Neurocognitive effects of adjunctive levetiracetam in children with partial-onset seizures: a randomized, double-blind, placebo-controlled, noninferiority trial. Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Efficacy and safety of levetiracetam (up to 2000 mg/day) in Taiwanese patients with refractory partial seizures: a multicenter, randomized, double-blind, placebo-controlled study. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in Chinese patients with refractory partial-onset seizures. Once-daily extended-release levetiracetam as adjunctive treatment of partial-onset seizures in patients with epilepsy: a double-blind, randomized, placebo-controlled trial. Efficacy and safety of levetiracetam (3,000 mg/Day) as an adjunctive therapy in Chinese patients with refractory partial seizures. Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control following craniotomy: a randomized phase II pilot study. Topiramate in medically intractable partial epilepsies: double-blind placebo-controlled randomized parallel group trial. Korean Topiramate Study Group. Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy.
Evaluate potential neurocognitive effects of adjunctive levetiracetam in children with inadequately controlled partial-onset seizures (POS).
                Randomized, double-blind, placebo-controlled, noninferiority safety study. Children (4-16 years; IQ > or =65) with > or =1 POS during 4 weeks before screening despite taking 1-2 antiepileptic drugs (AEDs) were randomized (2:1) to levetiracetam (20-60 mg/kg/day) or placebo for 12 weeks.
                Ninety-nine patients were randomized with 98 (levetiracetam 64, placebo 34) in intent-to-treat (ITT) and 73 (levetiracetam 46, placebo 27) in per protocol (PP) populations. Primary cognitive assessment was the Leiter International Performance Scale-Revised Attention and Memory Battery with the memory screen composite score change from baseline as the primary endpoint. PP Least Square Mean [LSM (standard error)] were 5.36 (1.78) for levetiracetam; 5.17 (2.33) for placebo; difference [two-sided 90% confidence interval (CI)] 0.19 (-4.69, 5.08). Levetiracetam was noninferior to placebo because the 90% CI lower bound was greater than the defined noninferiority margin (-9.0). There were no statistically significant differences between groups in Wide Range Assessment of Memory and Learning-2 indexes and Leiter-R Examiner's Rating Scale scores. Median reductions from baseline in weekly POS frequency were 91.5% versus 26.5% for levetiracetam versus placebo; > or =50% responder rates: 62.5% versus 41.2%; seizure freedom rates: 46.9% versus 8.8% (ITT). Adverse events were reported by 89.1% levetiracetam-treated and 85.3% placebo-treated patients; those reported by > or =10% levetiracetam patients and more often with levetiracetam were headache, nasopharyngitis, fatigue, vomiting, somnolence, and aggression.
                Neurocognitive effects were no different in pediatric patients with POS treated with adjunctive levetiracetam or placebo. Levetiracetam was effective and well tolerated. To evaluate the efficacy and tolerability of levetiracetam (LEV) as adjunctive therapy in children (4 to 16 years) with treatment-resistant partial-onset seizures.
                This multicenter, randomized, placebo-controlled trial consisted of an 8-week baseline period followed by a 14-week double-blind treatment period. During the treatment period, patients received either placebo or LEV add-on therapy and were up-titrated to a target dose of 60 mg/kg/day.
                One hundred ninety-eight patients (intent-to-treat population) provided evaluable data. The reduction in partial-onset seizure frequency per week for LEV adjunctive therapy over placebo adjunctive therapy was significant (26.8%; p = 0.0002; 95% CI 14.0% to 37.6%). A 50% or greater reduction of partial seizure frequency per week was attained in 44.6% of the LEV group (45/101 patients), compared with 19.6% (19/97 patients) receiving placebo (p = 0.0002). Seven (6.9%) LEV-treated patients were seizure-free during the entire double-blind treatment period, compared with one (1.0%) placebo-treated patient. One or more adverse events were reported by 88.1% of LEV-treated patients and 91.8% of placebo patients. The most common treatment-emergent adverse events were somnolence, accidental injury, vomiting, anorexia, hostility, nervousness, rhinitis, cough, and pharyngitis. A similar number of patients in each group required a dose reduction or withdrew from the study as a result of an adverse event.
                Levetiracetam adjunctive therapy administered at 60 mg/kg/day is efficacious and well tolerated in children with treatment-resistant partial seizures. To assess the efficacy and safety of adjunctive levetiracetam (LEV) therapy in controlling partial-onset seizures refractory to other antiepileptic drugs (AEDs) in a multicenter study in Taiwanese adults.
