate dose escalation (placebo-treated patients). Because patients enrolled in the continuation studies were provided with unblinded lamotrigine during the taper and follow-up phase (including placebo patients who had not previously received lamotrigine), our analysis does not include adverse event information from the taper and follow-up phase.
Statistical analyses.
All patients randomized to treatment at the end of the baseline phase were included in the safety and efficacy analyses (intent-to-treat). For patients withdrawn before completion of the treatment period, all safety and efficacy data collected before withdrawal are included in the analyses.
The primary end point of the study was the percentage change in seizure frequency between the 8-week baseline stage of the study and 1) the entire 18-week treatment stage, or 2) the 12-week period of maintenance dosing (i.e., on completion of dose escalation). Average weekly seizure frequency was computed for each patient to derive the percentage change values. The percentage change values were compared between treatment groups using the Cochran-Mantel-Haenszel chi-square test, adjusted for center effects. A sample size of 90 patients per treatment group was calculated to permit the detection of a difference of 25% between treatment groups in improvement from baseline with 80% power. For patients who had seizures too numerous to count (n = 4 lamotrigine, 3 placebo), the highest recorded seizure frequency during the treatment period was used as the imputed seizure frequency on days of innumerable seizure activity. Statistical significance was assumed when p ≤ 0.05.
Secondary efficacy end points included the same analyses for the subset of patients with partial seizures with secondary generalization. In addition, treatment groups were compared for the number of patients who achieved reductions of 25% or less, 26% to 49%, or 50% or more in the weekly frequency of seizures by the Fisher’s Exact test and the number of days when each patient was seizure free by the Cochran-Mantel-Haenszel test.
For adverse events, 95% CIs were calculated for treatment group differences in the incidence of individual adverse events. Serious adverse events (i.e., cancers; congenital abnormalities; adverse events that result in death, are life threatening, may be permanently or significantly disabling, require or prolong hospitalization, or result from a drug overdose) were also tabulated. Twelve-lead EKG data were summarized, and the frequency of treatment-emergent EKG abnormalities was tabulated by treatment group.
Results.
Study population.
Figure 1 illustrates the progression of patients through the trial. There were 201 patients at 40 study sites (range, 1 to 15 patients per study site). Two patients were prematurely withdrawn from the study during the baseline observation phase and before randomization. Of the 199 patients randomized to lamotrigine (n = 98) or placebo (n = 101) treatment, a similar proportion of each group was discontinued for withdrawn consent, inadequate response, protocol violations, and adverse experiences. A total of 84 lamotrigine-treated and 83 placebo-treated patients completed the study. The demographic characteristics, seizure history, cutaneous drug reaction history, and baseline seizure characteristics of the treatment groups at randomization were similar (table 2). In addition, approximately half of each group was receiving one versus two concurrent AEDs, and approximately half experienced secondarily generalized seizures.
Figure 1. Flow diagram of patient disposition.
Study population
Protocol violations were infrequent. Of the 199 randomized patients, 4 did not meet all inclusion/exclusion criteria at the screening stage of the study. Two patients not stabilized appropriately on concomitant AEDs before baseline and 1 patient treated for a psychiatric disorder were randomized to lamotrigine. One patient treated with methotrimeprazine for attention deficit-hyperactivity disorder was randomized to placebo. After consultation with the medical monitor, all were allowed to participate in the study. In addition, one investigator measured plasma lamotrigine concentrations in 3 patients and entered the concentrations in the patients’ charts, thus violating the protocol (breaking the blind); this study site was closed after all study medication was properly discontinued.
Overall, 94% of patients took at least 90% of the prescribed study medication doses. Two lamotrigine-treated and 2 placebo-treated patients were discontinued from treatment for noncompliance. Ninety-eight patients took lamotrigine for at least 1 week; of these, 89 took lamotrigine for at least 18 weeks. Mean doses for the 93 patients on lamotrigine in the maintenance period were 11.6 ± 3.6 (median, 12.9) mg/kg/day for patients taking concurrent EIAEDs and no VPA (n = 53), 2.7 ± 0.4 (median, 2.7) mg/kg/day for patients taking VPA alone or with a non-EIAED (n = 22), and 3.9 ± 0.9 (median, 4.2) mg/kg/day for patients taking concurrent VPA and EIAEDs (n = 18).
