Pivotal Trials of LEV in Partial-Onset Seizures
A clinical development plan normally includes several phase III studies, some of which may address special issues (e.g., effects on cognitive function and cognitive outcome; efficacy and tolerability in special groups, such as children, the elderly, or cognitively impaired patients) (Arroyo et al. 2004). The pivotal trial leading toward registration will be an adjunctive therapy trial in refractory partial seizures (Arroyo et al. 2004). Both the FDA and the EMEA are likely to grant approval for use of LEV as an adjunctive therapy for partial epilepsy after at least two adequate and well-controlled trials (Arroyo et al. 2004).
At least four multicenter, double-blind placebo-controlled studies have shown the safety and effectiveness of LEV add-on therapy for refractory partial epilepsy in a clinical setting. These studies used comparable inclusion criteria, selecting male and female adult patients suffering from refractory partial seizures (with or without secondary generalization) that were on a stable regimen of one or two concomitant ACDs and had a stable and reasonable number of seizures. In general, outcome measures were comparable among the studies: the reduction in (weekly) seizure frequency was usually the primary outcome measure and the percentage of responders was usually chosen as the secondary efficacy parameter (according to the Committee for Human Medicinal Products [CHMP] of the EMEA, this refers to the proportion of patients experiencing a reduction in seizure frequency of at least 50% when comparing baseline recordings to the treatment period). Safety and tolerability were reported in all trials and are discussed in detail later. Three studies (N132, N138, and N052) were parallel trials and one (N051) was a crossover trial.
Shorvon and colleagues (Study N051) conducted their 32-week crossover study in 62 centers in Europe (Shorvon et al. 2000). A large group of patients (n = 324) was distributed across a placebo group, an LEV 1000 mg/day group, or an LEV 2000 mg/day group. In the 1000 mg/day and 2000 mg/day LEV-treated groups, seizure frequency was reduced by 17.1% and 21.4%, respectively (p≤ 0.001 for either dose vs. placebo), with responder rates of 20.8% and 35.2% (compared to 6.3% in the placebo group, p≤ 0.001 for either dose) (Shorvon et al. 2000). The withdrawal rate was limited throughout the experiment: 7.5% and 14.2% the 2000 mg/day in LEV 1000mg/day and groups, respectively withdrew from the study because of one or more adverse events, compared to 5.4% in the placebo group (Shorvon et al. 2000). The incidence of serious adverse events possibly related to the test drug were 2.7% with placebo, 1.9% in the LEV 1000 mg/day group, and 7.5% in the LEV 2000 mg/day group (Shorvon et al. 2000). In general, there were no significant differences in the incidence of adverse events for either LEV-treated group as compared to placebo, although somnolence, asthenia, and headache were seen more often in patients receiving LEV (Table 1) (Shorvon et al. 2000).
Table 1. Most frequently reported adverse events during large clinical trials with LEV.
|Study||Treatment||Accidental injury %||Asthenia %||Dizziness %||Headache %||Infection %||Nausea %||Somnolence %|
|Shorvon et al. 2000||Placebo||15.2|| 8.0|| 3.6|| 8.9|| 6.3|| 4.5|| 4.5|
|LEV 1000 mg/day||12.3|| 7.5|| 4.7||13.2|| 9.4|| 5.7|| 9.4|
|LEV 2000 mg/day||13.2||31.2|| 6.6||16.0|| 6.6|| 2.8||11.3|
|Betts et al. 2000||Placebo||15.4||15.4||×||×|| 7.7|| 2.6||25.6|
