Original Article
Efficacy of Felbamate in Childhood Epileptic Encephalopathy (Lennox-Gastaut Syndrome)
N Engl J Med 1993; 328:29-33January 7, 1993
- Abstract
Background
The Lennox-Gastaut syndrome is a childhood disorder characterized by multiple types of seizures, mental retardation, characteristic electroencephalographic abnormalities, and resistance to standard antiepileptic drugs. Felbamate is an investigational antiepileptic drug with a preclinical profile that suggests it would be effective in patients with multiple types of seizures. In controlled clinical trials, felbamate was superior to placebo in reducing the frequency of refractory partial-onset seizures.
Methods
We studied the efficacy of felbamate in 73 patients ranging in age from 4 to 36 years who had the Lennox-Gastaut syndrome. During a 28-day base-line phase, the patients received their usual antiepileptic therapies. At the end of this phase, felbamate or placebo was administered for 70 days in addition to the current antiepileptic medications. The dosage of felbamate was titrated during the first 14 days of the treatment phase to a maximum of 45 mg per kilogram of body weight per day or 3600 mg per day, whichever was less. The primary efficacy variables were the total number of seizures counted during a four-hour period of video recording, parents' or guardians' global evaluations of the patients' quality of life, and the total number of atonic seizures, as reported by parents or guardians.
Results
The patients treated with felbamate had a 34 percent decrease in the frequency of atonic seizures, as compared with a 9 percent decrease in the patients who received placebo (P = 0.01). The felbamate-treated patients had a 19 percent decrease in the total frequency of seizures, as compared with a 4 percent increase in the placebo group (P = 0.002). The global-evaluation scores were significantly higher in the felbamate group than in the placebo group from day 49 to the end of the study. There were no significant differences in the frequency of seizures occurring during video monitoring, but there was a significant reduction (P = 0.017) in the number of tonic-clonic seizures during the maintenance period in the felbamate group. The types and frequency of side effects were similar in the two treatment groups.
Conclusions
Felbamate is beneficial in patients with the Lennox-Gastaut syndrome.
Media in This Article
Figure 1
Relation of the Daily Dose of Felbamate to the Number of Atonic Seizures per Day and to Plasma Felbamate Concentrations in 28 Patients with the Lennox-Gastaut Syndrome.Table 1
Characteristics of the Patients with Lennox-Gastaut Syndrome, According to Treatment Group.Article Activity
- Article
The Lennox-Gastaut syndrome is a severe epileptic encephalopathy that affects children and constitutes approximately 5 percent of childhood epilepsies1. The syndrome is characterized by the onset of multiple types of seizures during childhood, including atypical absence and atonic seizures; slow spike-wave electroencephalographic patterns; and mental retardation that is frequently progressive2. It is difficult to control the seizures in these patients, even with multiple anticonvulsant drugs,3 and the prognosis for cognitive development is poor.
Valproate, benzodiazepines, and other antiepileptic drugs are of some benefit in patients with the Lennox-Gastaut syndrome4-6. The control of seizures sometimes improves when the use of multiple drugs is discontinued and the patient's treatment program is simplified7. Cinromide, an investigational antiepileptic drug, was effective in an open-label trial8 but ineffective in a placebo-controlled trial9.
Felbamate (2-phenyl-1,3-propanediol dicarbamate) is an investigational antiepileptic drug undergoing clinical trials in the United States. In preclinical studies, felbamate proved effective against electrically and chemically induced seizures,10 with little systemic toxicity. Although its mechanism of action is not known, the effectiveness of felbamate in these seizure models suggests that the drug exerts its anticonvulsant activity by increasing the seizure threshold and preventing the spread of seizures. In well-controlled add-on studies (studies in which the new medication or placebo is added to current medications),11,12 felbamate was superior to placebo in reducing the frequency of seizures in patients with refractory partial seizures. The objective of this double-blind, placebo-controlled, add-on trial was to evaluate the efficacy and safety of felbamate in patients with the Lennox-Gastaut syndrome.