Efficacy.
Treatment with lamotrigine significantly reduced the frequency of partial seizures from baseline compared with placebo during the entire treatment period (weeks 1 to 18) as well as during the maintenance period (weeks 7 to 18; figure 2). The median percentage changes from baseline in seizure counts with lamotrigine and placebo treatment for weeks 1 to 18 were 36.1% versus 6.7%, respectively (p = 0.008), and for weeks 7 to 18, 44.0% versus 12.8%, respectively (p = 0.012).
Figure 2. Median weekly counts of all types of partial seizures in patients randomized to lamotrigine (n = 98) or placebo (n = 101). *p ≤ 0.05 change from baseline versus placebo.
The frequency of secondarily generalized seizures was also significantly reduced from baseline by lamotrigine treatment compared with placebo during weeks 1 to 18 and 7 to 18 (figure 3). The median percentage changes from baseline in seizure counts with lamotrigine and placebo treatment for weeks 1 to 18 were 53.0% versus 8.6%, respectively (p = 0.003), and for weeks 7 to 18, 66.7% versus 11.2%, respectively (p = 0.013).
Figure 3. Median weekly counts of secondarily generalized partial seizures in patients randomized to lamotrigine (n = 40) or placebo (n = 46). *p ≤ 0.05 change from baseline versus placebo.
The percentages of patients who achieved less than 26%, 26% to 49%, or at least a 50% reduction in the frequency of seizures during weeks 1 to 18 are shown in figure 4. The percentage of patients who achieved at least a 50% reduction in the frequency of all partial seizures during weeks 1 to 18 was 42% with lamotrigine compared with 16% with placebo (p < 0.001), and during weeks 7 to 18 was 45% with lamotrigine compared with 25% with placebo (p = 0.004, data not shown). The percentage of patients who achieved at least a 50% reduction in frequency of partial seizures with secondary generalization during weeks 1 to 18 was 53% with lamotrigine compared with 26% with placebo (p = 0.015), and during weeks 7 to 18 was 57% with lamotrigine compared with 30% with placebo (p = 0.023, data not shown).
Figure 4. Population distribution of seizure frequency reduction in patients randomized to lamotrigine or placebo. *p ≤ 0.05 versus placebo.
For weeks 1 to 18, patients treated with lamotrigine experienced a median increase in days free of all partial seizures of 28.0%, compared with 3.2% for patients treated with placebo (p = 0.003). This difference for weeks 7 to 18 was 33.3% versus 1.3% for lamotrigine and placebo, respectively (p = 0.001). Similarly, lamotrigine-treated patients had a greater increase in days free of secondarily generalized seizures than placebo-treated patients: 39.0% versus 3.6% (p = 0.002) during weeks 1 to 18, and 53.7% versus 4.2% (p = 0.007) during weeks 7 to 18, respectively.
Safety.
At least one treatment-emergent adverse event was reported by 188 patients (92 lamotrigine-treated and 96 placebo-treated patients). The most commonly reported adverse events (i.e., those reported by ≥10% of patients in either treatment group) are listed in table 3. With the exception of ataxia, dizziness, tremor, and nausea, which occurred more frequently in the lamotrigine group, the differences in the frequency of adverse events between treatment groups were not statistically significant. Most were rated as mild or moderate in severity.
Adverse events reported by at least 10% of patients in either treatment group
A similar number of patients in each treatment group was withdrawn because of an adverse experience (five lamotrigine- and six placebo-treated patients). The adverse events leading to withdrawal of lamotrigine were rash (n = 4) and tremor (n = 1); those leading to withdrawal of placebo were rash (n = 3), increased seizures (n = 1), brain tumor (n = 1), and threatened suicide (n = 1). Seven patients on lamotrigine (including three patients with rash leading to withdrawal) and nine patients on placebo (including the patients withdrawn for brain tumor and threatened suicide) reported serious adverse experiences during treatment.
Rash was reported for 16 lamotrigine- and 18 placebo-treated patients (see table 3). Among the lamotrigine-treated patients, 14 reported nonspecific rash, 1 erythema multiforme, 1 vesiculobullous rash, and 1 Stevens-Johnson syndrome. (Patients could report more than one kind of rash.) Among placebo-treated patients, 15 reported nonspecific rash, 2 maculopapular rash, and 1 urticaria. All placebo-treated patients reported mild rash, whereas 12 patients using lamotrigine reported mild rash, 2 moderate rash, and 2 severe rash. Nine patients in the lamotrigine group had rashes that were judged by the investigator to be reasonably attributable to study drug, resulting in dose reductions or drug discontinuation in 6 patients. Six patients in the placebo group had rashes that were considered reasonably attributable to study drug.