|LEV 2000 mg/day|| 2.4||31.0|| 4.8||×|| 2.4||×||26.2|
|LEV 4000 mg/day||13.2||13.2||10.5||×||15.8||13.2||44.7|
|Cereghino et al. 2000||Placebo||24.2||11.6|| 7.4||20.0||12.6||×||13.7|
|LEV 1000 mg/day||16.3||16.3||17.3||21.4||27.6||×||20.4|
|LEV 3000 mg/day||12.9||12.9||19.8||20.8||26.7||×||18.8|
|Ben-Menachem and Falter 2000||Placebo|| 9.5|| 6.7||×||10.5|| 3.8||×|| 3.8|
|LEV 3000 mg/day|| 2.2||13.8||×|| 3.3|| 7.2||×|| 6.1|
|Glauser et al. 2006||Placebo||10.0|| 3.0|| 2.0||×||×||×||11.0|
|LEV 60 mg/kg/day||17.0|| 9.0|| 7.0||×||×||×||23.0|
|Ben-Menachem et al. 2003||LEV 3000 mg/day (median dose)||28.0||22.6||18.9||25.8||26.6|| 9.1||23.0|
|Morrel et al. 2003||LEV 1000, 2000, or 3000 mg/day||×|| 8.3|| 7.2|| 5.9||×||×||12.8|
|Genton et al. 2006||LEV 2000 mg/day (median dose)||×||19.2|| 9.7||11.2||×||×||16.7|
|Ben-Menachem et al. 2006||CBZ 434.1 mg/day||×||14.1||13.7||25.4||×||10.7|| 9.3|
|LEV 1170.4 mg/day (mean dose)||×||16.5||10.9||20.7||×|| 7.0||11.2|
|Verdru et al. 2005||Placebo||×||×||×||23.3||×||×||×|
|LEV 2935 mg/day (mean dose)||×|| 6.5||10.2||23.3||×||×||13.9|
The crossover part of this study was elaborated on further by Boon and colleagues (Boon et al. 2002). Their study provided additional information on dose–response relationship and on withdrawal effects, showing that LEV displayed dose-dependent effects (the dose of 2000 mg/day was more effective than 1000 mg/day) and demonstrating a lack of typical withdrawal-related adverse events or rebound phenomena after withdrawal or down-titration of the drug (Boon et al. 2002).
Betts and colleagues (Study N052) started a 24-week study in 37 sites in Belgium and the UK (Betts et al. 2000). Although safety and tolerability were the primary outcome measures, the efficacy of LEV at 2000 mg/day and at 4000 mg/day was compared to that of placebo in patients with either partial or primary generalized refractory epilepsy (n = 119). The median reductions in seizure frequency were 41.2% or 66.7% in the LEV 2000 mg/day group and 43.4% or 46.8% in the LEV 4000 mg/day group (partial or generalized seizures, respectively) (Betts et al. 2000). These differences were not significant compared to placebo (Betts et al. 2000). After 24 weeks of treatment, responder rates of 48.1% and 28.6% (2000 mg/day and 4000 mg/day, respectively) were reported, compared to 16.1% in the placebo group (p= 0.01 for the LEV 2000 mg daily treatment group compared to placebo) (Betts et al. 2000). Adverse events were reported in 83.3% of the LEV 2000 mg/day group, in 84.2% of the LEV 4000 mg/day group, and in 84.6% of the placebo group (Betts et al. 2000). The most frequently reported adverse events were somnolence and asthenia (Table 1). The somnolence was most commonly seen in the LEV 4000 mg/day group; the incidence was comparable between the LEV 2000 mg/day and the placebo groups. Asthenia was more often reported in the LEV 2000 mg/day group, but its incidence was similar in the LEV 4000 mg/day and the placebo groups (Betts et al. 2000). Other frequently reported adverse events were accidental injury (most frequent in the placebo group), infection, nausea, dizziness, and urinary tract infection (Table 1) (Betts et al. 2000). Serious adverse events were 7.7% in the placebo group, 7.1% in the LEV 2000 mg/day group, and 10.5% in the LEV 4000 mg/day group, but none of these events was considered to be related to the drug treatment (Betts et al. 2000). In general, the incidence of adverse events was not significantly different between treatment groups (Betts et al. 2000).
