Epilepsia, 42(Suppl. 4):31 35, 2001 Blackwell Science, Inc. International League Against Epilepsy Efficacy of : A Review of Three Pivotal Clinical Trials Michael Privitera University of Cincinnati Medical Center, Department of Neurology, Cincinnati, Ohio, U.S.A. Summary: is a novel antiepileptic drug (AED) with favorable pharmacologic characteristics and demonstrated activity in improving seizure control. Three multicenter doubleblind, placebo-controlled studies were conducted in 904 patients with refractory partial-onset seizures. Patients were required to have a minimum of two or four seizures per week (depending on the study) and were maintained on a stable regimen of one or two AEDs at baseline that was continued during the study period. Patients ranged in age from 14 to 70 years, with a mean age of 37 years. After an 8- to 12-week baseline period, patients were randomized and had doses titrated upward every 2 weeks over a period of 4 weeks to a target dose of 1,000, 2,000, or 3,000 mg/day of levetiracetam or placebo. Treatment was continued for a 12- to 14-week evaluation phase followed by an optional open-label treatment phase. The treatment period consisted of the dose titration period combined with the evaluation period. The median percentage reduction in seizure frequency (over placebo) was calculated for each of the levetiracetam treatment groups over the entire treatment period. For all levetiracetam dose groups, in all studies, reduction in seizure frequency over placebo was statistically significant (p 0.001). Median percentage reductions were 26.1% and 17.1% in the 1,000-mg/day groups (study 1 and study 2, respectively), 21.4% in the 2,000-mg/day group (study 2), and 30.1% and 23.0% in the 3,000-mg/day groups (study 1 and study 3, respectively). The percentage of patients achieving a 50% reduction from baseline in seizure frequency compared with the treatment period was 37.1% and 20.8% in the 1,000- mg/day groups (study 1 and study 2, respectively), 35.2% in the 2,000-mg/day group (study 2), and 39.6% and 39.4% in the 3,000-mg/day groups (study 1 and study 3, respectively). These responder rates were significantly higher than those for placebo (p < 0.001 for all comparisons). was generally well tolerated in all studies. from these three pivotal studies demonstrate that levetiracetam, as adjunctive therapy, is a safe and effective treatment for refractory partial-onset seizures in adults. Key Words: Antiepileptic drugs Clinical trials Efficacy. The most important test of an antiepileptic drug (AED) is its ability to prevent seizures. The effectiveness of levetiracetam as adjunctive antiepileptic therapy was established in three multicenter, well-controlled phase III studies in patients with a history of partial-onset seizures with or without secondary generalization. A stable dosage regimen of one to two concomitant AEDs was held constant throughout. The results of these studies, which have recently been published, are reviewed here. EFFICACY STUDIES Address correspondence and reprint requests to Dr. M. Privitera at Department of Neurology, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, OH 45267-0525, U.S.A. E-mail: Michael.privitera@uc.edu The efficacy of levetiracetam has been evaluated in three randomized, double-blind, placebo-controlled clinical studies enrolling a total of 904 patients (1 3). Inclusion criteria and patient demographics in the three pivotal studies are summarized in Tables 1 and 2, respectively. Detailed descriptions of patient eligibility criteria and demographics for each study have been published elsewhere (1 3). A complete description of the safety profile of levetiracetam can be found in the article by Dr. Cynthia Harden included in this supplement, Safety Profile of. Study 1 (U.S. study) Study 1 was a 38-week, double-blind, parallel group, multicenter, placebo-controlled study conducted at 41 study sites in the United States (1). Patients with refractory partial epilepsy were randomized into one of three treatment groups: placebo, levetiracetam 1,000 mg/day (500 mg, b.i.d.), or levetiracetam 3,000 mg/day (1,500 mg, b.i.d.). There was a prospective 12-week placebo baseline period during which patients continued to take their AED regimen with the addition of a single-blind placebo. This was followed by an 18-week treatment period that consisted of 4 weeks of dose titration then 14 weeks of double-blind evaluation on the regimen to 31