Methods
Patients
We studied 51 male and 22 female patients with the Lennox-Gastaut syndrome. Patients were eligible for the study if they had a history of multiple types of seizures and a minimum of 90 atonic seizures (seizures characterized by a sufficient change in posture to cause a fall from the sitting or standing position) or atypical absence seizures per month during an eight-week prestudy screening phase, were taking no more than two antiepileptic drugs, had no evidence of progressive central nervous system lesions on magnetic resonance imaging or computed tomography, weighed at least 11.3 kg, and had a slow spike-wave complex ( ≤ 2.5 Hz) on electroencephalography. Female patients were excluded if they were pregnant or were not using adequate contraception. Patients with a history of identifiable progressive neurologic disorders, anoxic episodes within the past year, poor compliance with past antiepileptic therapy, recent drug or alcohol abuse, a major medical illness, or previous suicide attempts were excluded. Patients who had recently received corticotropin, were following ketogenic diets, or had inadequate supervision by parents (or guardians) were also excluded. The protocol was approved by the institutional review board at each institution, and informed consent was obtained from all patients or their parents or guardians before the study began.
Study Design
The trial was divided into two phases: a 28-day base-line phase and a 70-day double-blind treatment phase. Two days before the base-line phase began, the dosages of patients receiving valproate or phenytoin were reduced by 20 percent to minimize potential drug interactions11,13. During a two-day inpatient period at the start of the base-line phase, the patients were monitored for four hours by closed-circuit television and electroencephalography in order to classify the types and frequencies of seizures, and the parents were taught how to count and classify seizures on the basis of observations and video recordings. The number of seizures recorded by videotape was counted. All electroencephalograms were subsequently analyzed at one center by investigators who were unaware of the patients' treatment status. The seizures were coded according to the international classification, as modified in 198114. On the first or second day of the base-line phase, a global evaluation of each patient was made, based on the parents' or guardians' impressions of the patient's quality of life with respect to alertness, verbal responsiveness, general well-being, and seizure control. The following neuropsychological tests were conducted: visual-choice reaction time, grooved pegboard, the digit-span and digit-symbol portions of the Wechsler Adult Intelligence Scale, and controlled word-association tests. During a 26-day outpatient period, the patients received the same doses of the standard antiepileptic drugs that they had been given during the prestudy screening phase, and the parents kept a seizure diary. At the end of the base-line phase, each patient underwent another four-hour session of monitoring by closed-circuit television and electroencephalography. The patients were then randomly assigned in blocks of two to receive either felbamate or placebo by a separate computer-generated randomization schedule at each study center. Felbamate or placebo was added to the standard antiepileptic drug regimen at the end of the base-line phase.
The treatment phase consisted of a 14-day titration period and a 56-day maintenance period. The initial dose of felbamate was 15 mg per kilogram of body weight per day; the daily dose was increased to 30 mg per kilogram after 7 days and to the maximal dose after 14 days. The maximal dose was either 45 mg per kilogram per day or 3600 mg per day, whichever represented the lower dose. During the maintenance period (study days 43 to 98), the patients continued to receive the maximal tolerated dose of the study drug. On study days 49, 70, 84, and 98, vital signs were measured, blood samples (obtained after an overnight fast before the morning dose of drug was given) were drawn for determinations of plasma concentrations of felbamate and standard antiepileptic drugs, global evaluations were made by the parents, and seizure diaries were evaluated. The patients were monitored for four hours by closed-circuit television and electroencephalography on study days 42, 49, 70, and 98. Neurologic examinations, neuropsychological tests, and clinical laboratory evaluations were done on study days 42, 70, and 98. The patients had a complete physical examination on study day 98.
Administration of Study Drugs
Felbamate (200 mg) and placebo were prepared in identical-appearing capsules. The doses of felbamate were established on the basis of body weight and were given four times daily. To maintain the double-blind conditions, the number of capsules taken by patients in the placebo group at each dosage level was based on body weight. If side effects occurred, the number of capsules was decreased at the discretion of the investigator. Compliance was documented by capsule counts.