Another pivotal trial was performed by Cereghino and colleagues (Study N132). It was a 38-week study conducted at 41 sites in the U.S.A. (Cereghino et al. 2000). A large cohort of patients with refractory partial epilepsy (n = 294) was randomly distributed over either a placebo, an LEV 1000 mg/day group, or an LEV 3000 mg/day group. Again, promising results were obtained, showing highly significant reductions in seizure frequency of 26.1% and 30.1% for LEV 1000 mg/day and LEV 3000 mg/day, respectively (p≤ 0.001 for both doses versus placebo). Responder rates were 37.1% and 39.6% for LEV 1000 mg/day and LEV 3000 mg/day, respectively, compared to 7.4% for placebo (p≤ 0.001 for both doses versus placebo). One or more adverse events were reported by 88.4% of patients in the placebo group, 88.8% in the LEV 1000 mg/day group, and 89.1% in the LEV 3000 mg/day group. Withdrawal rates due to adverse events were low: only 5.3% in placebo-treated patients, 6.1% in the LEV 1000 mg/day group, and 6.9% in the LEV 3000 mg/day group. The withdrawals were mostly due to increased somnolence. Other frequent adverse events more commonly reported in the LEV-treated groups were infection, headache, dizziness, asthenia, rhinitis, and flu syndrome, whereas accidental injury was seen more frequently in the placebo group (Table 1). Serious adverse events were 10.5% in the placebo group, 7.1% in the LEV 1000 mg/day group, and 2.0% in the LEV 3000 mg/day group. Again, no statistically significant differences were found between the incidence of adverse effects in placebo-treated and LEV-treated patients (Cereghino et al. 2000).
Ben Menachem and Falter (Study N138) conducted their phase III study in 47 centers in Europe (Ben Menachem and Falter 2000). A total of 286 patients were randomly distributed over a placebo or a LEV 3000 mg/day groups. A highly significant reduction in seizure frequency of 23% was found in the 3000 mg/day LEV-group (p≤ 0.001 compared to placebo). The reported responder rate for LEV 3000 mg/day was 39.4%, compared to 14.4% for placebo-treated patients (p≤ 0.001). In patients who experienced improved seizure control under add-on treatment, LEV was also evaluated as monotherapy. As in the previously described studies, LEV was in general well tolerated and the incidence of adverse events was low and similar between LEV-treated patients and the placebo-treated group (Table 1). Mild to moderate asthenia and somnolence were the most frequently reported adverse events; they rarely led to drug discontinuation.
Several analyses on the pooled data from the regulatory trials are available. Results of the retrospective analyses vary depending on the inclusion criteria used, but they all clearly show the beneficial effects of LEV add-on therapy in refractory partial epilepsy.
A pooled efficacy analysis by Privitera (2001) demonstrated that patients receiving LEV showed a median decrease in partial seizures of 31.3% compared to baseline (p≤ 0.001 compared to placebo groups). In general, 35% of LEV-treated patients were classified as responders, compared to 9.4% in the placebo groups (p≤ 0.001). The proportion of responders increased with the increase in dose; 28.6%, 35.2%, and 39.5% of patients responded at 1000, 2000, and 3000 mg/day of LEV, respectively (no statistical analyses were performed on these data). Shorvon and van Rijckevorsel (2002) reported that the percentage of patients experiencing a 75% or greater reduction in seizures was 11.8%, 16.8%, and 22.3% for patients receiving 1000, 2000, and 3000 mg/day of LEV, respectively, compared with 3.3% in placebo-treated patients (p≤ 0.001 for all doses versus placebo). Of all patients treated with LEV, 5.7% became seizure-free, compared to 0.6% in the placebo group (p≤ 0.001) (Shorvon and van Rijckevorsel 2002). Leppik and colleagues made a separation between seizure types and showed that the median percentage of seizure reduction was 42.7% for simple partial seizures, 36.1% for complex partial seizures, and 68.5% for secondarily generalized seizures, respectively (p≤ 0.05 for all seizure types vs. placebo). The authors concluded that LEV seems to act at two levels: suppression of simple/complex partial seizures and prevention of secondary generalization (Leppik et al. 2003).