Two lamotrigine-treated patients were hospitalized for rash. One of these cases occurred in a 10-year-old girl who was receiving concurrent VPA and had previously been treated with antibiotics for varicella. The rash was observed 12 days after a 0.5 mg/kg/day dose of lamotrigine was introduced. She was hospitalized with a generalized maculopapular rash, which was later diagnosed as Stevens-Johnson syndrome. Later review of the case by three external expert dermatologists did not confirm the diagnosis. Lamotrigine was withdrawn, she was treated with intravenous steroids, and her condition improved. The other child hospitalized because of rash was a 3-year-old boy on concurrent phenytoin. The patient was started on a lamotrigine dose of 2 mg/kg/day with dose escalation every 2 weeks, per protocol. He was hospitalized with a pruritic and papular rash with some erythema 54 days after study drug initiation while receiving 15 mg/kg/day of lamotrigine. The patient was treated with oral antihistamines and topical hydrocortisone cream, and lamotrigine was discontinued. Later rechallenge with lamotrigine led to another incident of rash in this patient. These two cases of rash were considered reasonably attributable to lamotrigine therapy.
There were no consistent changes in clinical laboratory tests or EKG data with either treatment, and no pregnancies occurred.
Discussion.
This placebo-controlled study demonstrated the efficacy of lamotrigine as adjunctive therapy in children with partial seizures. The frequency of all types of partial seizure was significantly reduced by 44% during lamotrigine treatment compared with 13% during placebo treatment in the maintenance period. The frequency of secondarily generalized seizures was also reduced. In addition, more patients receiving lamotrigine had at least a 50% improvement and more seizure-free days than those receiving placebo. Lamotrigine reduced seizure frequency, although these patients were resistant to stable regimens of conventional AEDs. The results can be extrapolated to clinical application because the design of the current study was similar to approaches used in clinical practice (adjustments based on concurrent AED therapy, individual tolerability, and individual efficacy).
These data are consistent with previous findings of open-label or retrospective studies demonstrating the effectiveness of lamotrigine as adjunctive therapy in children, including those with partial seizures.18-23 Besag et al.18 found that a substantial number of children (31%) with intractable partial seizures experienced a reduction of at least 50% in seizure frequency during the first 12 of 48 weeks treatment with lamotrigine in five pooled, open-label studies. This effect is comparable with the response rate (42%) during the entire 18-week treatment period in the current study. Schlumberger et al.19 collected data from 120 children, including those with partial seizures, and also found that lamotrigine was effective in reducing seizure frequency.
The results of this study contribute to the overall understanding of the spectrum of lamotrigine effectiveness across seizure types and patient groups. In the current study, add-on lamotrigine was effective in children with partial seizures, including those with secondary generalization. Lamotrigine has also been evaluated in children for the treatment of primary generalized absence seizures24 and has been demonstrated to reduce the frequency of generalized seizures associated with the Lennox-Gastaut syndrome.10,25 In adults, lamotrigine treatment for partial seizures is effective both as an adjunctive treatment11,16 and as monotherapy.17
Lamotrigine was in general well tolerated in these children. The incidence of adverse events and withdrawals due to adverse events was similar to that observed in the placebo group. The type and incidence of adverse events also were similar to those reported in adults treated with lamotrigine.26
The incidence of cutaneous adverse reactions in the current study was similar in the lamotrigine and placebo groups; however, there were two cases of rash in patients taking lamotrigine that were associated with hospitalization and discontinuation of treatment. Other cases of rash resulting in hospitalization after lamotrigine treatment have been previously reported.27,28 Other AEDs can cause similar cutaneous reactions,6-8,29-31 and the concurrent use of VPA, carbamazepine, or phenytoin or resulting drug interactions may have affected the results in the current study. Although the mechanism by which AEDs cause rash remains obscure, there may be an immunologic component.32-34 In addition, the initial dose and dose escalation of lamotrigine in this study, higher than currently recommended, could have resulted in an increased incidence in rash. It is now clear that the risk of rash increases with coadministration of VPA, exceeding the recommended initial dose of lamotrigine, or exceeding the recommended dose escalation of lamotrigine. The new dose initiation and escalation recommendations for add-on lamotrigine use in children 2 to 12 years of age35 are summarized in table 1 and compared with those used in the current study.
