Treatment Of Refractory Partial-onset Seizures Research Articles

An Investigation into Retigabine (Ezogabine) Associated Dyspigmentation in Rat Eyes by MALDI Imaging Mass Spectrometry.

Retigabine (RTG) is an antiepileptic drug approved as an adjunctive treatment for refractory partial-onset seizures in adults. In April 2013, the Food and Drug Administration issued a warning that RTG could cause changes in retinal pigmentation and discoloration of skin, resulting in a blue appearance. As part of a larger preclinical effort to gain a mechanistic understanding as to the origins of retinal pigment changes associated with RTG, we conducted a long-term repeat dosing study in rats. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) was used to determine the distribution of RTG and its metabolites in the rat eye following 13 and 39 weeks of dosing. IMS revealed the presence of RTG, a previously characterized N-acetyl metabolite of RTG (NAMR), and several species structurally related through the dimerization of RTG and NAMR. These species were highly localized to the melanin-containing layers of the uveal tract of the rat eye including the choroid, ciliary body, and iris, suggesting that the formation of these dimers occurs from melanin bound RTG and NAMR. Furthermore, several of the RTG-related dimers have UV absorbance which give them a purple color in solution. We propose that the melanin binding of RTG and NAMR effectively concentrates the two compounds to enable mixed condensation reactions to occur when the binding provides the proper geometry in the redox environment of the uveal tissues. High lateral resolution images illustrate that the blood-retinal barrier effectively restricts retinal access to RTG-related compounds. The spatial information provided by MALDI IMS was critical in contextualizing the homogenate concentrations of key RTG-related compounds and helped provide a basis for the mechanism of dimer formation.

Efficacy of antiepileptic drugs in the adjunctive treatment of refractory partial-onset seizures: Meta-analysis of pivotal trials

ObjectiveIn the absence of randomized clinical trials (RCTs) assessing the relative efficacy of antiepileptic drugs (AEDs), meta-analyses are useful resources for informing treatment choices. This meta-analysis assesses the relative efficacy and tolerability of AEDs for adjunctive treatment of refractory partial onset seizures (POS). MethodsA systematic literature review was conducted to identify pivotal AED trials serving as the basis for US Food and Drug Administration (FDA) approval. Inclusion criteria: 1) double-blind, placebo-controlled, parallel-group design, with 8- to 14-week maintenance period; 2) enrolled patients ≥16years with refractory POS, including complex partial seizures; 3) study was conducted between 1993 and 2013; and; 4) patients received FDA-approved dosage. Outcomes analyzed: 1) 50% responder rate (≥50% reduction from baseline in seizure frequency); 2) seizure freedom (proportion of seizure-free patients); and 3) discontinuation due to adverse events (AEs). DerSimonian and Laird random-effects model was used to derive odds ratios (OR) and 95% confidence intervals (CI). ResultsA total of 29 publications for 11 AEDs (eslicarbazepine, ezogabine, gabapentin, lacosamide, levetiracetam, perampanel, pregabalin, tiagabine, topiramate, vigabatrin, and zonisamide) were included in the meta-analysis. Tiagabine 56mg/day (OR 8.82, 95% CI: 2.77–28.11), pregabalin 600mg/day (OR 8.08, 95% CI: 5.45–11.98), and vigabatrin 3000mg/day (OR 6.23, 95% CI: 1.46–26.20) had the highest OR versus placebo of 50% response. The odds of seizure freedom were ≥7 times greater than placebo for levetiracetam 3000mg/day (OR 11.00, 95% CI: 2.08–58.06), vigabatrin 3000mg/day (OR 7.41, 95% CI: 1.31–41.84), and ezogabine 1200mg/day (OR 7.09, 95% CI: 0.36–58.06). Patients were more likely to discontinue any AED (except low-dose pregabalin) than placebo. ConclusionIn this meta-analysis of >9000 patients, those treated with AEDs were more likely than placebo to achieve seizure response or freedom. Patients receiving pregabalin, tiagabine, and vigabatrin had the highest odds of ≥50% reduction in seizures, and patients receiving ezogabine, levetiracetam, and vigabatrin had the highest odds of seizure freedom.