                Ninety-four patients aged 16-60 years with refractory partial seizures were randomized to receive LEV (n = 47) or placebo (47) for 14 weeks and composed the intention-to-treat (ITT) population. After the first 2 weeks, LEV patients had their dosage increased from 500 mg twice daily to 1,000 mg twice daily. A 12-week maintenance phase followed, after which patients switched to long-term, open-label LEV therapy or entered a 4-week phase of medication discontinuation.
                All patients from the ITT population, except one LEV-treated patient with missing seizure-count data, were included in the primary efficacy analysis. The least square mean of logarithmically transformed weekly partial-seizure frequency was significantly lower in the LEV than in the placebo group (0.813 vs. 1.085; p = 0.001). LEV reduced log-transformed weekly partial-seizure frequency by 23.8% (95% confidence interval, 10.4-35.2%) relative to placebo. Significantly more LEV than placebo patients (43.5% vs. 10.6%) experienced a response of a >or=50% decrease from baseline in weekly frequency of partial seizures [odds ratio, 6.5 (95% CI, 2.2-19.3); p < 0.001]. Adverse events were reported in 34 (72.3%) of 47 LEV-treated patients and 32 (68.1%) of 47 placebo patients. The three most common adverse events in the LEV and placebo groups were somnolence (40.4% and 14.9%), dizziness (14.9% and 8.5%), and headache (10.6% and 8.5%), respectively. Only four patients (three LEV-treated patients and one placebo patient) were withdrawn from the study because of adverse events.
                Adjunctive LEV therapy, <or=1,000 mg twice daily, was significantly more effective than placebo and was generally well tolerated in Taiwanese adults with treatment-resistant partial-onset seizures. To evaluate efficacy and tolerability of levetiracetam (LEV; Keppra) as add-on therapy in Chinese patients with refractory partial-onset seizures.
                In this multicenter, double-blind, randomized, placebo-controlled trial, 206 patients aged 16-70 years with uncontrolled partial-onset seizures were randomized to receive LEV (n =103) or placebo (n =103); 202 patients (LEV, n =102; placebo, n = 100) comprised the intent-to-treat population. An 8-week historical baseline period confirmed eligibility according to seizure count. The 16-week treatment period consisted of a 4-week up-titration period (LEV, 1,000-3,000 mg/day in two equal divided doses) followed by a 12-week maintenance period. Efficacy assessments were based on weekly frequency of partial-onset seizures during the 16-week treatment period.
                LEV significantly decreased weekly partial-onset seizure frequency over placebo by 26.8% (p < 0.001). Median percentage reductions in weekly partial-onset seizure frequency from historical baseline were 55.9% for LEV and 13.7% for placebo (p < 0.001). The >or=50% responder rates were 55.9% for LEV, compared with 26.0% for placebo (p < 0.001). Freedom from partial-onset seizures during treatment period was achieved by 11 LEV patients (10.8%) and 2 placebo patients (2.0%) (p = 0.012). Adverse events were reported by 65 LEV-treated patients (63.1%) and 62 placebo-treated patients (60.2%); most were of mild-to-moderate intensity. The most common adverse events were somnolence (LEV, 17.5%; placebo, 17.5%), decreased platelet count (LEV, 9.7%; placebo, 9.7%), and dizziness (LEV, 7.8%; placebo, 13.6%).
                Add-on LEV was effective and well-tolerated in Chinese patients with refractory partial-onset seizures. Double-blind randomized trial to assess efficacy and tolerability of once-daily extended-release levetiracetam (LEV XR) tablets (2 x 500 mg) as add-on therapy in patients (12-70 years old) with partial-onset seizures (POS) refractory to one to three antiepileptic drugs.
                After an 8-week prospective baseline-period, eligible patients were randomized (1:1) to once-daily LEV XR 1,000 mg/day or placebo for 12 weeks. Evaluations included changes from baseline in POS-frequency/week, responders (>or=50% reduction in POS-frequency/week), seizure-freedom, adverse events, laboratory tests, physical and neurologic examinations, vital signs, body-weight, and 12-lead electrocardiogram.