Evaluation of Efficacy and Safety
The primary evaluation of efficacy was based on two variables: the frequency of seizures during periods of video monitoring, which was performed at the same time of the day to minimize circadian effects,15 and a compound variable consisting of parents' or guardians' global evaluations and parents' or guardians' counts of atonic seizures. At each global evaluation, the parents or guardians assessed the patient's status with use of a seven-point scale, in which a score of +3 indicated that the patient's condition was very much improved, a score of 0 that the condition was unchanged, and a score of -3 that the condition was very much worse. Efficacy was also assessed by two secondary variables: parental counts of total seizures and parental counts of generalized tonic-clonic seizures. The relation of the dose of felbamate to the frequency of atonic seizures was examined during the titration period for patients receiving increasing weekly doses of 15, 30, and 45 mg per kilogram per day. The evaluation of safety included watching for adverse symptoms, monitoring vital signs and body weight, general physical and neurologic examinations, measurements of plasma concentrations of felbamate and standard antiepileptic drugs, and clinical laboratory evaluations.
Statistical Analysis
The efficacy variables were evaluated by analysis of variance. The analysis of variance was performed on a model consisting of a treatment effect, a center effect, and a center-by-treatment interaction. If no evidence of a statistically significant treatment-by-center interaction or center effect was found (P ≥ 0.05), a second analysis of variance assessing the statistical significance of the effect of treatment was performed. If assumptions of normality and homogeneity of variance were violated, nonparametric procedures (Wilcoxon rank-sum test) were performed. For the primary variables, we compared the results during the treatment phase and the maintenance period of the treatment phase. A separate analysis for the latter period was performed because it could be considered more representative of the effects of treatment. For the secondary variables, we compared the total seizure counts and the numbers of generalized tonic-clonic seizures during the treatment phase and the maintenance period. All patients were included in the efficacy analyses.
For the first primary variable, the average number of all seizures occurring during the session of monitoring by closed-circuit television and electroencephalography at the beginning and the end of the base-line phase was compared with the average number of seizures occurring during the four sessions conducted during the treatment phase, and the percent change from the base-line phase was computed for each patient. For the compound primary variable, the mean percent change per day from base line in the parental counts of atonic seizures and in the parents' global evaluations for study days 35, 42, 49, 70, 84, and 98 (or the last evaluation) were analyzed. Global-evaluation scores were analyzed by a weighted least-squares model, consisting of a treatment effect, a center effect, and a center-by-treatment interaction. For the secondary efficacy variables, the daily total seizure counts and generalized tonic-clonic seizure counts provided by the parents were analyzed in the same way as atonic seizure counts.
All patients were included in the statistical analyses of safety. Data on adverse effects were summarized descriptively. Data on vital signs, body weights, and laboratory values were analyzed for changes from base line with Student's t-test for paired data. All tests of statistical significance were two-sided.
Results
The felbamate and placebo groups were comparable with respect to demographic and pretreatment characteristics (Table 1Table 1
Characteristics of the Patients with Lennox-Gastaut Syndrome, According to Treatment Group.).Primary Variables
According to the results of monitoring by closed-circuit television and electroencephalography, the patients who received felbamate had an 11 percent decrease in the frequency of seizures, whereas the patients who received placebo had a 1 percent increase (P = 0.32) during the treatment phase as compared with the base-line phase (Table 2Table 2
Frequency of Seizures in Patients with the Lennox-Gastaut Syndrome during Treatment with Felbamate or Placebo.). During the maintenance period, the frequency of seizures in the felbamate and placebo groups was 1 percent and 3 percent higher, respectively, than during the base-line phase (P = 0.19). Three patients treated with felbamate had no seizures during the television-monitoring and electroencephalographic-recording sessions during the treatment phase, and six had no seizures during these sessions during the maintenance period, when they were taking the maximal tolerated dose of felbamate.Twenty-eight patients in the felbamate group and 22 patients in the placebo group had atonic seizures during the base-line phase. During the treatment phase, the patients treated with felbamate had a 34 percent reduction in the frequency of atonic seizures, whereas the patients given placebo had a 9 percent decrease (P = 0.01). During the maintenance period, the patients treated with felbamate had a 44 percent reduction, as compared with a 7 percent reduction among the patients given placebo (P = 0.002). Three patients treated with felbamate had no atonic seizures during the treatment phase, and five had no seizures during the maintenance period. The global-evaluation scores during the maintenance period were significantly (P<0.001) higher in the felbamate group than in the placebo group from day 49 to the end of the study.