Psychiatric and cognitive adverse events: A pooled analysis of three phase III trials of adjunctive eslicarbazepine acetate for partial-onset seizures

ObjectiveTo evaluate the nature and incidence of psychiatric and cognitive adverse events (AEs) reported with eslicarbazepine acetate (ESL) used as adjunctive treatment for refractory partial-onset seizures (POS) in adults. MethodsThis was a post-hoc analysis of data pooled from three randomized double-blind, placebo-controlled trials (BIA-2093-301, -302, -304). After an 8-week baseline period, patients received placebo or adjunctive ESL 400mg (studies 301 and 302 only), 800mg, or 1200mg once daily (QD) for 14weeks (2-week titration period, 12-week maintenance period). Psychiatric and cognitive AEs were identified from individual patient data. Suicidality was also evaluated using the Columbia-Classification Algorithm of Suicide Assessment (C-CASA), or the Columbia-Suicide Severity Rating Scale (C-SSRS). P-values were obtained using the chi-square test of independence or Fisher's exact test, without correcting for multiplicity. ResultsThe analysis population included 1447 patients (ESL, n=1021; placebo, n = 426). Psychiatric treatment-emergent AEs (TEAEs) occurred in 10.8% of patients receiving ESL, and in a comparable proportion (10.3%) of patients receiving placebo (p=0.802). However, the incidence of depression and suicidality-related TEAEs was significantly higher for ESL (7.4%) vs. placebo (3.8%) (p=0.009). The occurrence of these TEAEs differed between treatment groups (p = 0.010), but there was no notable trend between increasing ESL dose and increasing incidence of depression and suicidality-related TEAEs. Aggression/hostility-related TEAEs occurred in <0.1% of patients taking ESL vs. 0.9% taking placebo. The incidence of cognitive TEAEs was significantly higher for ESL (7.1%) vs. placebo (4.0%) (p=0.023); incidences of memory impairment, attention disturbance, apathy, aphasia, and bradyphrenia were higher for ESL 1200mg than for other treatment groups. Incidences of psychiatric and cognitive serious AEs (SAEs) were 0.6% and 0.2% with ESL, and 0.5% and 0% with placebo, respectively. Psychiatric and cognitive TEAEs leading to discontinuation occurred in 1.9% and 1.4% of patients taking ESL, and 0.7% and 0.5% taking placebo, respectively. ConclusionsIn phase III clinical trials of adjunctive ESL for treatment-refractory POS, psychiatric and cognitive TEAEs were reported infrequently with ESL and placebo. However, the incidences of depression and suicidality-related TEAEs and of cognitive TEAEs were significantly higher for patients taking ESL vs. placebo. Incidences of psychiatric and cognitive SAEs, and TEAEs leading to discontinuation, were low with ESL and placebo.

A review of the efficacy and safety of extended-release topiramate in the adjunctive treatment for refractory partial-onset seizures.

Topiramate has been widely utilized worldwide as an effective medication against partial- and generalized-onset seizures. Extended-release topiramate was developed to provide patients with the convenience of once-daily dosing and potentially improved tolerability by reducing serum concentration fluctuation. USL255 is a once-daily, extended-release formulation of topiramate, which was recently approved in the USA. Compared with immediate-release topiramate taken twice daily, once-daily USL255 provides equivalent topiramate exposure with a 26% reduction in plasma fluctuations. A multinational, phase III, randomized, double-blind, placebo-controlled clinical trial in patients with refractory partial-onset seizures demonstrated that USL255 (200 mg/day) significantly improved seizure control and was well tolerated with low overall neuropsychiatric and neurocognitive adverse events.

Pharmacodynamic and pharmacokinetic interactions of perampanel and other antiepileptic drugs in a rat amygdala kindling model