Several pooled analyses focusing on tolerability are available as well. Reviews by Harden, French, Arroyo, and their respective colleagues have pooled safety data from the well-controlled clinical trials discussed previously (Ben-Menachem and Falter 2000; Betts et al. 2000; Cereghino et al. 2000; Shorvon et al. 2000; French et al. 2001; Harden 2001; Arroyo and Crawford 2003). Adverse effects often limit the potential use of ACDs. During clinical trials with LEV, adverse effects were reported to be low, often not being significantly different from placebo, and easily resolved by dose reduction or discontinuation (Buck 2002; Welty et al. 2002). A summary of the most frequent adverse effects reported during the large clinical trials discussed in this review can be found in Table 1. In general, adverse events can be classified into three categories: somnolence/asthenia, coordination difficulties, and behavioral abnormalities/psychoses (Harden 2001). During the controlled trials, the most frequently reported side effects in LEV-treated patients were somnolence (14.8% vs. 8.4% in placebo), asthenia (14.7% vs. 9.1% in placebo), headache (13.7% vs. 13.4% in placebo), infection (13.4% vs. 7.5% in placebo), and dizziness (8.8% vs. 4.1% in placebo) (Harden 2001). These adverse events were seen most frequently in the first month of therapy and typically decreased or resolved with continued treatment (Harden 2001; Buck 2002; Welty et al. 2002). Coordination difficulties, including ataxia and abnormal gait, were present in 3.4% of LEV-treated patients compared to 1.6% in the respective placebo-treated group (Harden 2001; Arroyo and Crawford 2003). In the LEV groups, 13.3% of patients reported behavioral disorders including agitation, hostility, anxiety, apathy, emotional lability, depersonalization, depression, or other behavioral symptoms, compared to 6.2% in placebo-treated patients (Harden 2001). Few patients also displayed psychotic symptoms (0.7% compared to 0.2% in placebo) or suicidal behavior (0.5% compared to none in placebo) (Harden 2001). No clear relationship was noticeable between the dose of LEV used and the occurrence of the most frequent adverse events within the therapeutic dosage range of 1000–3000 mg/day (Harden 2001; Arroyo and Crawford 2003).
Although most reported adverse events were mild to moderate, 14.7% of LEV-treated patients and 11.2% of the placebo-treated groups experienced severe adverse events. Severe somnolence (3.1%), asthenia (1.6%), convulsions (1.6%), grand mal convulsions (1.0%), dizziness (0.7%), depression (0.7%), and personality disorders (0.5%) occurred more frequently in LEV-treated patients. Severe accidental injury (2.1%), headache (2.1%), status epilepticus (0.9%), pain (0.5%), confusion (0.5%), and insomnia (0.5%) had a higher prevalence in the placebo group (Harden 2001). In total, 15.0% of LEV-treated patients and 11.6% of placebo-treated patients either withdrew from their respective trial or required a dosage reduction (French et al. 2001; Harden 2001; Arroyo and Crawford 2003). Most common causes for withdrawal from the trial in the LEV group were somnolence (4.4% compared to 1.6% in placebo), convulsions (3% vs. 3.4% in placebo), dizziness (1.4% vs. 0% in placebo), asthenia (1.3% vs. 0.7% in placebo), and rash (none of the LEV group compared to 1.1% of placebo-treated patients) (French et al. 2001; Harden 2001; Arroyo and Crawford 2003).
When verifying for potential laboratory abnormalities and a possible influence of LEV on vital signs, statistically significant differences were found in LEV-treated patients compared to placebo (French et al. 2001; Harden 2001; Arroyo and Crawford 2003). Red blood cell count (mean change of −0.05 × 109/L, p= 0.035), hemoglobin (mean change of −0.11 g/dL, p= 0.010), and hematocrit values (mean change of −0.37%, p= 0.005) were significantly lower in the LEV groups, but did not exceed standard laboratory normal ranges. White blood cell counts were slightly, but not significantly lower in the LEV group, and drug discontinuation due to neutropenia was not necessary in any of the patients. Results of various liver function tests were not different between patients taking LEV and the placebo group, and there was no evidence of LEV-induced changes in renal function or body weight. The adverse event profile was independent of gender (French et al. 2001; Harden 2001; Arroyo and Crawford 2003). Other than hypersensitivity to LEV or ingredients of the formulation, no contraindications for LEV have been formulated (Harden 2001).