                Of 188 patients screened, 158 were randomized (intention-to-treat population): LEV XR (n = 79) or placebo (n = 79). Seventy-one (89.9%) LEV XR and 72 (91.1%) placebo patients completed the trial. Median POS-frequency/week reduction was 46.1% on LEV XR and 33.4% on placebo. Estimated reduction with LEV XR over placebo was 14.4% (p = 0.038). Thirty-four (43%) LEV XR and 23 (29.1%) placebo patients experienced >or=50% reduction in POS-frequency/week. Eight (10.1%) patients receiving LEV XR and one (1.3%) receiving placebo were free of POS during the 12-week treatment period. Forty-one (53.2%) LEV XR and 43 (54.4%) placebo patients reported >or=1 adverse event. Adverse events reported with an incidence >5% and seen more often with LEV XR than with placebo were somnolence, influenza, irritability, nasopharyngitis, dizziness, and nausea.
                Once-daily LEV XR 1,000 mg was effective and well-tolerated as adjunct therapy in patients with POS. Ten percent of patients randomized to LEV XR experienced freedom from POS. These results support the clinical value of this new LEV XR formulation. To evaluate the efficacy and safety of 3,000 mg daily levetiracetam (LEV; Keppra) as an adjunctive therapy for Chinese patients with refractory partial seizures.
                This randomized, placebo-controlled trial consisted of an 8-week baseline period followed by a 4-week titration interval and a 12-week maintenance period, and concluded with a 4-week medication withdrawal period or entered an open-label study. LEV was compared with placebo.
                The 50% responder rate (the proportion of patients with a minimum of 50% reduction in partial seizure frequency) occurred in 46.4% of the LEV group, compared with 39.3% of the placebo group (p = 0.590). The median of the absolute weekly frequency reduction from baseline of partial seizures was 0.66 per week for LEV versus 0.48 per week for placebo (p = 0.187). The most common treatment-emergent adverse events, mostly mild to moderate in severity, were somnolence, dizziness and agitation.
                In this study, adjunctive therapy with LEV 3,000 mg daily was well tolerated but not as effective as expected in controlling partial seizures in this study population. Considering the lower mean weight of this study population, we suggest the dosage of LEV 3,000 mg daily may contribute to the results.
                Copyright 2009 S. Karger AG, Basel. Seizures are common in patients with gliomas, and phenytoin (PHT) is frequently used to control tumor-related seizures. PHT, however, has many undesirable side effects (SEs) and drug interactions with glioma chemotherapy. Levetiracetam (LEV) is a newer antiepileptic drug (AED) with fewer SEs and essentially no drug interactions. We performed a pilot study testing the safety and feasibility of switching patients from PHT to LEV monotherapy for postoperative control of glioma-related seizures. Over a 13-month period, 29 patients were randomized in a 2:1 ratio to initiate LEV therapy within 24 h of surgery or to continue PHT therapy. 6 month follow-up data were available for 15 patients taking LEV and for 8 patients taking PHT. In the LEV group, 13 patients (87%) were seizure-free. In the PHT group, 6 patients (75%) were seizure-free. Reported SEs at 6 months was as follows (%LEV/%PHT group): dizziness (0/14), difficulty with coordination (0/29), depression (7/14) lack of energy or strength (20/43), insomnia (40/43), mood instability (7/0). The pilot data presented here suggest that it is safe to switch patients from PHT to LEV monotherapy following craniotomy for supratentorial glioma. A large-scale, double-blinded, randomized control trial of LEV versus PHT is required to determine seizure control equivalence and better assess differences in SEs. To evaluate the efficacy and safety of topiramate (TPM) as add-on therapy in medically intractable partial epilepsies.
                We used a multicenter double-blind placebo-controlled randomized parallel-group trial consisting of 12 weeks of baseline phase, 10 weeks of titration phase, and 8 weeks of stabilization phase. The primary efficacy variable was the median seizure frequency reduction rate (MSFRR), and the other efficacy variables included responder rate, seizure-free rate, and global evaluations by the patient and the physician. The patient should have partial epilepsies refractory to the maximally tolerable doses of one to two antiepileptic drugs (AEDs) and should have two or more episodes of clinical seizures every 4 weeks during the baseline phase. The target dose of study drugs was 600 mg/day. The study drugs were started at the initial dose of 50 mg/day and gradually increased to the target dose over a 10-week period.