32 M. PRIVITERA TABLE 1. Overview of inclusion criteria for three pivotal studies (1 3) Inclusion criteria Study 1 Study 2 Study 3 History of partial-onset seizures (minimum no. of years before study) 2 2 1 Refractory to standard AED therapy Yes Yes Yes Concomitant AEDs 1 2 1 2 1 Stable AED regimen a Yes Yes Yes Sex M/F M/F M/F Age (yr) 16 70 16 65 16 70 Baseline seizures (minimum no. of seizures every 4 wk) 2 b 4 2 AED, antiepileptic drug. a AED regimen unchanged for the 4 weeks prior to study entry and during the baseline period. b Also, a minimum of 12 seizures within 12 weeks prior to study entry. TABLE 2. Baseline demographics of patients in three pivotal studies (4) Parameter (n 592) (n 312) Gender Male 317 (53.5%) 156 (50.0%) Female 275 (46.5%) 156 (50.0%) Age (yr) Mean 37.2 ± 11.1 37.0 ± 11.7 Range 14 70 16 69 Race White 563 (95.1%) 295 (94.5%) Black 19 (3.2%) 9 (2.9%) Other 10 (1.7%) 8 (2.6%) which they were randomized. doses were increased every 2 weeks during the titration period until the target dose was achieved. In the 1,000-mg/day dose group, levetiracetam was initiated at 333 mg/day (166.5 mg, b.i.d.), was increased to 666 mg/day (333 mg, b.i.d.) after 2 weeks, and was increased again to the final 1,000- mg/day dose level (500 mg, b.i.d.) after an additional 2 weeks of titration. Patients assigned to the 3,000-mg/day dose level were started on levetiracetam 1,000 mg/day (500 mg, b.i.d.), were increased to 2,000 mg/day (1,000 mg, b.i.d.) after 2 weeks, and were further increased to 3,000 mg/day (1,500 mg, b.i.d.) after 2 more weeks. Concomitant AED regimens were maintained at the dosage being administered at study entry. Of the 294 patients randomized, 95 received placebo, 98 received levetiracetam 1,000 mg/day, and 101 received levetiracetam 3,000 mg/day. The 18-week treatment period was followed by either an 8-week, double-blind withdrawal period or entry into an open-label follow-up study. The primary efficacy variable was a between-group comparison of the percentage reduction in weekly partial seizure frequency (mean number of partial-onset seizures per week) relative to placebo. Secondary efficacy variables included the responder rate (the percentage of patients with 50% reduction in seizure frequency compared with baseline) and a retrospective analysis of the categoric response to treatment ( 75, 90, and 100% seizure reduction). Efficacy analyses were performed on patients who had both baseline and ontreatment seizure count data (n 293) and were calculated over the entire 18-week treatment period, unless otherwise noted (1). Of 294 randomized patients, 268 completed the 18- week treatment period, with 266 of these patients electing to enter the open-label follow-up study (1). During the treatment period, the median percentage reduction in seizure frequency over placebo was 26.1% in the levetiracetam 1,000-mg/day group and 30.1% in the levetiracetam 3,000-mg/day group (p < 0.001 for both doses versus placebo) (Table 3). There was also a statistically significant difference in the responder rate between the placebo group and the two treatment groups. The responder rate was 7.4% in the placebo group, 37.1% in the 1,000-mg/day group, and 39.6% in the 3,000-mg/day group (p < 0.001 for both doses versus placebo) (Table 3). More levetiracetam-treated patients exhibited a categoric response to treatment than did placebo-treated patients (Table 3). Up to 19.8% achieved 75% seizure reduction, up to 10.9% achieved 90% seizure reduction, and up to 5.9% achieved 100% seizure reduction (4). Worsening of seizure frequency (increases >25% as compared with baseline) during the 14-week evaluation period was reported by 25.8% of placebo patients versus 13.8% and 12.2% of patients taking levetiracetam 1,000 and 3,000 mg/day, respectively (1). Seizures were counted every 2 weeks during the titration period, a frequency sufficient to allow an analysis of the onset of effect. Daily doses for the levetiracetam 1,000-mg/day group were 333 mg/day at visit 5 (weeks 1 and 2 with drug) and 666 mg/day at visit 6 (weeks 3 and 4 with drug). Doses for the levetiracetam 3,000-mg/day group were 1,000 mg/day at visit 5 (weeks 1 and 2 with drug) and 2,000 mg/day at visit 6 (weeks 3 and 4 with TABLE 3. Reduction in seizure frequency and responder rate during study 1 treatment period (1,4) (n 95) 1,000 mg/day (n 97) 3,000 mg/day (n 101) Percentage reduction in seizure frequency over placebo 26.1% a 30.1% a 50% 7.4% 37.1% a 39.6% a 75% 1.1% 13.4% 19.8% 90% 0 8.3% 10.9% 100% 0 4.1% 5.9% a p < 0.001 vs. placebo.