The safety review by French and colleagues analyzed not only adverse event profiles of the controlled trials in epilepsy patients, but also those from several placebo-controlled studies of LEV in cognitive and anxiety disorders (French et al. 2001). Patients from the latter two populations were often on LEV monotherapy and in general received much lower doses than epilepsy patients (mean dose of 516 mg compared to 2421 mg in the epilepsy population). There were several interesting differences between the different populations. In epilepsy patients, infections (mainly respiratory and skin infections) were more common in the LEV-treated than in placebo groups, but this was not seen in the other populations. The authors hypothesized that the increase in infections in LEV-treated epilepsy patients was the result of an increase in social interactions due to seizure improvement. A higher incidence of behavioral problems was also reported in epilepsy patients taking LEV, but again not duplicated in any of the other two populations. This could suggest that epilepsy patients are more prone to experience behavioral disturbances than patients with cognitive or anxiety disorders, meaning that epilepsy patients with a history of behavioral problems treated with LEV should be carefully observed (French et al. 2001).
In conclusion, analysis of the regulatory trials provides strong evidence for the anticonvulsant effects of LEV add-on in adult patients with refractory partial epilepsy. LEV was shown to have a beneficial tolerability profile, a favorable responder ratio, and a low withdrawal rate, especially when compared indirectly with several other ACDs. LEV had a better responder rate than GPT and LTG, while equally well tolerated and a significantly lower withdrawal rate than TPM and OXZ with comparable efficacies (Otoul et al. 2005).
Long-term Results with LEV Add-on Therapy in Partial-Onset Seizures
In an attempt to clarify the long-term efficacy and retention rates for LEV add-on therapy, several reviews have pooled all original and follow-up data gathered during the clinical development program for LEV. This includes data from the four double-blind randomized multicenter controlled (regulatory-type) trials, five follow-up studies, and 26 phase II or open-label continuation trials, providing data from 1422 refractory patients with partial epilepsy who underwent LEV add-on therapy (intention-to-treat population) (Krakow et al. 2001; Ben-Menachem et al. 2003). The median daily dose of LEV was 3000 mg (Krakow et al. 2001; Ben-Menachem et al. 2003). LEV therapy showed a high continuation rate, similar to or better than those reported for various other ACDs during development; 60% after one year, 37% after three years, and 32% after five years. Most withdrawals (43%) were due to problems intrinsic to ACD trials. Withdrawal due to adverse effects occurred in 15.8% of patients, with the most common causes being convulsions (3.4%)—inherent to a population of epilepsy patients, somnolence (2.0%), asthenia (0.6%), depression (0.6%), dizziness (0.5%), and headache (0.5%) (Krakow et al. 2001). The median reduction in seizure frequency over the whole treatment period was 39.6%, and responder rates determined after three months of LEV treatment were 39.2% (Krakow et al. 2001; Ben-Menachem et al. 2003). These numbers did not decrease significantly over time and no evidence for the development of tolerance was found. Again, no evidence was found for serious drug-related side effects or increased mortality (Krakow et al. 2001; Ben-Menachem et al. 2003).
Additional data on the long-term effects and retention rate of LEV are provided by several large-scale open-label trials. Patients in these community-based clinical settings are more diverse than patients in controlled clinical trials; they are more likely to have co-morbid medical conditions, to be older, to be receiving multiple ACDs, and to have less severe epilepsy than subjects enrolled in controlled trials (Morrel et al. 2003). The multicenter KEEPER1 trial was a 16-week, phase IV open-label community-based trial that enlisted 1030 patients who responded inadequately to their current medications at the time (Morrel et al. 2003). LEV was added to their existing regimen at a maximum dose of 1000 mg/day (37.7%), 2000 mg/day (27.6%), or 3000 mg/day (29.8%). During the trial, the median reduction in partial seizure frequency was 62.3%, and 57.9% of patients showed at least 50% reduction in seizure frequency. A total of 72.5% of all patients originally included in the study (intention-to-treat [ITT] population) completed the entire study, with 12.9% of patients withdrawing due to adverse events, 2.8% due to lack of efficacy, and 11.8% due to other reasons. Adverse events were reportedly low and are summarized in Table 1. Serious adverse events, considered to be related to LEV treatment, occurred only in 0.3% of patients. Behavioral adverse events occurred at a low rate; hostility was noted in 1.7% of patients, emotional lability in 1.7%, depression in 1.5%, agitation in 1.2%, anxiety in 1.2%, and depersonalization in 0.1% of patients.
