Efficacy of gabapentin as adjunctive therapy in a large, multicenter study. The Steps Study Group.

The objective of this study was to determine the efficacy of gabapentin as adjunctive therapy in doses required to achieve the most effective seizure control. There were 2016 patients with partial seizures requiring adjunctive therapy who received gabapentin at doses up to 3600 mg/day in this open-label, multicenter, 16-week study. Of the 1055 patients evaluable for efficacy, 573 received gabapentin < or =1800 mg/day and 482 received > 1800 mg/day as the highest dose received. For the overall efficacy evaluable population, the percentage of patients achieving at least a 50% reduction in seizure frequency was 76.0%; 46.4% of the patients were seizure free. Patients whose highest gabapentin dose did not require > 1800 mg/day had, at baseline, fewer seizures and were receiving fewer concomitant antiepileptic drugs (AEDs) at baseline than those patients requiring > 1800 mg/day. This suggests that patients requiring higher doses of gabapentin were more refractory to drug treatment at the start of the study. Gabapentin was well tolerated at all doses in this study. The results of the study demonstrate that gabapentin is effective as adjunctive therapy in patients with partial seizures whose seizures are inadequately controlled by traditional AEDs.     

Efficacy and safety of levetiracetam in children with partial seizures: an open-label trial

PURPOSE: To assess the efficacy and safety of levetiracetam (LEV) as adjunctive therapy in children with treatment-resistant partial-onset seizures. METHODS: Children (aged 6-12 years) with treatment-resistant partial-onset seizures receiving one standard antiepileptic drug (AED) were eligible. After a 4-week baseline period, children received LEV in a 6-week titration phase (target dose, 40 mg/kg/day) followed by an 8-week evaluation phase. Seizure frequency during the evaluation period with individualized LEV doses (20-40 mg/kg/day) were compared with the 4-week baseline seizure frequency. Plasma concentrations of LEV and other AEDs were determined to evaluate potential drug interactions. RESULTS: Twenty-four subjects enrolled and received LEV; 23 entered the evaluation phase, and 22 completed the evaluation phase. Compared with their baseline seizure frequency, 12 (52%) of 23 subjects entering the evaluation phase had their seizure frequency decrease by >50%. Two subjects remained seizure free during the entire evaluation period. LEV did not significantly affect plasma concentrations of any concomitant AED during this study, and no alteration of mean clinical laboratory values was observed. The most commonly reported adverse events were headache, infection, anorexia, and somnolence. CONCLUSIONS: This open-label study of adjunctive LEV therapy (at 20-40 mg/kg/day) suggests that LEV is effective, safe, and well tolerated in children ages 6-12 years with treatment-resistant partial-onset seizures. A randomized, placebo-controlled, double-blind trial of LEV adjunctive therapy in children with treatment-resistant partial-onset seizures is needed and ongoing to confirm these open-label findings.     

Evaluation of Gabapentin in an Outpatient and Office-based Sample of Epilepsy Patients

A retrospective analysis of charts of patients who received gabapentin (GBP) as adjunctive anticonvulsant therapy in its first year of marketing, between March 1994 and April 1995 was conducted to evaluate patterns of use, side effects, and efficacy in the general epilepsy population. Ninety patients (45 men, 45 women) with an average age of 33.5 years (range: 7 months–78 years) were included. Average GBP dosage was 1700 mg/day; 46 patients took <1800 mg, and 44 patients took ⩾1800 mg/day. Duration of GBP treatment ranged from 1 month–14 months. Patients took an average of 1.7 concurrent antiepileptic drugs while on GBP. A total of 13 patients were on GBP monotherapy, four at the outset joined by nine others during the study. Gabapentin was associated with improvement as assessed by reduction of seizure frequency in 69 patients (77%). Sixty patients (67%) who reported no side effects had a mean GBP dosage of 1900 mg/day (median: 2000 mg/day). The 30 patients who experienced side effects had a mean GBP dosage of 1600 mg/day (median: 1500 mg/day). Gabapentin was discontinued in 21 patients, six because of side effects, nine because of lack of efficacy, and six because of a combination of both. Gabapentin was used in more difficult patients with intractable epilepsy and was generally well tolerated. Higher doses were not associated with more side effects, suggesting that GBP-related side effects may not be dose-related.     

Adjunctive lacosamide in clinical practice: sodium blockade with a difference?

