Losigamone add-on therapy in partial epilepsy: a placebo-controlled study. Efficacy and safety of Losigamone in partial seizures: a randomized double-blind study. Lamotrigine extended-release as adjunctive therapy for partial seizures. Double-blind, placebo-controlled study of topiramate in patients with refractory partial epilepsy. Double-blind, placebo-controlled trial of topiramate as add-on therapy in patients with refractory partial seizures. Double-blind, placebo-controlled trial of topiramate (600 mg daily) for the treatment of refractory partial epilepsy. Double-blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant generalised epilepsy. A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children. Lamictal Pediatric Partial Seizure Study Group. Adjunctive lamotrigine for partial seizures in patients aged 1 to 24 months.
To evaluate the efficacy and tolerability of losigamone (LSG).
                Double-blind, placebo-controlled add-on study with 3x500 mg LSG/die for the treatment of chronic partial seizures in 203 patients (99 treated with LSG, 104 on placebo).
                The median percent change of seizures was 14.9% (LSG) versus 6.7% (placebo) (P=0.004). Seizure frequency was decreased by more than 50% in 22.3% (LSG) and 14.6% (placebo) of patients (P=0.13). Mean percent change of seizures was best in patients with only one additional anticonvulsant drug (LSG versus placebo, P=0.004). Adverse events (usually CNS-related side effects of mild to moderate intensity) were reported in 59.6% (LSG) and 37.5% (placebo) of patients.
                LSG proved to be an effective and well tolerated anticonvulsant drug for the treatment of chronic partial seizures. The objective of the study was to investigate the efficacy and safety of two different dosages of Losigamone (LSG) in add-on treatment of partial seizures. In a multi-center, double-blind, randomized clinical trial, patients received one of three 12-week treatments: placebo, LSG 1200 mg/day, or 1500 mg/day, in addition to up to three standard anticonvulsants after a prospective period of 12 weeks to assess baseline seizure frequency. The primary efficacy measure was the relative reduction of seizure frequency per 4 weeks in the double-blind phase as compared to baseline. In the intention-to-treat population of 264 patients, the relative median reduction of partial seizure frequency was 3.3% for placebo, 19.7% for LSG 1200 mg/day, and 25.3% for LSG 1500 mg/day. The differences of both LSG groups versus placebo were significant (P<0.01, two-tailed). In the responder analysis, 11.8% of the patients in the placebo group, 17.2% in the LSG 1200 mg/day group, and 29.3% in the LSG 1500 mg/day group showed a seizure reduction versus baseline of at least 50%. A positive association between dosage and response was observed (P=0.003). Adverse events during treatment were reported by 58.8% of the patients for placebo, by 62.1% for LSG 1200 mg/day and by 76.1% for LSG 1500 mg/day. Most events in the LSG groups occurred during the first 4 weeks of double-blind (during or immediately after up-titration) and subsided quickly. Over the last 4 weeks of treatment, the incidence of adverse events in the LSG groups was close to the placebo level. Based on the study's results, LSG is an effective and safe add-on drug for refractory partial epilepsy in adults. To evaluate the efficacy and tolerability of once-daily adjunctive lamotrigine extended-release (XR) for partial seizures in epilepsy.
                Patients more than 12 years old diagnosed with epilepsy with partial seizures and taking one to two baseline antiepileptic drugs were randomized to adjunctive once-daily lamotrigine XR or placebo in a double-blind, parallel-group trial. The study comprised a baseline phase, a 7-week double-blind escalation phase, and a 12-week double-blind maintenance phase during which doses of study medication and concomitant antiepileptic drugs were maintained.
                Of the 243 randomized patients, 239 (118 lamotrigine XR, 121 placebo) entered the escalation phase and received study medication. Lamotrigine XR was more effective than placebo with respect to median percent reduction from baseline in weekly partial seizure frequency (primary endpoint-entire 19-week treatment phase: 46.6% vs 24.5%, p = 0.0001 [corrected] via Wilcoxon test; escalation phase: 29.8% vs 15.6%, p = 0.027; maintenance phase: 58.4% vs 26.8%, p [corrected] < 0.0001). The percentage of patients with >or=50% reduction in partial seizure frequency (44.0% vs 20.8%, p = 0.0002) [corrected] and time to >or=50% reduction in partial seizure frequency (p = 0.0001) [corrected] also favored lamotrigine XR over placebo. A similar pattern of results was observed for secondarily generalized seizures. The most common adverse events were headache (lamotrigine XR 16%, placebo 18%) [corrected] and dizziness (lamotrigine XR 19%, [corrected] placebo 5%). Differences between lamotrigine XR and placebo on health outcomes measures were not significant.