PurposeThis study explored the pharmacodynamic and pharmacokinetic effects of combining perampanel (PER) with commonly co-administered AEDs. MethodA strong stimulus intensity (three-fold higher than after-discharge threshold) was used to elicit drug-resistant seizures in a rat amygdala kindling model. Vehicle, low-dose PER (0.75mg/kg), or high-dose PER (1.5mg/kg), in combination with vehicle, levetiracetam (LEV) 50mg/kg, lamotrigine (LAM) 20mg/kg, carbamazepine (CBZ) 20mg/kg, or valproic acid (VPA) 200mg/kg, were administered intraperitoneally to groups of 6–13 rats. Seizure score, electroencephalography (EEG) seizure duration, and motor seizure duration were evaluated, with pharmacodynamic interactions determined by two-way analysis of variance (ANOVA). Motor impairment was evaluated by rotarod test and two-way ANOVA. ResultsHigh-dose PER, but not low-dose PER, LEV, LAM, CBZ, or VPA, reduced EEG seizure duration, motor seizure duration, and seizure score compared with vehicle alone. However, when low-dose PER was administered in combination with LEV, LAM, CBZ, or VPA, seizure severity parameters were reduced compared with the concomitant AEDs alone. These pharmacodynamic interactions were statistically significant in some cases, but the same AED combinations were not associated with statistically significant neurotoxic interactions. Efficacy may have been slightly affected by changes in PER plasma concentrations in the presence of other AEDs:PER plasma concentrations increased with LEV or LAM co-administration, and decreased with CBZ or VPA co-administration. ConclusionOverall, these data support published Phase III data demonstrating the efficacy of PER as adjunctive therapy for the treatment of refractory partial-onset seizures in patients aged ≥12 years.

Introduction

Based on a 2010 systematic review and meta-analysis, Beyenburg et al. 1 recently concluded that modern antiepileptic drugs (AEDs) have little impact on patients with refractory epilepsy, lamenting the lack of progress in the development of novel AEDs. Such articles have highlighted the importance of the continued quest for effective, novel therapies to help patients with this condition. This supplement provides an overview of the development of perampanel, the first non-competitive AMPA-type glutamate receptor antagonist to be developed as an adjunctive treatment for refractory partial-onset seizures. After years of development, this AED has now been approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). Perampanel has completed clinical evaluation in three pivotal, randomized, double-blind, placebo-controlled Phase III registration studies in patients experiencing partial-onset seizures despite treatment with up to three AEDs 2-4. In these studies, adjunctive perampanel provided significant improvements in seizure reduction. In addition, perampanel was associated with a favorable adverse event profile, with few cognitive or psychiatric side effects: a vital attribute in this vulnerable population. Previously, most AEDs have been discovered through serendipity, screening large numbers of compounds, or the further development of existing AEDs. Perampanel, however, is one of the few to be developed based upon a specific hypothesis of seizure inhibition. This development program will be reviewed by Andrew Satlin and colleagues in the first article in this supplement 5. In the second article, Michael Rogawski 6 provides an in-depth account of the role of AMPA receptors in seizures and epileptogenesis, while in the third article, Michael Rogawski and Takahisa Hanada 7 will go on to review the exciting possibilities of AMPA receptor antagonism and how perampanel utilizes this mechanism to inhibit seizure occurrence. As perampanel is now approved for use in Europe and the USA, it is important that clinicians have an understanding of how this drug can be used to treat patients in a real-life clinical setting. With this in mind, the fourth article in this supplement, by Frank Kerling and Burkhard Kasper 8, will provide an overview of efficacy data from the published Phase II and Phase III clinical trials. Alongside this, Jose Serratosa, Vicente Villanueva, Frank Kerling and Burkhard Kasper 9 will provide an overview of Phase II and Phase III safety data in the fifth article. Severe seizures are particularly difficult to control, and the more AEDs a patient has tried previously, the less likely they are to respond to the next AED 10. Therefore, in the sixth and final article in this supplement, David Ko and Eugene Ramsay 11 will discuss the efficacy of perampanel for the treatment of severe seizures in refractory patients already receiving one or more concomitant AEDs. As perampanel is now approved for use in Europe and the USA, we hope that the information covered in this supplement will support the reader in treating eligible and appropriate patients with this third-generation AED. However, it is important to recognize that the full potential of perampanel is not yet known and many challenges still remain. For example, ‘How effective will perampanel be in monotherapy?’ and ‘Will patients with generalized seizure types also benefit from treatment (as indicated in animal models) 12?’ Only further rigorous studies will be able to answer the question of whether perampanel is a broad spectrum AED for patients with varied seizure types and syndromes or not. The future is indeed exciting. David Squillacote, MD, of Eisai Inc. assisted in the preparation of the article by providing up-to-date data access and editorial support. Editorial support was provided by Hannah FitzGibbon, PhD, of Complete Medical Communications and was funded by Eisai Inc. E. Ben-Menachem is currently an investigator for Eisai and UCB Pharma and is a consultant for Biocontrol, Eisai, Janssen-Cilag, Lundbeck, and UCB Pharma. She has received a research grant from Västra Götelands Region and is chief editor of Acta Neurologica Scandinavica.