Lacosamide (LCM) was licensed in the United Kingdom in 2008 for the adjunctive treatment of partial-onset seizures. It exerts its effect by enhancing sodium channel slow inactivation. This article reports preliminary outcomes with adjunctive LCM in the everyday clinical setting. To date, 113 patients (57 males, 56 females; aged range = 18–74 years, median = 39 years) with uncontrolled partial-onset seizures (monthly frequency range = 1–300, median = 4) have been included in the audit. Patients were taking 1–4 (median = 1) antiepileptic drugs (AEDs), having previously tried 1–12 (median 3) drug schedules. After 12 weeks on stable AED dosing, LCM was added, aiming at an initial target range of 200–400 mg/day. Review took place every 6–8 weeks until one of four endpoints was reached: seizure freedom for ≥ 6 months on a given LCM dose; ≥ 50% (responder) or < 50% (marginal benefit) seizure reduction over 6 months compared with baseline on the highest tolerated LCM dose; withdrawal of LCM because of lack of efficacy, side effects, or both. An endpoint has been reached by 65 (57.5%) patients so far. Seventeen (26.2%) have remained seizure free on a median daily LCM dose of 100 mg (range = 50–300 mg). Patients were more likely to become seizure free when LCM was used as a first add-on (15/36, 41.7%), compared with a later treatment schedule (1/27, 3.7%, P = 0.001). With appropriate dose manipulation, patients taking traditional sodium blockers (5/26, 19.2%) were as likely to become seizure free as those taking AEDs with other mechanisms of action only (11/37, 29.7%). Fifty percent or greater seizure reduction was achieved in an additional 16 (24.6%) patients (1 monotherapy); 18 (27.7%) reported marginal benefit. Two patients were established on LCM monotherapy (one seizure free, one responder). Patients remaining on LCM were as likely to also be taking sodium blockers only (23/27, 85.1%) as AEDs with other mechanisms (26/36, 72.2%). LCM was withdrawn in 14 patients (12.3% of ongoing patients, 21.5% of those at an endpoint; 10 for side effects, 4 for lack of efficacy). The most common side effects leading to withdrawal were sedation, ataxia, and dizziness. Of the 10 with side effects, only 2 patients took concomitant sodium blockers. Patients on sodium valproate were more likely to discontinue LCM (8/21, P = 0.018) than those also taking other AEDs; 5 of the 8 did so because of side effects and 3 because of lack of efficacy. In patients with partial-onset seizures, LCM is an effective and well-tolerated adjunctive AED when combined with appropriate doses of traditional sodium blockers, as well as agents with other mechanisms of action. Seizure freedom was more likely when LCM was used as a first add-on compared with a later treatment schedule. Patients also taking sodium valproate were significantly more likely to discontinue LCM compared with those taking other AEDs. These data suggest that the pharmacological effect of LCM differs importantly from that of AEDs that influence fast inactivation of the sodium channel.     

Safety Profile of Levetiracetam

Summary: Levetiracetam was approved in November 1999 as add-on therapy for the treatment of partial-onset seizures in adults (age 16 years and older). This review focuses on recently published data from four well-controlled studies in patients with partial-onset seizures with or without secondary generalization. When levetiracetam was given along with other antiepileptic drugs (AEDs), the most frequently reported adverse events were central nervous system related. Adverse events were usually mild to moderate in intensity, with the most frequently reported events occurring predominantly during the first 4 weeks of treatment. No relationship was apparent between the dose of levetiracetam and the most commonly reported adverse events in well-controlled clinical trials within the recommended dose range of 1,000–3,000 mg/day. Levetiracetam is a Pregnancy Category C drug. Overall, when used in combination with other AEDs, levetiracetam was generally well tolerated as add-on treatment for partial-onset seizures.     

Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy

PURPOSE: This randomised, double-blind study compared the newer antiepileptic drugs (AEDs) gabapentin (GBP) and lamotrigine (LTG) as monotherapy in newly diagnosed epilepsy. METHODS: Patients with partial seizures with and/or without secondary generalization or primary generalized tonic-clonic seizures were randomized to either GBP or LTG. During 2- and 6-week titration periods, respectively, GBP dosage reached 1,800 mg/day, and LTG, 150 mg/day. In the subsequent 24-week maintenance phase, the dose could be adjusted based on seizure control or adverse events between 1,200 and 3,600 mg/day for GBP and 100 and 300 mg/day for LTG. The primary end point was time to exit, a composite of efficacy and tolerability. Evaluable patients were used for the primary efficacy analysis, whereas tolerability was examined on an intent-to-treat basis. RESULTS: A total of 309 patients was randomized, and 291 (148 GBP, 143 LTG) were included in the evaluable population. Nineteen patients in each group had an exit event. The median time to exit was 69 days for GBP and 48 days for LTG. The hazard ratio was estimated as 1.043 (90% confidence intervals, 0.602-1.809). Overall, 106 (71.6% of the evaluable population) GBP-treated and 96 (67.1%) LTG-treated patients completed the study. Of those, 80 (75.5%) patients taking GBP and 73 (76.0%) taking LTG remained seizure free during the final 12 weeks of treatment. Only 14 (8.9%) GBP-treated patients and 15 (9.9%) LTG-treated patients withdrew because of study drug-related adverse events. CONCLUSIONS: GBP and LTG monotherapy were similarly effective and well tolerated in patients with newly diagnosed epilepsy.     

Gabapentin: Discussion

Summary: Gabapentin (GBP, Neurontin) is a novel anti-epileptic drug (AED) that was shown to be effective against refractory partial seizures in five placebo-controlled trials. However, a number of patients with complex partial seizures experienced an increase in seizure frequency, suggesting that patients suffering from complex partial seizures are not a homogeneous group. In fact, we found that currently available AEDs are likely to be ineffective when staring is a prominent component of complex partial seizures. The poor response of this group of patients may reflect the fact that staring spells are inhibitory seizures and that the AEDs prescribed for partial seizures appear to facilitate inhibitory mechanisms. GBP resembles phenytoin (PHT) and carbamazepine (CBZ) in depressing segmental and reticular excitatory mechanisms and facilitating segmental inhibitory mechanisms, just as it resembles PHT and CBZ in efficacy against some partial seizures and against secondarily generalized seizures. Perhaps the patients in whom GBP increased seizure frequency had complex partial seizures with staring and were therefore unlikely to benefit from drugs such as GBP, CBZ, and PHT, which enhance inhibitory mechanisms in the brain. These findings suggest that future AED trials would greatly benefit from a categorization of complex partial seizures into no-sologically distinct groups.     

Conversion to High Dose Gabapentin Monotherapy in Patients with Medically Refractory Partial Epilepsy

Summary: Purpose: To evaluate the safety and efficacy of high dose gabapentin (GBP) monotherapy (3,0004,800 mg/ day) in patients with medically refractory partial epilepsy.
Methods: GBP monotherapy at daily doses up to 4,800 mg was attempted in patients participating in the open-label phase of a double-blind, dose-controlled, GBP monotherapy trial. For those who achieved monotherapy, the types and severity of adverse events were assessed and the average seizure frequency per 28 days while maintained on the highest daily GBP dose was compared to the seizure frequency during the baseline phase of the double blind trial. Correlation analysis between GBP serum level, total daily dose, and percentage of seizure change from baseline was performed.
Results: A total of 45 patients participated in the open-label phase of the trial and 23 (51%) were converted successfully to GBP monotherapy. In those patients, the average daily gabapentin dose was 3,900 mg and the mean length of follow-up was 252 days. Compared to baseline, there was a mean reduction of 54%, 43%, and 14% for simple partial, complex partial and secondarily generalized seizures respectively, while maintained on high-dose GBP monotherapy. A significant linear correlation between daily GBP dosage (2,4004,800 mg) and resultant mean serum levels was found (r = 0.51; p < 0.01). There was no significant correlation between seizure frequency and total daily GBP dose or with serum levels. High-dose GBP monotherapy was well tolerated; only one patient exited the trial because of adverse events. The most common adverse event was tiredness/sleepiness and was not dose-related.
Conclusions: GBP monotherapy is well tolerated in daily doses of up to 4,800 mg and is effective in a subgroup of patients with medically refractory partial epilepsy.     

Gabapentin in childhood epilepsy: a prospective evaluation of efficacy and safety

PURPOSE: To evaluate the efficacy and safety of gabapentin (GBP) in partial epilepsy in children. METHODS: We performed a prospective open label add-on study in 52 children and adolescents (age 1.8-17.5 years, mean 11.1 years) with refractory partial seizures. Gabapentin was added to one other baseline drug and the efficacy was rated according to seizure type and frequency. RESULTS: The GBP dose ranged from 26 to 78 mg/kg per day (mean 52 mg/kg per day) and was well tolerated in most patients. The seizure frequency remained unchanged in 34 patients (65%). We saw a provocation of seizures in three children (6%). Initially 15 patients (29%) benefited from GBP: five (10%) with a seizure reduction of 50-74%, seven (13%) with a reduction of 75-99% and three (6%) became seizure free. All but three experienced a development of tolerance within the next weeks to months. CONCLUSIONS: Although gabapentin seems also to be safe in children, the efficacy in refractory partial seizures was disappointing.     