Secondary Variables
With respect to the parental counts of total seizures, the patients treated with felbamate had a 19 percent reduction in the total frequency of seizures, whereas the patients given placebo had a 4 percent increase (P = 0.002) during the treatment phase. During the maintenance period, the patients given felbamate had a 26 percent reduction in the frequency of seizures, as compared with a 5 percent increase among the patients given placebo (P<0.001). Four patients in the felbamate group had no seizures during the maintenance period.
A total of 16 patients treated with felbamate and 13 patients given placebo had generalized tonic-clonic seizures during the base-line phase. During the maintenance period, the felbamate-treated patients had a 40 percent reduction in the frequency of seizures, as compared with a 12 percent increase among the patients given placebo (P = 0.017). Seven patients in the felbamate group had no generalized tonic-clonic seizures during the maintenance period.
Dose-Response Analysis
The dose-response and dose-concentration relations, expressed in terms of parental counts of atonic seizures, were examined during the intervals when the doses of felbamate were increased from 15 to 45 mg per kilogram per day. There was a linear decrease in the frequency of atonic seizures that coincided with the increase in the plasma concentration of felbamate (Figure 1Figure 1
Relation of the Daily Dose of Felbamate to the Number of Atonic Seizures per Day and to Plasma Felbamate Concentrations in 28 Patients with the Lennox-Gastaut Syndrome.). The mean plasma concentration of felbamate after one week of therapy at a daily dose of 45 mg per kilogram was 43.8 μg per milliliter, 86 percent of the mean maximal concentration (51.0 μg per milliliter) during the maintenance period.Safety
The side effects were similar in the two treatment groups (Table 3Table 3
Side Effects of Treatment with Felbamate or Placebo among Patients with the Lennox-Gastaut Syndrome.). Anorexia, vomiting, and somnolence occurred more frequently in the felbamate group, whereas diarrhea occurred more frequently in the placebo group. Most side effects were mild or moderate in severity and self-limited, so that adjustments in the dose of study drug were rarely necessary. Severe side effects were reported by eight patients in the felbamate group and three patients in the placebo group. One patient in the felbamate group withdrew from the trial on study day 47 because of somnolence and ataxia, and one patient in the placebo group withdrew from the trial on study day 42 because of pancreatitis.There were no changes in vital signs in either group during the course of the trial. The incidence of abnormalities on the general physical examination was similar in the two groups, whereas abnormalities on the neurologic examination that were typical of the Lennox-Gastaut syndrome, such as speech disorders and abnormal gait, were twice as frequent in the placebo group; however, the types of neurologic abnormalities were similar in the two groups. The only statistically significant change from base line among the neuropsychological tests performed was an improvement in the digit-symbol test on study day 70 in the felbamate group.
The frequency of laboratory values above or below the normal ranges was similar in the two groups (Table 4Table 4
Frequency of Out-of-Range Laboratory Values in Patients with the Lennox-Gastaut Syndrome during Treatment with Felbamate or Placebo.). Among the patients treated with felbamate, statistically significant (P<0.05) changes from base-line values at each of the three laboratory evaluations during the treatment phase were found only for the leukocyte counts, serum uric acid, and blood urea nitrogen. At the last evaluation, the mean leukocyte count was reduced by 1650 per cubic millimeter (1.65 × 109 per liter), the uric acid concentration was reduced by 0.74 mg per deciliter (44.0 μmol per liter), and the blood urea nitrogen level was reduced by 2.4 mg per deciliter (0.86 μmol per liter). Mild or moderate leukopenia (leukocyte count, 4000 per cubic millimeter [4.0 × 109 per liter]) occurred in two patients treated with felbamate. The patients in the placebo group had significantly lower leukocyte counts at all times during the treatment phase, with a mean decrease of 930 per cubic millimeter (0.93 × 109 per liter) at the last evaluation. One patient who was receiving valproate and clonazepam had a low platelet count (119,000 per cubic millimeter [119 × 109 per liter]) during the base-line phase, and the count decreased to 42,000 per cubic millimeter (42 × 109 per liter) after 13 days of treatment with felbamate. The platelet count returned nearly to the base-line value after the daily dosage of valproate was lowered from 1000 mg to 625 mg. During the treatment phase, the mean plasma concentrations of valproate and phenytoin did not vary by more than 22 percent from their concentrations during the base-line phase.Discussion
The results of this trial indicate that felbamate is effective in the treatment of patients with the various types of seizures associated with the Lennox-Gastaut syndrome. Treatment with felbamate significantly reduced the frequency of atonic seizures in these patients and, according to parental observations, improved the overall quality of life by increasing alertness and verbal responsiveness. The control of seizures in patients with refractory epilepsy is often improved by doses of medication that cause loss of function. The improvement in both components of the compound variable in the felbamate-treated patients indicates that this drug has properties that differ from those of other anticonvulsant drugs.