Efficacy of perampanel: a review of clinical trial data

The efficacy of adjunctive perampanel has been investigated in an extensive clinical development program across a broad, multinational population of patients with refractory partial-onset seizures. Further to the results of two Phase II dose-finding studies, perampanel was evaluated in three large Phase III registration studies at the predicted no-effect dose of 2 mg/day and the predicted effective doses of 4, 8, and 12 mg/day. In all three studies, perampanel 4, 8, and 12 mg/day consistently provided significant reductions in the frequency of partial-onset seizures compared with placebo. Improvements in responder rates and seizure freedom rates were also observed. In addition, data from recent interim analyses of extension studies have indicated that these efficacy outcomes may be maintained with long-term treatment. Overall, these studies form a solid evidence base to support the efficacy of adjunctive perampanel in the treatment of refractory partial-onset seizures.

Safety and tolerability of perampanel: a review of clinical trial data

The Phase II and Phase III clinical development program of perampanel is providing a wealth of data on the safety and tolerability of this alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist as an adjuvant treatment for refractory partial-onset seizures. In Phase II dose-finding studies, perampanel was associated with an acceptable tolerability profile up to the maximum evaluated dose of 12 mg/day. Subsequent multinational, multicenter, randomized, double-blind, placebo-controlled Phase III registration studies further supported the tolerability of perampanel across the dose range 2-12 mg/day, with interim data from ongoing extension studies indicating that safety outcomes may be maintained over several years. An analysis of the pooled Phase III data indicated that the frequency of adverse events reported with perampanel generally increased in a dose-dependent manner, and the most common adverse events were dizziness and somnolence. Overall, perampanel has been associated with an acceptable and consistent safety profile that is maintained over long-term settings.

Vigabatrin for partial-onset seizure treatment in patients with tuberous sclerosis complex

Vigabatrin (VGB) has been shown to be particularly effective in the treatment of infantile spasms for those with tuberous sclerosis complex (TSC). However, many patients with TSC continue to have treatment-resistant seizures. For many patients with TSC, partial-onset seizures are prominent. Therefore, we examined the efficacy and tolerability of VGB for treatment of refractory partial-onset seizures. We performed a retrospective cohort study on 49 TSC patients with treatment-resistant seen at our center from 1997 to 2010, examined seizure outcomes, and reported adverse effects. We found that 13 (24.5%) patients became seizure-free or experienced a >90% decrease in seizure episode frequency with the addition of VGB to their regimens. Only one patient stopped VGB use because of excess sedation. The remaining 21 patients discontinued VGB use because of lack of efficacy. We conclude that VGB may be a safe and effective treatment in TSC patients with refractory partial-onset seizures.

Retigabine (ezogabine) as add-on therapy for partial-onset seizures: an update for clinicians

The present study reviewed the pharmacology, pharmacokinetics, efficacy, and safety of retigabine (ezogabine), a potential agent for use as adjunctive treatment in refractory partial-onset seizures. A MEDLINE search (1966-May 2011) was conducted using the key words retigabine, ezogabine, D-23129, epilepsy, and anticonvulsant. Bibliographies of all articles retrieved were also reviewed. All studies including humans and published in English with data describing retigabine for the adjunctive treatment of partial-onset seizures were reviewed. Retigabine has been shown to interact with the KCNQ2/KCNQ3 subunits of the potassium channels, GABA(A) receptors, and weakly block sodium and calcium channels. Retigabine is 50-60% bioavailable, metabolized by N-glucuronidation and N-acetylation, 80% protein bound, and has few drug-drug interactions. Recent data suggest that retigabine may have a role as adjunctive treatment for refractory partial-onset seizures. Placebo-controlled trials demonstrated a 23.4-44.3% reduction in seizure frequency with 50% responder rates ranging from 23.2% to 47.0% with varying doses of retigabine. The most common adverse effects, occurring in greater than 10% of subjects in the clinical trials, include abnormal gait, confusion, dizziness, fatigue, headache, nausea, somnolence, speech disorder, tremor, urinary tract infection, and blurred vision. Retigabine is a promising agent for adjunctive treatment of refractory partial-onset seizures.