AUStralian Study of Titration to Effect Profile of Safety (AUS-STEPS): High-Dose Gabapentin (Neurontin) in Partial Seizures

PURPOSE: To evaluate the safety, tolerability, efficacy, and impact on quality of life of gabapentin (Neurontin; GBP) as adjunctive therapy in patients with refractory partial seizures. METHODS: AUS-STEPS was an open-label, multicenter, prospective study in patients experiencing partial seizures who were inadequately controlled with one to three concurrent antiepileptic drugs (AEDs). GBP treatment was titrated to a maximum of 4,800 mg/day, over a treatment period of 24 weeks, to achieve an efficacious and tolerable dosage. Efficacy was assessed by seizure-frequency data. Quality of life was evaluated by using the QOLIE-10 questionnaire, and safety was assessed by adverse-event reports and clinical laboratory findings. RESULTS: A total of 176 patients received treatment with GBP, with 174 evaluable for intention-to-treat (ITT) efficacy analysis. A reduction of >50% in overall seizure frequency was observed in 93 patients (53%). There was a small (4.6%) overall improvement in QOLIE-10 score. The most frequent adverse events were dizziness (31%), fatigue (29%), somnolence (27%), headache (21%), and ataxia (20%), with no major increase seen in adverse events necessitating discontinuation as the dose of GBP was titrated upward. CONCLUSIONS: This study indicates that patients with partial epilepsy may be effectively treated with GBP at dosages of < or =4,800 mg/day, without altering the safety profile of the drug.     

Gabapentin as add-on therapy in focal epilepsy: a computerized EEG study.

OBJECTIVES: Gabapentin (GBP) possesses a well documented clinical efficacy in those types of focal epilepsy otherwise resistant to conventional antiepileptic drugs (AEDs); on the basis of this, it appears important to investigate the drug effects on the EEG epileptiform and background activity. METHODS: Twenty-five patients with cryptogenic or symptomatic partial epilepsy resistant to conventional AED treatment were included in the study. All patients underwent long-term video-EEG recordings before and after GBP addition (900-1200 mg/day). RESULTS: Quantitative analysis of the interictal EEG paroxysms revealed that GBP had no effect on the rate of occurrence of interictal and ictal EEG abnormalities. GBP was active in delimiting the spatial extent of the interictal spiking activity in those patients who displayed a significant reduction (> or =50%) in seizure occurrence (32% of the patients). EEG background activity recorded under rest condition from 18 out of 25 epileptic patients, before GBP therapy, was characterised by a higher content of the slow spectral components (delta and theta) with respect to control subjects. After GBP addition, the increase of theta relative power was also evident during task performance. CONCLUSIONS: These findings suggest that GBP does not interfere with the generation of interictal EEG spiking while it appears to reduce the susceptibility to seizures concomitantly with a limiting effect on the spiking activity spatial extent. The utilization of GBP in controlling focal seizures is reinforced by the absence of negative influence on cognitive functioning.     

Long-term safety and efficacy of gabapentin (neurontin) as add-on therapy in patients with refractory partial seizures

In an international, multicenter, open-label study, the long-term efficacy and safety of gabapentin (GBP, Neurontin) as add-on therapy were investigated in 203 patients with partial seizures refractory to standard antiepileptic drugs (AEDs). All patients enrolled in this study had experienced improved seizure control with GBP in one of four previous, short-term studies. Patients received mean GBP dosages of 1,283 to 2,220 mg/day for periods of ⩽1,894 days (mean, 385 days). For purposes of efficacy analyses, data were divided into 12-week treatment periods. During long-term treatment, the efficacy of GBP was shown to be maintained by several primary efficacy measures. In all of the 12-week treatment periods, the percentage of change in seizure frequency from baseline was equal to or less than −24%, responder rate was >35%, and response ratio ranged between −0.2 and −0.338. Results for secondary efficacy measures also indicated that efficacy was maintained. The favorable safety profile of GBP also was maintained during long-term treatment. Our results suggest that GBP is an effective, safe, and well-tolerated add-on treatment for long-term use in patients with partial seizures refractory to standard AEDs.     