                A total of 177 patients was randomized into the TPM group (n = 91) and the placebo (PLC) group (n = 86). Baseline median seizure frequencies were 5.6 episodes/4 weeks in the TPM and the PLC groups. Among those who were randomized, 174 patients (TPM, 89 patients; PLC, 85 patients) were available for the efficacy measurement by intention-to-treat analysis. The MSFRR was 51.3% for TPM and 9.1% for PLC, which was highly in favor of TPM (p = 0.0001). The responder rate was 50.6% for TPM and 12.9% for PLC (p = 0.001). Seven (7.9%) of 89 patients taking TPM became seizure free compared with one (1.2%) of 85 patients taking PLC (p = 0.004). The global evaluation greatly favored TPM (p = 0.001). The incidence of adverse events (AEs) was higher in the TPM (81.3%) than in the PLC (48.9%) group, with central nervous system (CNS)-related AEs being the most frequent. Among individual AEs, anorexia (20.9%) and abdominal pain or discomfort (20.9%) were the most common AEs in the TPM group. AEs precipitated early drop-out in seven (7.6%) patients taking TPM and three (3.5%) patients taking PLC. No serious systemic AEs were observed.
                TPM was highly effective and safe as add-on therapy in medically intractable partial epilepsies. Slower titration of TPM might be responsible for the lesser drop-out rate than previous trials, but the incidence of AEs was still high. The AE profile of TPM in Koreans was different from that in whites. The medical treatment of childhood epilepsy is largely influenced by clinical trials in adult patients. We know of only one randomised comparative trial (of two drugs) in newly diagnosed childhood epilepsy. We have undertaken a long-term, prospective, randomised, unmasked, pragmatic trial of the comparative efficacy and toxicity of four standard antiepileptic drugs used as monotherapy in children with newly diagnosed epilepsy.
                Between 1981 and 1987, 167 children aged 3-16 years, who had had at least two previously untreated tonic-clonic or partial seizures, with or without secondary generalisation, were randomly allocated treatment with phenobarbitone, phenytoin, carbamazepine, or sodium valproate. The protocol was designed to conform to standard clinical practice. Efficacy was assessed by time to first seizure after the start of treatment and time to achieving 1-year remission.
                The overall outcome with all four drugs was good. 20% of children remained free of seizures and 73% had achieved 1-year remission by 3 years of follow-up. We found no significant differences between the drugs for either measure of efficacy at 1, 2, or 3 years of follow-up. The overall frequency of unacceptable side-effects necessitating withdrawal of the randomised drug was 9%. This total included six of the first ten children assigned phenobarbitone; no further children were allocated this drug. Of the other three drugs, phenytoin (9%) was more likely to be withdrawn than carbamazepine (4%) or sodium valproate (4%). INTERPRETATION Our data will inform choice of drug and outcome with four of the standard drugs available for newly diagnosed tonic-clonic or partial seizures with or without secondary generalisation in children.
This update adds seven more trials to the original review, which contained four trials. At every dose analysed, levetiracetam significantly reduced focal seizure frequency relative to placebo. This indicates that levetiracetam can significantly reduce focal seizure frequency when it is used as an add-on treatment for both adults and children with drug-resistant focal epilepsy. As there was evidence of significant levels of statistical heterogeneity within this positive effect it is difficult to be precise about the relative magnitude of the effect. At a dose of 2000 mg, levetiracetam may be expected to be 3.9 times more effective than placebo; with 30% of adults being responders at this dose. At a dose of 60 mg/kg/day, levetiracetam may be expected to be 0.9 times more effective than placebo; with 25% of children being responders at this dose. When dose was ignored, children were better responders than adults by around 4% to 13%. The results grossly suggest that one child or adult may respond to levetiracetam for every four or five children or adults, respectively, that have received levetiracetam rather than placebo. The drug seems to be well tolerated in both adults and children although non-specific changes in behaviour may be experienced in as high as 20% of children. This aspect of the adverse-effect profile of levetiracetam was analysed crudely and requires further investigation and validation. It seems reasonable to continue the use of levetiracetam in both adults and children with drug-resistant focal epilepsy. The results cannot be used to confirm longer-term or monotherapy effects of levetiracetam or its effects on generalised seizures. The conclusions are largely unchanged from those in the original review. The most significant contribution of this update is the addition of paediatric data into the analysis.