Clinical response and tolerability of eslicarbazepine in treatment of partial onset seizures: impact of a novel metabolic pathway

Clinical response and tolerability of eslicarbazepine in treatment of partial onset seizures: impact of a novel metabolic pathway Enrique Serrano1, Cynthia L Harden21Comprehensive Epilepsy Center, Department of Neurology, University of Miami, Miami, FL, USA; 2Comprehensive Epilepsy Care Institute, Long Island Jewish School of Medicine, Hofstra North Shore, New Hyde Park, NY, USAAbstract: Epilepsy is a common chronic neurological condition affecting 50 million people worldwide. Because at least 30% of patients with partial seizures do not achieve seizure control with the current antiepileptic drugs, there remains an urgent need for novel antiepileptic drugs with more favorable safety profiles. Eslicarbazepine acetate (formerly known as BIA 2-093) is a novel voltage-gated sodium channel blocker used as adjunctive therapy in the treatment of refractory partial-onset seizures. Eslicarbazepine acetate is a dibenzazepine that is chemically related to carbamazepine and oxcarbazepine, designed to avoid production of active metabolites, as occurs with both carbamazepine and oxcarbazepine. Carbamazepine is metabolized by the liver to the active metabolite, carbamazepine-10, 11-epoxide, which contributes to clinical toxicity. Eslicarbazepine acetate is reduced by esterases in the liver to the active metabolite eslicarbazepine, the S (+) enantiomer of licarbazepine,27 without production of the 10,11-epoxide, resulting in a lower drug interaction potential and fewer adverse neurological effects. Further, while oxcarbazepine is a prodrug that is metabolized into both the S- and R- enantiomers of licarbazepine, eslicarbazepine acetate is metabolized to solely the S- enantiomer of licarbazepine. Eslicarbazepine acetate stabilizes the inactivated state of the voltage-gated sodium channels, preventing their return to an activated state and sustaining repetitive neuronal firing. Eslicarbazepine acetate also has a higher affinity for the inactivated state of the sodium channel compared with the resting state, suggesting enhanced selective inhibition of rapidly firing neurons associated with epileptic discharges. Consequently, eslicarbazepine acetate is less likely to bind to normally active neurons, and, therefore, less likely to cause adverse neurological effects. In clinical trials, eslicarbazepine acetate shows significant efficacy in reducing seizure frequency, and a favorable adverse effect profile at once per day doses of 800 mg or 1200 mg. This novel antiepileptic drug is a promising addition to the treatments for people with partial epilepsy.Keywords: antiepileptic drugs, neurotransmission, seizures

Lacosamide and Epilepsy

We will review all available studies on the use of lacosamide in the treatment of partial-onset seizures. The available evidence includes two open-label studies and three randomized controlled trials evaluating the safety and efficacy of oral lacosamide. One open-label study and one randomized controlled trial evaluating the safety and tolerability of intravenous lacosamide was also identified. Lacosamide was found to be efficacious with significant reduction in seizure frequency dosed 400-600 mg daily. Moreover, its adverse drug effects were mild and infrequently reported in the literature. Findings suggest that lacosamide is an effective agent for adjunctive treatment of refractory partial-onset seizures.

Randomized trial of adjunctive topiramate therapy in infants with refractory partial seizures

To evaluate the efficacy and safety of adjunctive topiramate (sprinkle capsules or oral liquid) in reducing daily rates of partial-onset seizures (POS) in infants with refractory POS. In this double-blind, placebo-controlled, parallel-group, international study, infants (n = 149) with clinical or EEG evidence of refractory POS were randomly allocated (1:1:1:1) to receive adjunctive topiramate 5, 15, or 25 mg/kg/d or placebo for 20 days. The primary variable was the median percentage reductions in daily POS rate from baseline to final assessment as recorded on a 48-hour video-EEG. Of the 149 infants (mean age 12 months) included in the intent-to-treat analysis set, 130 completed the study. Median percentage reduction from baseline in daily POS rate was not significantly different (p = 0.97) between topiramate 25 mg/kg (20.4%) and placebo (13.1%). Lower doses were not formally tested, but nominal p values for comparisons with placebo were not significant (15-mg/kg/d dose: p = 0.97; 5-mg/kg/d dose: p = 0.91). Treatment-emergent fever, diarrhea, vomiting, anorexia, weight decrease, somnolence, and viral infection occurred more frequently (> or = 10% difference) with topiramate than with placebo. In infants aged 1-24 months, topiramate 5, 15, or 25 mg/kg/d was not effective as adjunctive treatment for refractory partial-onset seizures. No new safety concerns associated with topiramate use were noted. This interventional study provides Class I evidence that topiramate 5, 15, or 25 mg/kg/d compared with placebo does not significantly reduce seizure rates in infants aged 1 month to 2 years with refractory partial-onset seizures.