In an additional subgroup analyses of only elderly patients (n = 78) included in the KEEPER trial, 76.9% of patients were responders and an impressive number of 40.0% became seizure-free. As in the general population, LEV was well tolerated (Ferrendelli et al. 2003; Morrel et al. 2003).
The SKATE2 study was another large, 16-week community-based phase IV multicenter trial that further evaluated the safety and efficacy of adjunctive LEV therapy in uncontrolled partial seizures in daily clinical practice (Genton et al. 2006). The study was completed in December 2005 and an interim analysis has recently been presented. Seven hundred and thirty-one patients were included in the analysis, showing a median reduction in seizure frequency of 47.8%, a responder rate of 48.4%, and a seizure-free rate of 16.8% at a median dose of LEV 2000 mg/day. Again, retention rates were high, with 84.4% of the ITT population completing the treatment period. Adverse events were not frequently reported and were mostly mild to moderate in nature (Table 1). Behavioral and psychiatric side effects were closely monitored and proved to be rare, including depression (3.4%), hostility (2.2%), emotional lability (1.1%), personality disorder (1.1%), anxiety (0.5%), and agitation (0.4%). Overall, 8.9% of patients experienced serious side effects. Adverse events led to withdrawal in 11.1% of patients, which was similar to the premarketing studies (10.3%) and the KEEPER trial (12.9%).
Results from the 16-week KEEPER and SKATE trials indicate that LEV is generally well tolerated in a patient population with refractory epilepsy as seen by epileptologists worldwide. Adverse events reported during long-term open-label studies have confirmed that chronic use of LEV does not appear to be associated with an increase in the incidence of adverse events or with the development of unexpected adverse effects (Arroyo and Crawford 2003; Bauer et al. 2006). In a long-term open label study of 505 patients receiving LEV (median dose: 3000 mg/day) with a mean follow-up of almost three years (range: 24 days to more than seven years), Bauer and colleagues reported adverse event profiles that were similar to those in short-term controlled trials, with the exception of somnolence, which was less prevalent in their trial (Bauer et al. 2006). The most commonly reported adverse effects during follow-up were convulsions (30.5%), accidental injury (28.1%), infection (21%), headache (20%), pain (13.9%), asthenia (12.9%), flu (11.3%), and dizziness (10.7%). In their population, the most common serious side effects were convulsions (9.5%) and accidental injuries (7.9%) and 7.7% of patients discontinued the study due to an adverse event. Bauer and colleagues confirmed the favorable tolerability profile of LEV at therapeutic doses in the treatment of refractory epilepsy, even when taken for several years (Bauer et al. 2006).
In conclusion, results from open label studies indicate that LEV is efficacious in a patient population with refractory epilepsy as seen by epileptologists worldwide and have also confirmed that LEV is generally well tolerated, with adverse events being mild to moderate in nature and serious adverse events being rare (Morrel et al. 2003; Genton et al. 2006). These studies seem to suggest a rule of thumb of roughly achieving a 50% reduction in seizure frequency in 50% of patients. This efficacy is higher than reported in the phase-III controlled studies, which could be explained by multiple reasons, mainly related to differences in study design and patient population (Morrel et al. 2003; Genton et al. 2006). In addition, long-term retention rates for LEV have proven to be high. In a large cohort of patients with chronic focal epilepsy, Depondt and colleagues reported an average retention rate (Kaplan–Meier survival analyses) in clinical practice of 58% at three years, suggesting LEV to be either more efficacious, better tolerated, or both, compared to LTG, TPM, and GPT (Depondt et al. 2006). Additionally, this report confirmed that almost half of patients involved in the study experienced a seizure reduction of at least 50%.
LEV Monotherapy in the Treatment of Partial-Onset Seizures
One of the regulatory trials discussed previously made the first switch into LEV monotherapy (Ben-Menachem and Falter 2000). Following the add-on phase of the trial, 69 responders were selected for down-titration of concomitant ACDs, with 71% being successfully converted to LEV monotherapy at 3000 mg/day and 52% completing the study. The median reduction in partial seizure frequency compared to baseline was 73.8% (p= 0.037), and the responder rate was 59.2%. Little more than 18% of patients remained seizure-free on LEV monotherapy. Ben-Menachem and Falter provided the first clear evidence that refractory patients responding to LEV add-on therapy could be successfully switched to LEV monotherapy. Since then, numerous case reports and small open-label studies have corroborated these findings (e.g., Alsaadi and Thieman 2003; Alsaadi et al. 2005; Ben-Menachem 2003).