                Once-daily adjunctive lamotrigine extended-release compared with placebo effectively reduced partial seizure frequency and was well tolerated in this double-blind study. Results support the clinical utility of this new once-daily formulation. The efficacy and safety of topiramate 400 mg/day as adjunctive therapy to traditional antieleptic drugs for partial onset seizures with or without secondary generalization were assessed in a double-blind, parallel-group, placebo-controlled trial. Forty-seven patients with at least one seizure per week during an 8 week baseline were randomly assigned to topiramate (N = 23) or placebo (N = 24) double-blind treatment for a 3 week titration and an 8 week stabilization period. Median percent reduction from baseline in monthly seizure frequency during the double-blind phase was not significantly greater in the topiramate group than in the placebo group (41% vs. 1%; P = 0.065). Nevertheless, other efficacy variables evidenced statistically significant differences in favor of topiramate: a greater number of treatment responders (> or = 50% reduction in seizures; 35% vs. 8%; P = 0.033); better investigator (P = 0.002) and patient (P = 0.021) global assessments; and greater reductions in secondarily generalized seizures compared to placebo (P = 0.002). The most commonly reported topiramate treatment-emergent adverse events were somnolence, fatigue, abnormal vision, weight decrease, and anxiety. Most adverse events were mild or moderate in severity. Among 7 withdrawals due to limiting adverse events, 6 were CNS-related (in 5 topiramate-treated patients). Results of this trial strongly suggest that topiramate 400 mg/day is effective and well tolerated in the treatment of refractory partial epilepsy. In a double-blind, randomized, parallel-group trial, we compared topiramate (TPM) with placebo as add-on therapy in patients with refractory partial epilepsy. TPM was titrated either to the target dosage of 800 mg/ day [400 mg twice daily (b.i.d)] or to the maximal tolerated dose if lower. Twenty-eight (28) patients were randomized to each treatment group. In the intent-to-treat analysis, the net median percent reduction relative to placebo in average monthly seizure rate was 54% for patients in the TPM group (p < 0.001). None of the placebo-treated patients and 43% of the patients treated with TPM experienced > or = 50% reduction in seizures (p = 0.001), and 36% of patients assigned to TPM had a 75-100% reduction in seizures (p < 0.01). Secondarily generalized seizures were also significantly reduced in the TPM group (p = 0.044). The most common adverse events (AE) reported in the TPM group were fatigue, impaired concentration, weight loss, dizziness, and paresthesias. AE occurring either during the rapid titration of TPM or at high dosages led 21% of TPM-treated patients to withdraw from the study. Half of these occurred during the titration study period. No serious AE or clinically important changes in clinical laboratory measures were observed. The present study further establishes the favorable profile and good benefit/risk ratio of TPM in resistant partial epilepsy. We wished to evaluate adjunctive therapy for partial-onset seizures with topiramate (TPM) for efficacy and safety in a double-blind, placebo-controlled, randomized, parallel-group study.
                Sixty outpatients with epilepsy (47 men and 13 women, mean age 32.9 years) were studied. All had a documented history of partial-onset seizures with or without secondarily generalized seizures. After an 8-week baseline during which patients had at least one seizure per week, 30 patients each were randomized to TPM 300 mg twice daily (b.i.d.) or placebo for 12 weeks.
                TPM was significantly superior to placebo, as indicated by all efficacy assessments: greater median percent reduction from baseline in the average monthly seizure rate (46 vs. -12%, p = 0.004); greater number of treatment responders (patients with > or = 50% reduction in seizure rate) (47 vs. 10%, p = 0.001), and better investigator (p = 0.002) and patient (p = 0.010) global assessments of treatment. Among TPM-treated patients, the most commonly reported adverse events (AE) were headache, somnolence, fatigue, dizziness, and abnormal thinking. Most AE were mild or moderate in severity.
                The results of the present trial indicate that TPM 600 mg/day is effective in the treatment of refractory partial-onset seizures with or without secondarily generalized seizures. Lamotrigine (LTG) is recognised as effective add-on therapy for focal epilepsies, but this is the first double-blind, placebo-controlled, crossover study in treatment-resistant generalised epilepsy.