Lacosamide: An Adjunctive Agent for Partial-Onset Seizures and Potential Therapy for Neuropathic Pain

To review the pharmacology, pharmacokinetics, efficacy, and safety of lacosamide, a new agent for use as adjunctive treatment in partial-onset seizures and a potential agent for treatment of neuropathic pain. A MEDLINE search (1966-July 2009) was conducted using the key words lacosamide, harkoseride, SPM-927, ADD-234037, epilepsy, anticonvulsant, and neuropathic pain. Bibliographies of all articles retrieved were also reviewed. All studies including humans and published in English with data describing lacosamide for the adjunctive treatment of partial-onset seizures and for treatment of neuropathic pain were reviewed. Lacosamide is a functionalized amino acid molecule that selectively enhances the slow inactivation of voltage-gated sodium channels and interacts with the collapsin-response mediator protein-2. With its bioavailability of approximately 100%, minimal protein binding, and few drug-drug interactions, lacosamide has a favorable pharmacokinetic profile. Recent data suggest that lacosamide may have a role as adjunctive treatment of partial-onset seizures. Open-label studies showed a 14-47% reduction in seizure frequency, while placebo-controlled trials demonstrated a 26-40% reduction in seizure frequency. The 50% responder rates ranged from 32.7% to 41.2% with varying doses of lacosamide. Although lacosamide use is not approved by the Food and Drug Administration for treatment of neuropathic pain, studies demonstrated reductions of 2.01-3.60 in pain scale scores. The most common adverse effects, occurring in greater than 10% of subjects in the clinical trials, include arthralgia, ataxia, blurred vision, diplopia, dizziness, fatigue, headache, injection site pain (only in intravenous studies), nausea, tremor, upper respiratory tract infection, and vomiting. Lacosamide is an effective agent for adjunctive treatment of refractory partial-onset seizures. Its exact role in the treatment of neuropathic pain needs to be determined.

Review of United States and European clinical trials of zonisamide in the treatment of refractory partial-onset seizures

Zonisamide is an antiepilepsy drug (AED) with both sodium and calcium channel-blocking properties. This dual mechanism may predict efficacy in some refractory patients, and a broad spectrum of action against different seizure types. Zonisamide has been commercially available in Japan since 1989, and became available in the United States for treatment of adults over the age of 12 with partial–onset seizures in March 2000. Several multicenter clinical trials have been conducted in the United States over the past 15 years. These have included three double-blind, placebo-controlled trials as well as long-term open-label studies. Zonisamide was characterized in these studies as a safe and effective adjunctive treatment for partial-onset seizures. Zonisamide has not yet been studied in the United States as an initial monotherapy, but in one long-term study, some patients were able to discontinue other AEDs and successfully transition to monotherapy. The most frequently reported adverse events were somnolence, dizziness, and anorexia. Current United States labeling states that 12 patients with epilepsy receiving zonisamide had symptomatic kidney stones; however, after more than a dozen years of zonisamide use in Japan, the incidence of kidney stones associated with zonisamide remains low.

Efficacy of Levetiracetam: A Review of Three Pivotal Clinical Trials

Levetiracetam is a novel antiepileptic drug (AED) with favorable pharmacologic characteristics and demonstrated activity in improving seizure control. Three multicenter double-blind, 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 approximately 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 < or = 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 > or = 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). Levetiracetam was generally well tolerated in all studies. Results from these three pivotal studies demonstrate that levetiracetam, as adjunctive therapy, is a safe and effective treatment for refractory partial-onset seizures in adults.