In a preliminary review on the long-term experience with LEV monotherapy, Ben-Menachem (2003) reported 67 patients who had been placed on LEV monotherapy for at least three months. Their seizure frequencies were low and remained stable over time. These patients had a high likelihood of becoming seizure-free; the probability of having a seizure-free period of almost three years was 52.2%. Little more than 73.5% of patients experienced one or more adverse events, but treatment-related serious adverse events were reported in only 4.1% of patients. Of the entire study population, 67.3% of patients on LEV monotherapy for at least three months completed the study (the duration of monotherapy in these patients ranged from 132 to 1968 days). Withdrawal due to adverse events occurred in 2% of patients, whereas 6.1% discontinued the drug due to loss or lack of efficacy. In general, LEV monotherapy proved to be well tolerated. The adverse events profile was consistent with that previously described in add-on therapy, but specific adverse effect ratios were not mentioned.
In April 2006, a first, well-controlled study was presented demonstrating the efficacy of LEV monotherapy in patients with partial or generalized seizures (Ben-Menachem et al. 2006). In this study, newly or recently diagnosed epilepsy patients (n = 579) were randomized to receive either LEV at a starting dose of 1000 mg/day or CBZ controlled release (CR) at a starting dose of 400 mg/day. This dose was maintained for a six-month evaluation period or until the next seizure. When a seizure occurred, doses were increased (LEV to 2000 mg/day or CBZ CR to 800 mg/day, and subsequently to LEV 3000 mg/day or to CBZ CR 1200 mg/day). Once six months of seizure freedom were achieved, patients entered a six-month maintenance period. In the ITT population, 66.7% of LEV- and 66.7% of CBZ CR-treated patients became seizure-free for at least six months. Of the 472 patients who adhered to the treatment protocol (per-protocol [PP] population), 56.6% of LEV and 58.5% of CBZ CR patients were seizure-free for one year. In addition, fewer patients on LEV (14.7%) than patients on CBZ CR (19.3%) required discontinuation of the treatment or change in the dose because of an adverse event. On the other hand, more patients discontinued the study because of lack of efficacy in the LEV group (17.5%) than in the CBZ CR group (10.0%). Overall, 80.8% of patients in the CBZ CR group and 79.6% of patients in the LEV group reported one or more adverse events (Table 1). Serious adverse events were seen in 10.0% of CBZ CR-treated patients and in 6.3% of the LEV-treated group. Overall, the safety profile appeared slightly more favorable in the LEV-treated patients, mainly because of the lower overall discontinuation rate. Neurological adverse events (depression, nervousness, and insomnia) were more prevalent in the LEV group than in the comparative CBZ CR group, whereas skin rash and gastrointestinal adverse effects were more prevalent in the CBZ CR group. Not unexpected, the tolerability profile of LEV in monotherapy was comparable to that in the adjunctive therapy in partial-onset seizures and again, the benefit–risk profile for LEV was highly favorable. Ben-Menachem and colleagues thus clearly demonstrated that LEV is noninferior to CR CBZ when used as monotherapy in the first-line treatment of adult patients with partial or generalized seizures. Although a margin of 15% (noninferiority) was selected, the adjusted absolute difference between the two treatments proved to be only 0.2%. As stated previously, these key results convinced the Committee for Medicinal Products for Human Use (CHMP) of EMEA to issue a positive opinion to approve marketing authorization for LEV as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. The manufacturers plan to review these data with the FDA. To date, no superiority trials have been published, and approval for monotherapy has not yet been granted by the FDA. An elaborate conversion-to-monotherapy trial for partial seizures will start to enlist patients in the U.S.A. as of April 2007. The primary objective of this study3 is to assess the efficacy of LEV compared with a historical control as the placebo, in the monotherapy of patients with partial onset seizures.