There was an inverse relation between the plasma concentration of felbamate and the frequency of atonic seizures. The patients treated with felbamate also had statistically significant reductions in the total frequency of seizures and in the frequency of generalized tonic-clonic seizures. Video monitoring indicated an improvement in the frequency of seizures during treatment with felbamate, but the change was not significantly different from that in the placebo group. The decreases in the frequency of seizures in the felbamate-treated patients were more pronounced during the maintenance period of the trial, when the patients were treated with the maximal allowable dose.
The type and frequency of side effects in the felbamate group were similar to those reported in the double-blind trials of felbamate as adjunctive therapy in adults11,12. These side effects were typically mild or moderate in severity, required no change in the dose of felbamate, and generally resolved spontaneously or with a reduction in the doses of concomitantly administered antiepileptic drugs. The abnormalities in neurologic examinations and in clinical laboratory tests in both groups were consistent with the types of findings that would be expected in a group of mentally retarded patients receiving multiple anticonvulsant drugs.
Cinromide (a cinnamamide compound), which has anticonvulsant activity in animals with different types of seizures, was not effective in the Lennox-Gastaut syndrome in a controlled trial9. We used several methods and end points designed to alleviate the inherent difficulties in evaluating anticonvulsant therapy in the Lennox-Gastaut syndrome. The frequency of atonic seizures, rather than that of all seizures, was chosen as the primary end point. Atonic seizures are the most consistently identifiable and reliably documented seizures as well as the most debilitating in this syndrome. The global evaluations were performed by parents or guardians rather than investigators because they would probably be more cognizant of the patients' daily activities, allowing a more accurate estimation of the patients' quality of life. The inclusion criteria specified that patients had to have at least 90 atypical absence or atonic seizures per month, which increased the homogeneity of the study group and ensured that only the most severely affected patients were included. The accuracy of the identification of various types of seizures was improved by having the parents view videotapes of their own child rather than reference examples. These methods and end points may have contributed to the low placebo response in our trial in contrast to the high placebo response in other trials. The improvement in the control of seizures and quality of life combined with the favorable safety profile in these therapy-resistant patients indicates that felbamate represents an important advance in the treatment of epilepsy.
Supported by a grant from Wallace Laboratories, Division of Carter-Wallace, Inc., Cranbury, N.J., and by a grant (M01-RR-00865) from the Public Health Service.
We are indebted to Applied Logic Associates, Inc., Houston, for the statistical analysis of the data.
Source Information
The members of the Felbamate Study Group in Lennox-Gastaut Syndrome are as follows: Frank J. Ritter, M.D., and Ilo E. Leppik, M.D., University of Minnesota, St. Paul; Fritz E. Dreifuss, M.D., Ihor Rak, M.D., Nancy Santilli, R.N., and Roberta Homzie, R.N., University of Virginia Health Science Center, Charlottesville; W. Edwin Dodson, M.D., and Tracy A. Glauser, M.D., Washington University, St. Louis; J. Chris Sackellares, M.D., Larry Olson, M.D., and Elizabeth A. Garafolo, M.D., University of Michigan Hospital, Ann Arbor; W. Donald Shields, M.D., UCLA Medical Center, Los Angeles; Jacqueline French, M.D., and Michael Sperling, M.D., Graduate Hospital, Philadelphia; and Lynn D. Kramer, M.D., Marc Kamin, M.D., Alberto Rosenberg, M.D., Robert Shumaker, Ph.D., James L. Perhach, Ph.D., and Robert Dix, Ph.D., Wallace Laboratories, Cranbury, N.J.
Address reprint requests to Dr. Frank J. Ritter at the Minnesota Epilepsy Group, 310 N. Smith Ave., Suite 300, St. Paul, MN 55102.
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