The impact of background antiepileptic drugs on the efficacy and safety of pregabalin in treating partial-onset seizures: a post hoc analysis of combined clinical trials

Pregabalin is used as adjunctive treatment for partial-onset seizures and is often combined with multiple antiepileptic drugs (AEDs) from different classes. The objectives of this post hoc analysis were to evaluate the efficacy and safety of pregabalin when added to different AED regimens and to identify specific AED combinations that in conjunction with pregabalin yield high responder rates. Data from six double-blind, randomized studies of pregabalin in patients with partial-onset seizures were pooled for analysis (N=1775). When the treatment groups (placebo, 150mg, 300mg, 600mg, and flexible dose) were stratified by the number of concomitant AEDs (one, two or three or more), modeling results suggested that the magnitude of improvement on either ≥50% responder rate or mean response ratio remained consistent regardless of the number of concomitant AEDs. Adverse events were typical of pregabalin and, in general, did not vary as the number of concomitant AEDs increased. A cluster analysis was performed to identify possible combinations of AEDs that yielded high ≥50% responder rates. The majority of patients (>90%) fell within two clusters that yielded high responder rates, while <10% of the patients fell within two clusters that yielded low responder rates. Numerous AED combinations, ranging from 6 to 11, occurred within each cluster. In summary, pregabalin provided a consistent improvement in seizure reduction and comparable tolerability in patients with partial-onset epilepsy regardless of the number of concomitant AEDs.     

Lack of Interaction of Gabapentin with Carbamazepine or Valproate

Summary: Gabapentin (GBP) studies were conducted in patients with epilepsy receiving carbamazepine (CBZ, n= 12) or valproate (VPA, n = 14) monotherapy. The effects of GBP coadministration on steady-state CBZ or VPA concentrations and of these antiepileptic drugs (AEDs) on GBP pharmacokinetics were investigated. GBP (400 mg) was coadministered every 8 h for 3% days with CBZ or for 5 1/3 days with VPA. GBP was well tolerated. Mean steady-state plasma CBZ/CBZ-10, ll-epoxide (CBZ-E) and serum VPA concentrations before, during, and after GBP administration were not significantly different. Mean steady-state GBP pharmacokinetic parameters during CBZ or VPA coadministration were similar to steady-state parameters reported in healthy subjects. Thus, no pharmacokinetic interaction exists between CBZ or VPA and GBP. No dosage adjustment is necessary when GBP and CBZ or VPA are coadministered.     

Clinical Efficacy of New Antiepileptic Drugs in Refractory Partial Epilepsy: Experience in the United States With Three Novel Drugs

Summary: A number of new antiepileptic drugs (AEDs), including topiramate (TPM), felbamate (FBM), and gabapentin (GBP), are approved or believed to be close to approval for marketing in the United States. Key efficacy findings for these AEDs in refractory partial epilepsy were reviewed. Large and significant drug-placebo differences were observed with TPM in two large dose-finding trials conducted in the United States. The minimal effective dose of TPM in the population studied was determined to be approximately 200 mg/day, and doses above 600 mg/day produced good efficacy but little incremental benefit versus the lower dosages for the overall study population. FBM is active in partial epilepsy, although seizure reduction is less marked and drug interactions complicate the findings. GBP is also active in this population, but only the 1,800 mg/day dosage was significantly better than placebo with respect to percent re-sponders. It may be useful to explore higher dosage ranges for both FBM and GBP if they can be well tolerated.     

Advances in the Pharmacotherapy of Epilepsy

Summary: Three new antiepileptic drugs (AEDs) are likely to be approved in the United States by the Food and Drug Administration in the near future. In general, all three have good safety profiles, causing only mild, well-tolerated side effects. Felbamate (FBM) is effective in the treatment of partial seizures and Lennox-Gastaut epilepsy. FBM appears to have a broader spectrum of antiepileptic activity than carbama-zepine (CBZ) or phenytoin (PHT). Gabapentin (GBP) was designed to be a structured analogue of γ-aminobutyric acid (GABA). GBP is most effective in the maximal electroshock model of seizures but may have a different mechanism of action than CBZ and PHT. Unique pharmacokinetic properties (no hepatic metabolism and no protein binding) may make GBP especially useful for certain patients, such as those with hepatic disease and elderly patients who are receiving multiple medications. The overall profile of activity of la-motrigine (LTG) is similar to that of PHT and may act on voltage-sensitive sodium channels to stabilize neuronal membranes. LTG is effective in partial seizures, and there is some indication that LTG may be helpful in primary generalized seizures. The long half-life and lack of effect on other AEDs will make LTG easy to dose and add to a patient's existing regimen. These new agents will provide physicians with more effective medications from which to choose in the treatment of the patient with epilepsy.     