LEV Add-on Therapy in Primary Generalized Epilepsy
In 2006, LEV was approved by both the EMEA and the FDA as adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents from 12 years of age suffering from JME. This approval came about following a key trial by Verdru and colleagues (N166), extended with an open-label study (Verdru et al. 2005). In their phase III double-blind randomized placebo-controlled study, the effect of LEV adjunctive therapy was assessed in patients (n = 120) suffering from primary generalized epilepsy with myoclonic seizures. Patients were randomized into a LEV 3000 mg/day or a placebo group, with both populations receiving only one concomitant ACD. Throughout the placebo-controlled trial, patients in the LEV group showed a mean reduction in myoclonic seizure-days/week of 48.5% and a responder rate of 58.3% compared to 8.9% and 23.3%, respectively, in the placebo group (p= 0.0002). A therapeutic benefit of LEV add-on therapy was already observed at a starting dose of 1000 mg/day. During the stable dosage period, 21.7% of LEV-treated patients became completely seizure-free compared to 3.4% in the placebo group (p= 0.0001).
During this placebo-controlled trial, 66.7% of placebo-treated patients and 75% of the LEV group experienced one or more adverse events, considered related to treatment in only half of the cases. In the LEV group, 3.2% of patients discontinued the therapy because of adverse events, compared to 1.7% in the placebo group. Of all patients exposed to LEV, 5% reported serious adverse events, while none occurred in the placebo group. In addition, nonpsychotic behavioral disorders (aggression, irritability, and staring), mood disorders (emotional lability, apathy, and depression), and sleep disorders occurred at least twice as often in the LEV group as in the placebo group (5.0%, 6.7%, and 6.7%, respectively, vs. 1.7%, 3.3%, and 1.7% in the placebo group). Nevertheless, LEV proved to be a safe and well-tolerated therapeutic option in this controlled trial; no new adverse effect findings were reported and the safety profile observed was comparable to that originally described in partial seizures. LEV thus proved to have a favorable benefit–risk profile in JME as well.
All of the patients included in this key trial were diagnosed with JME, but some also experienced primary generalized tonic–clonic seizures. Patients from this subgroup responded well to LEV therapy, with a median reduction of 84% in tonic–clonic seizure frequency, although this did not reach statistical significance due to the limited number of patients in this subpopulation (p= 0.1228). An even smaller subset of patients also presented themselves with absence seizures. LEV did not aggravate seizures—as is sometimes seen with several other ACDs effective in partial seizures—but also did not induce additional protection compared to placebo in this limited number of patients (Perucca 2001; Verdru et al. 2005).
Positive preliminary results of a phase III randomized, double blind, placebo-controlled trial have been recently presented (Rosenfeld et al. 2006). These investigators reported that during a 24-week trial, 72.2% of LEV-treated patients became responders, compared to 45.2% of placebo patients (p= 0.0005). During the stable dose period, 34.2% of LEV-treated and 10.7% of placebo-treated patients were free from primary generalized tonic–clonic seizures (p= 0.001). In addition, 24.1% of LEV-treated patients became completely seizure-free, compared to 8.3% in the placebo group (p= 0.009). Again, preliminary analysis suggested that LEV was safe and well tolerated in these patients. Safety data were similar to the established profile of LEV, the most commonly reported adverse effect being somnolence. During the double-blind period, 1.3% of LEV-treated patients and 4.8% of the placebo group withdrew due to adverse events. Further details on adverse events will be made available in the revised European Public Assessment Report (EPAR) after marketing authorization has been granted by the European Commission.
In response to this key trial, the CHMP of EMEA has issued a positive opinion recommending that the European Commission grant a marketing authorization for LEV as adjunctive therapy in the treatment of primary generalized tonic–clonic seizures in adults and adolescents from 12 years of age with IGE.
Additionally, a large number of anecdotal case reports and small-scale open-label studies are available on adjunctive LEV-therapy in primary generalized epilepsy (Grünewald 2005). In summary, LEV add-on therapy appears to be safe and effective in primary generalized epilepsy, although further follow-up studies are necessary to confirm its long-term anticonvulsant profile.