                The study consisted of 2 x 8-week treatment periods followed by a 4-week washout period. Patients received doses of either 75 or 150 mg daily, depending on their concomitant antiepileptic drugs (AEDs). Long-term continuation was offered at the end of the study with open-label LTG.
                Five centres in Australia recruited 26 patients who were having absence, myoclonic, or generalized tonic-clonic seizures or a combination of these. Twenty-two patients completed the study. There was a significant reduction in frequency of both tonic-clonic and absence seizure types with LTG. A 350% decrease in seizures was observed for tonic-clonic seizures in 50% of cases and for absence seizures in 33% of evaluable cases. Rash was the only adverse effect causing discontinuation. Twenty-three of 26 opted for open-label LTG, with 20 still receiving LTG for a mean of 26 months. In these 20, 80% had > or =50% seizure reduction and five (25%) were seizure free.
                This study shows that LTG is effective add-on therapy in patients with refractory generalised epilepsies. Statistically significant reduction in seizures in both absence and tonic-clonic seizure types was seen even with low doses of LTG. To compare the safety and efficacy of add-on lamotrigine and placebo in the treatment of children and adolescents with partial seizures.
                Add-on and monotherapy lamotrigine is safe and effective in adults with partial seizures, and reports of preliminary uncontrolled trials suggest similar benefits in children.
                We studied 201 children with diagnoses of partial seizures of any subtype currently receiving stable conventional regimens of antiepileptic therapy at 40 study sites in the United States and France. After a baseline observation period (to confirm that more than four seizures occurred in each of two consecutive 4-week periods), patients were randomized to add-on lamotrigine or placebo therapy. A 6-week dose-escalation period was followed by a 12-week maintenance period.
                Compared with placebo, lamotrigine significantly reduced the frequency of all partial seizures and the frequency of secondarily generalized partial seizures in these treatment-resistant patients. The most commonly reported adverse events in the lamotrigine-treated patients were vomiting, somnolence, and infection; the frequency of these and other adverse events was similar to that in the placebo-treated group, with the exception of ataxia, dizziness, tremor, and nausea, which were more frequent in the lamotrigine-treated group. The frequency of withdrawals for adverse events was similar between groups. Two patients were hospitalized for skin rash, which resolved after discontinuation of lamotrigine therapy.
                Lamotrigine was effective for the adjunctive treatment of partial seizures in children and demonstrated an acceptable safety profile. This randomized, double-blind, placebo-controlled trial was conducted to assess the efficacy and tolerability of adjunctive lamotrigine for the treatment of partial seizures in infants aged 1 to 24 months.
                The study used a responder-enriched design in which all patients received adjunctive lamotrigine during an open-label phase (n = 177; maximum maintenance dose 5.1 mg/kg/day for those on non-enzyme-inducing antiepileptic drugs [AEDs] or valproate and 15.6 mg/kg/day for those on enzyme-inducing AEDs). Patients meeting response criteria were randomly assigned to double-blind treatment for up to 8 weeks with continued lamotrigine (n = 19) or to withdrawal from lamotrigine (placebo; n = 19) while background AEDs were maintained.
                The proportion of treatment failures (patients who met escape criteria or withdrew before completing the double-blind phase) was lower with lamotrigine (58%) than with placebo (84%). This finding was not significant in the primary analysis (two-sided chi(2) test [primary endpoint]). A post hoc sensitivity analysis of the primary endpoint was also performed (p = 0.045 by one-sided, mid-p corrected Fisher exact test). The median time to meet escape criteria was longer with lamotrigine (42 days) than with placebo (22 days) (p = 0.059). During the last 28 days of the open-label phase, 53% of the patients had a >or=50% reduction in frequency of partial seizures with lamotrigine. Additional reduction in partial seizure frequency was observed during the double-blind phase compared with the last 4 weeks of the open-label phase among those randomly assigned to lamotrigine (32% with a >or=25% reduction) but not those randomly assigned to placebo (5% with a >or=25% reduction). Lamotrigine was well tolerated, with an adverse event profile comparable to that observed in older pediatric patients.
                Lamotrigine was well tolerated, and the data indicate that it may be efficacious in the treatment of partial seizures in infants aged 1 to 24 months.
The results of this review showed losigamone can reduce seizure frequency but was associated with more treatment withdrawals when used as an add-on therapy for people with partial epilepsy. However, trials included were of short-term duration and uncertain quality. Future well-designed randomized, double-blind, placebo-controlled trials with a longer-term duration are needed.