Gabapentin in refractory partial epilepsy — a trial in India

Gabapentin (GBP) has been shown to be effective an add-on drug for the treatment of refractory partial epilepsy. We undertook an open clinical trial to test its efficacy for the first time in India. Twenty-six patients with refractory partial seizures (> 4 per month) were given GBP in a titrated dose and the seizure frequency was noted for 3 months. The mean reduction in seizures was significant: 15.87 (SD = 4.5) vs 5.80 (SD = 10.25). The mean percentage change (PCH) from the baseline was - 36. Twenty-one of 26 (80%) patients had a reduction in the number of seizures, and 13/26 (50%) were identified as responders (> 50% reduction in seizures). The responders were significantly younger than the nonresponders. Adverse events were mild and noted in 46% patients. Although the trial has its limitations, this is probably the first trial of GBP in a developing country.     

Review of treatment options for refractory epilepsy: new medications and vagal nerve stimulation.

PURPOSE: the choices available for patients whose partial seizures are poorly controlled include seven new antiepileptic drugs (AEDs) or vagal nerve stimulation (VNS) as add-on therapy. Comparisons are needed to help physicians and patients select among the options for treatment. METHODS: we compared efficacy and adverse events of new treatments from controlled clinical trials of patients with uncontrolled partial seizures. Response rates (> or =50% decrease in partial seizures) at doses recommended in product labeling for adjunct therapy were tabulated for overall success (placebo response rate subtracted from AED response rate). Adverse events listed in product labeling were tabulated as complaint rates (placebo events subtracted from AED events). VNS trials used low dose stimulation as a pseudo-placebo. RESULTS: overall success rates fell into two general groups with ranges of 12-20% for gabapentin (GBP), lamotrigine (LTG), tiagabine (TGB), zonisamide and 27-29% for levetiracetam, oxcarbazepine, and topiramate (TPM). Summary Complaint Scores also fell into two general groups with ranges of -27 to -82 for GBP, levetiracetam, TGB, zonisamide and -113 to -205 for LTG, oxcarbazepine and TPM. VNS scores were in the lower or higher success and summary complaint categories depending on whether scores from the pseudo-placebo group were subtracted from the high dose group. CONCLUSIONS: these data allow comparisons among AEDs and VNS using similar data from standard types of clinical trials.     

The KEEPER trial: levetiracetam adjunctive treatment of partial-onset seizures in an open-label community-based study

PURPOSE: Three randomized, placebo-controlled trials have demonstrated the safety and efficacy of levetiracetam, a new antiepileptic medication, as add-on therapy for partial-onset seizures. The purpose of this study was to gather additional safety and efficacy data on levetiracetam in the real-world setting of community-based practice. METHODS: This was a phase IV prospective, open-label, multicenter, community-based trial. A total of 1030 patients (intent-to-treat (ITT) population) at least 16 years old (mean, 42.2 years) with partial-onset seizures were enrolled by over 300 investigators. Patients whose partial-onset seizures were inadequately controlled on their current medications had levetiracetam 500 mg bid added to their regimens. The levetiracetam dose was increased by 500 mg bid at the end of weeks 2 and 4 to a maximum dose of 1500 mg bid, unless the patient had been seizure-free during the preceding 2-week period. The dose was then to remain the same for 12 weeks. The main outcome measures were reduction in seizure frequency, global evaluation scale (GES), and adverse events. RESULTS: During the 16 weeks of the trial, 57.9% (542/936) experienced at least a 50% reduction in the frequency of partial-onset seizures, 40.1% (375/936) experienced at least a 75% reduction, and 20% (187/936) demonstrated a 100% seizure reduction. During the last 6 weeks of the study, 66.7% (500/750) experienced at least a 50% reduction in the frequency of partial seizures, 52.4% (393/750) experienced at least a 75% reduction, and 42.1% (316/750) demonstrated a 100% seizure reduction. On the investigator-completed clinical impression rating (GES), 74.3% (734/988) of patients were considered improved, with 37% of patients showing marked improvement. The most common adverse events were somnolence, dizziness, asthenia, and headache; these events were predominantly mild-to-moderate in nature. CONCLUSIONS: These results provide further evidence regarding the efficacy and safety of levetiracetam as adjunctive treatment for partial-onset seizures.