Appendix
The Lamictal Pediatric Partial Seizures Study Group also included Ricardo Ayala, MD (AMO Corporation, Tallahassee, FL); Jeffrey Buchhalter, MD, and Richard J. Konkol MD, PhD (Oregon Health Sciences University, Portland, OR); Raymond D. Cheng, MD, and Edwin Trevathan MD, MPH (Scottish Rite Children’s Medical Center, Atlanta, GA); J. P. Carriere, MD (Hôpital Purpan, Toulouse, France); Patricia K. Crumrine, MD, and Bryan J. Lynch, MB, BCh (Children’s Hospital of Pittsburgh, Pittsburgh, PA); Robert P. Cruse, DO (Health Advance Institute, Peoria, IL); Mauricio R. Delgado, MD (Texas Scottish Rite Hospital for Children, Dallas, TX); Thomas C. Enlow, MD (Akron Pediatric Neurology, Akron, OH); Toufic A. Fakhoury, MD (Medical Center South, Nashville, TN); Jose A. Ferreira, MD (Pediatric Neurology Associates, St. Petersburg, FL); L. Matthew Frank, MD (Neurodevelopmental Center, Norfolk, VA); William Garnett, PharmD (Medical College of Virginia, Richmond, VA); F. Goutieres, MD (Hôpital des Enfants Malades, Paris, France); May L. Griebel, MD (Arkansas Children’s Hospital, Little Rock, AR); Jin S. Hahn, MD (Stanford University Medical Center, Stanford, CA); Michael H. Kohrman, MD (Children’s Hospital of Buffalo, Buffalo, NY); Anthony T. Lassiter, MD (Toledo Neurological Associates, Toledo, OH); Kenneth D. Laxer, MD, and Daniel L. Bluestone, MD (The Medical Center of UCSF, San Francisco, CA); Stella B. Legarda, MD, and Bernard Maria, MD, MBA (University of Florida, Gainesville, FL); Ilo E. Leppik, MD, and Bernard H. Maister, MD (MINCEP Epilepsy Care, Minneapolis, MN); Paul M. Levisohn, MD (The Children’s Hospital of Denver, Denver, CO); Denise E. Malkowicz, MD, and James E. Wark, MD (Mid-Atlantic Regional Epilepsy Center, Philadelphia, PA); Mohammed A. Mikati, MD (Children’s Hospital, Boston, MA); Wagar U. Mirza, MD (St. Louis University Health Sciences Center, St. Louis, MO); Wendy Gayle Mitchell, MD (Children’s Hospital of Los Angeles, Los Angeles, CA); Eli M. Mizrahi, MD (Baylor College of Medicine, Houston, TX); Jacques Motte, MD (American Memorial Hospital, Reims, France); Amanda Naguiat, MD, and R. Eugene Ramsay, MD (University of Miami, Miami, FL); Bruce R. Parks, PhD, and Samuel R. Snodgrass, MD (University of Mississippi Medical Center, Jackson, MS); Franĉois Pouplard, MD (Chu D’Angers, Angers, France); Frank J. Ritter, MD (United and Children’s Hospital, St. Paul, MN); James R. Schimschock, MD (New Emmanuel Medical Center, Portland, OR); Raj D. Sheth, MD (West Virginia University, Morgantown, WV); Robert M. Shuman, MD (Health Advance Institute, South Bend, IN); Marc Tardieu, MD (Hôpital Bicetre, Bicetre, France); Michael B. Tennison, MD (University of North Carolina, Chapel Hill, NC); and Merrill S. Wise, MD (The Children’s Hospital, Birmingham, AL).
Acknowledgments
Acknowledgment
The authors thank Anthony W. Fox, MD, PhD, FFPM, of Carlsbad, CA, and Elizabeth Field, PhD, of Glaxo Wellcome, for editorial assistance with the manuscript.
Footnotes
- Received January 25, 1999.
- Accepted April 29, 1999.
References
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