Clobazam in therapy-resistant patients with partial epilepsy: a double-blind placebo-controlled crossover study. Clobazam for refractory focal epilepsy. A controlled trial. Clobazam in the treatment of Lennox-Gastaut syndrome. Diazepam versus clobazam for intermittent prophylaxis of febrile seizures. A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children. Lamictal Pediatric Partial Seizure Study Group. Double-blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant generalised epilepsy. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Lamotrigine extended-release as adjunctive therapy for partial seizures. Double-blind, placebo-controlled trial of topiramate as add-on therapy in patients with refractory partial seizures.
Clobazam was compared with placebo as antiepileptic adjunct medication in 129 therapy-resistant epileptic patients who were mainly suffering from complex partial seizures. The study was performed in five European countries according to a double-blind crossover design lasting 7 months. Two treatment periods of 3 months (1 month adjustment and 2 months maintenance medication) were separated by one medication switch-over month. The difference in seizure reduction between clobazam and placebo was significant (p less than 0.05). Nineteen percent of patients receiving clobazam became seizure-free during the maintenance dose period. In contrast, freedom from seizures was not observed in any placebo patient. Electroencephalogram (EEG) signs, mood ratings, and global impressions also indicated therapeutic effects of clobazam in epilepsy. The most frequent adverse reactions to clobazam were drowsiness and dizziness. However, the sedative effects of clobazam seemed to be less pronounced in comparison with other benzodiazepines. The study gives evidence of the therapeutic value of clobazam as adjunct medication in therapy-resistant partial seizures. The use of clobazam as monotherapy and long-term treatment, as well as the particular seizure response pattern to clobazam, has to be further investigated. The effect of 1,5-benzodiazepine clobazam was assessed in a double-blind add-on trial in 20 patients with chronic complex partial seizures uncontrolled by maximally tolerable daily dosage of standard antiepileptic drug therapy. The number of seizures was lower during the three months of active treatment. At the end of the third month, eight (40%) of the patients had a seizure reduction by more than 75%, including four patients (20%) who had complete control. Tolerance to the antiepileptic effect of clobazam was noted in 56% of the patients, and mild transient sedation occurred in 40% of the patients. Despite these drawbacks, clobazam is an effective add-on drug for individual patients with refractory focal epilepsy. This randomized, double-blind, dose-ranging study evaluated safety and efficacy of clobazam (CLB) as adjunctive therapy for drop seizures in patients with Lennox-Gastaut syndrome (LGS).
                Sixty-eight patients with LGS aged 2-26 years were administered CLB (low dose = target 0.25 mg/kg/day; high dose = target 1.0 mg/kg/day). The study consisted of 4-week baseline, 3-week titration, and 4-week maintenance periods, followed by a 3-week taper or continuation in an open-label study. Seizure frequency was recorded in a diary by the parent/caregiver throughout the study.
                Weekly drop seizure rates were significantly reduced from baseline in both the high-dose and low-dose groups; the reduction was significantly greater in the high-dose group. A significantly greater proportion of patients in the high-dose group experienced reductions in drop seizures of >or=25%, >or=50%, and >or=75% compared to the low-dose group; more patients in the high-dose group experienced a 100% reduction, but the difference was not significant. Nondrop seizures were also reduced in a dose-dependent manner. In both investigator and parent/caregiver global evaluations, patients in the high-dose group showed significantly greater improvements in overall symptoms compared to low-dose CLB. Adverse events were generally mild or moderate, and were similar between dose groups. Five serious adverse events were reported in four patients, but in no case was CLB discontinued.
                Clobazam was well tolerated and reduced drop seizure rates; high-dose CLB was more effective than low-dose CLB. Other seizure types were also reduced. To compare the effectiveness of intermittent clobazam versus diazepam therapy in preventing the recurrence of febrile seizures and assess adverse effects of each drug.
                This prospective randomized controlled trial was performed on neurologically normal children aged from 6 months to 5 years with a history of simple febrile seizures and normal electroencephalogram without any evidence of acute central nervous system infection. The patients were randomly prescribed with oral clobazam (37 cases) or diazepam (35 cases) when they developed a febrile disease. They were advised to use the medications during the first 48 h of the onset of fever. All the patients were monitored regarding developing seizure and adverse effects of the drugs. All patients were followed for 12 months.
                Overall, 243 episodes of fever occurred during the period, including 116 episodes in the clobazam group and 127 episodes in the diazepam group. Recurrence of seizures occurred in 2 (1.7%) subjects in the clobazam group, and in 4(3.1%) cases in the diazepam group. (P value=0.474). Twenty cases (54%) in the diazepam group and 5 (14.2%) cases in the clobazam group developed drowsiness and sedation during the follow-up period (P value=0.0001).
                Intermittent clobazam therapy seems advantageous to diazepam due to similar efficacy but significantly lower adverse effects such as drowsiness and sedation. 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. 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. Lamotrigine has been licensed widely as adjunctive therapy for partial and secondary generalised seizures. Use of the drug as monotherapy was investigated in a double-blind, randomised, parallel-group comparison with carbamazepine in newly diagnosed epilepsy. After 4 weeks of planned, fixed dose escalation, doses were adjusted according to efficacy, adverse events, and plasma concentrations. 151 of 260 patients (131 lamotrigine, 129 carbamazepine) in eight UK centres completed the 48-week trial. No differences in efficacy between the drugs were found for partial seizures with or without secondary generalisation or for primary generalised tonic-clonic seizures. The proportion of patients maintained seizure-free during the last 24 weeks of treatment was almost the same in both groups (39% lamotrigine, 38% carbamazepine). More patients with primary generalised tonic-clonic seizures (47% both groups) than those presenting with a focal onset (35%, 37%) were fully controlled. Overall, fewer patients on lamotrigine than on carbamazepine withdrew because of adverse events (15 vs 27%). The commonest side-effect leading to withdrawal with either drug was rash (9%, 13%). Sleepiness was less common in lamotrigine than in carbamazepine recipients (12 vs 22%, p < 0.05). More lamotrigine than carbamazepine recipients (65 vs 51%, p = 0.018) completed the study (hazard ratio 1.57 [95% CI 1.07-2.31]). Lamotrigine and carbamazepine showed similar efficacy against partial onset seizures and primary generalised tonic-clonic seizures in newly diagnosed epilepsy. Lamotrigine, however, was better tolerated. 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. 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.
Clobazam as an add-on treatment may reduce seizure frequency and may be most effective in partial onset seizures. However, it is not clear who will best benefit and over what time-frame. A large scale, randomised controlled trial conducted over a greater period of time, incorporating subgroups with differing seizure types, is required to inform clinical practice.