EFFICACY OF LEVETIRACETAM 33 drug). Efficacy during the titration period was evaluated by analyzing changes in seizure frequency from baseline over the first 4 weeks of levetiracetam exposure. Statistically significant (p < 0.05) reductions in the median seizure frequency were found after 2 and 4 weeks of treatment and were maintained throughout the evaluation period for both levetiracetam groups (Fig. 1) (4). This is an important observation, as it suggests that the antiepileptic effect of levetiracetam is apparent within 2 weeks of starting treatment. was generally well tolerated, with the incidence of adverse events being similar in the placebo and levetiracetam groups (1). Most side effects associated with levetiracetam were mild-to-moderate central nervous system (CNS) disturbances such as somnolence, asthenia, and dizziness. These CNS side effects, however, rarely led to drug discontinuation and were not dose related. Study 2 (European study) Study 2 was a double-blind, multicenter, placebocontrolled, crossover study conducted at 62 centers in Europe in which levetiracetam was evaluated as add-on therapy in patients with treatment-refractory partial seizures, with or without secondary generalization (2). Patients were randomized into one of three treatment groups: placebo, levetiracetam 1,000 mg/day (500 mg, b.i.d.), and levetiracetam 2,000 mg/day (1,000 mg, b.i.d.). There was an 8- to 12-week baseline period followed by the initiation of study medication. During the 4-week titration period, patients in the 1,000 mg/day dose group were started on placebo (b.i.d.) for the first 2 weeks and then had levetiracetam initiated at the full dose level (500 mg, b.i.d.) for the last 2 weeks of titration. In the 2,000-mg/day group, patients started at 1,000 mg/day (500 mg, b.i.d.) and were increased to 2,000 mg/day (1,000 mg, b.i.d.) after 2 weeks. Titration was followed by a 12-week evaluation period. Concomitant AED regimens were maintained at the dosage being administered at study entry. Of the 324 patients randomized, 112 received placebo; 106 received levetiracetam 1,000 mg/day; and 106 received levetiracetam 2,000 mg/ day. The primary efficacy variable was a between-group comparison of the percentage reduction in weekly partial seizure frequency (mean number of partial-onset seizures per week) relative to placebo. Secondary efficacy variables included responder rate and a retrospective analysis of categoric response to treatment (as described for study 1). Efficacy analyses were performed on patients who had both baseline and on-treatment seizure count data (n 322) and were calculated over the entire 16-week treatment period, unless otherwise noted (2). Of the 324 randomized patients, 278 completed the 16-week treatment period (2). The reduction in seizure frequency over placebo was 17.1% in the levetiracetam 1,000-mg/day group and 21.4% in the levetiracetam 2,000-mg/day group (p 0.001 for both doses) (Table 4). There also was a statistically significant difference in the responder rate between the placebo group and the two treatment groups (p < 0.001). The responder rate was 6.3% in the placebo group, 20.8% in the 1,000-mg/day group, and 35.2% in the 2,000-mg/day group (Table 4). More levetiracetam-treated patients exhibited a categoric response to treatment than did placebo-treated patients (Table 4). Up to 16.2% achieved 75% seizure reduction, up to 6.7% achieved 90% seizure reduction, and up to 2.9% achieved 100% seizure reduction (4). Worsening of seizure frequency (increases >25% as compared with baseline) during the 12-week evaluation period was reported by 29.2% of placebo patients versus 13.9% and 19.0% of patients treated with levetiracetam 1,000 or 2,000 mg/day, respectively (4). Similar to the results of study 1, the incidences of adverse events were similar in both the placebo and levetiracetam groups. Most adverse events were CNS related and included asthenia, headache, and somnolence. FIG. 1. Median percentage reduction from baseline in type I seizure frequency per week. Median % Change From Baseline 70 60 50 40 30 20 10 0 Baseline Titration Evaluation 12 14 16 18 22 26 30 Week LEV 1000 mg LEV 3000 mg
34 M. PRIVITERA TABLE 4. Reduction in seizure frequency and responder rate during study 2 treatment period (4) (n 111) 1,000 mg/day (n 106) 2,000 mg/day (n 105) Percentage reduction in seizure frequency over placebo 17.1% a 21.4% a 50% 6.3% 20.8% b 35.2% b 75% 1.8% 8.5% 16.2% 90% 0.9% 4.7% 6.7% 100% 0.9% 1.9% 2.9% a p 0.001 vs. placebo. b p < 0.001 vs. placebo. TABLE 5. Reduction in seizure frequency and responder rate during study 3 treatment period (4) (n 104) 3000 mg/day (n 180) Percentage reduction in partial seizure frequency over placebo 23.0% a 50% 14.4% 39.4% a 75% 4.8% 23.9% 90% 0 12.2% 100% 0 6.7% a p < 0.001 vs. placebo. Study 3 (European study) Study 3 was a double-blind, parallel-group, multicenter, placebo-controlled study conducted at 47 sites in Europe (3). The study consisted of a 12-week baseline period, a levetiracetam add-on phase, and a subsequent responder-selected monotherapy phase; only the add-on portion of the study is described in this review. Patients with clinically observed, treatment-refractory, partialonset seizures were randomized into one of two treatment groups: placebo or levetiracetam 3,000 mg/day (1,500 mg, b.i.d.). During the 4-week titration period, patients assigned to the levetiracetam group were started on levetiracetam 1,000 mg/day (500 mg, b.i.d.), were increased to 2,000 mg/day (1,000 mg, b.i.d.) after 2 weeks, and were further increased to 3,000 mg/day (1,500 mg, b.i.d.) after 2 more weeks. The treatment evaluation period continued for another 12 weeks. The concomitant single-aed regimen was maintained at the dosage being administered at study entry. Of the 286 patients randomized, 105 received placebo and 181 received levetiracetam 3,000 mg/day. The primary efficacy variable for the add-on portion of the study was a between-group comparison of the percentage reduction in weekly partial seizure frequency (median number of partial-onset seizures per week) relative to placebo. Secondary efficacy variables included responder rate and a retrospective analysis of categoric response (as described for study 1). Efficacy analyses were performed on patients who had both baseline and on-treatment seizure count data (n 284) and were calculated over the 16-week add-on treatment period, unless otherwise noted (3). Of the 286 randomized patients, 239 completed the add-on period of the study (3). The median percentage reduction in seizure frequency over placebo was 23.0% in the levetiracetam 3,000-mg/day group compared with 7.2% in the placebo group (p < 0.001) (Table 5). There also was a statistically significant difference in the responder rate between the placebo group (14.4%) and the levetiracetam 3,000-mg/day group (39.4%; p < 0.001). More levetiracetam-treated patients exhibited a categoric response to treatment than did placebo-treated patients. In the levetiracetam group, 23.9% achieved 75% seizure reduction, 12.2% achieved 90% seizure reduction, and 6.7% achieved 100% seizure reduction (4) (Table 5). Worsening of seizures (>25% increase in frequency from baseline) during the 12-week evaluation period occurred in 21.6% of the placebo group and in 12.9% of the levetiracetam 3,000-mg/day group (4). As in studies 1 and 2, levetiracetam was generally well tolerated, with the incidence of adverse events being low and similar in the placebo and levetiracetam groups (3). Most side effects associated with levetiracetam were mild to moderate and included the CNS-related side effects asthenia and somnolence. Pooled efficacy analysis A pooled efficacy analysis was performed on the 589 levetiracetam-treated patients (all doses combined) and 310 placebo-treated patients who had both baseline and on-treatment seizure-count data. Patients receiving levetiracetam had an overall 31.3% median decrease in the number of partial-onset seizures per week when comparing the treatment period (titration and evaluation period combined) with baseline. In comparison, there was a median decline in the placebo-treated group of 5.4%. The difference between the levetiracetam and placebo groups was statistically significant (p < 0.001) (4). Overall, 206 (35%) of 589 levetiracetam-treated patients responded to treatment, having a 50% reduction from baseline (during the treatment period) in weekly seizure frequency. Only 29 (9.4%) of 310 placebo patients responded. The difference in response rate was statistically significant (p < 0.001) (4). The proportion of patients who responded to levetiracetam over the treatment period increased with increasing dose. Whereas 9.4% of placebo-treated patients responded, the response rates for levetiracetam dose levels were 28.6%, 35.2%, and 39.5% at doses of 1,000,
EFFICACY OF LEVETIRACETAM 35 FIG. 2. Responder rate by dose group for the three pivotal trials pooled. 2,000, and 3,000 mg/day, respectively (Fig. 2). No statistical analysis was performed on these data. DISCUSSION Three placebo-controlled phase III studies have independently demonstrated that levetiracetam at doses ranging from 1,000 to 3,000 mg/day is effective as add-on therapy in reducing seizure frequency in patients with partial-onset seizures (1 3). Both the individual studies and the pooled data show a tendency toward a greater response with higher dose; however, a consistent increase in response with increased dose has not been shown. Although data from these three pivotal trials demonstrate the efficacy of levetiracetam (1 3), it is unclear how the efficacy compares with that of other recently introduced AEDs. However, in study 1, antiseizure activity was observed within 2 weeks of initiating therapy (1), suggesting a possible advantage for levetiracetam. Few studies have measured how rapidly AEDs exhibit effectiveness, but rapid onset of action is clearly an important consideration in clinical management of patients. As is the case for most new AEDs, studies performed to obtain approval were conducted in adults as add-on therapy for the treatment of partial-onset seizures. These studies were conducted and analyzed in a manner similar to studies of other recently approved AEDs. Efficacy in other seizure types and epilepsy syndromes, as well as in different patient populations (such as children), is being addressed in a continuing clinical development program. The full potential of levetiracetam as a well-tolerated and effective AED is still to be discovered and will likely be explored further to include other neurologic indications. REFERENCES 1. Cereghino JJ, Biton V, Abou-Khalil B, et al. for partial seizures: results of a double-blind, randomized clinical trial. Neurology 2000;55:236 42. 2. Shorvon SD, Lowenthal A, Janz D, et al. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. Epilepsia 2000; 41:1179 86. 3. Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. Epilepsia 2000;41:1276 83. 4. Data on file, UCB Pharma, Inc. Smyrna, GA, 1999.