Add-on melatonin improves quality of life in epileptic children on valproate monotherapy: a randomized, double-blind, placebo-controlled trial. Topiramate in medically intractable partial epilepsies: double-blind placebo-controlled randomized parallel group trial. Korean Topiramate Study Group. Melatonin in wake-sleep disorders in children, adolescents and young adults with mental retardation with or without epilepsy: a double-blind, cross-over, placebo-controlled trial. Outcomes of add-on treatment with lamotrigine in partial epilepsy. A randomized, double-blind, placebo-controlled trial of topiramate in adults with epilepsy and intellectual disability: impact on seizures, severity, and quality of life. Double-blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant generalised epilepsy. Controlled trial of lamotrigine (Lamictal) for refractory partial seizures. 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.
This randomized, double-blind, placebo-controlled study in epileptic children aged 3-12 years evaluated the effects of add-on melatonin administration on the quality of life of these children on sodium valproate (VPA) monotherapy using a parental questionnaire. Quality of Life in Childhood Epilepsy is a questionnaire designed to assess a variety of age-relevant domains such as physical function, emotional well-being, cognitive function, social function, behavior, and general health. Of the 31 patients, 16 randomly received add-on melatonin (MEL), whereas 15 received add-on placebo (P). The questionnaire had good internal consistency reliability, because for most of the multi-item scales Cronbach's alpha reliability exceeded 0.5 (range: 0.59-0.94). To our knowledge, this is the first study assessing quality of life in epileptic children with add-on melatonin administration in the form of a randomized, double-blind, placebo-controlled trial. The study suggests a potential use of melatonin as an adjunct to antiepileptic therapy due to its diverse spectrum of action as an antioxidant, neuroprotector, and free radical scavenger, thus offering the advantage of reducing oxidant stress and subsequent damage. The beneficial effects of melatonin on sleep, its wide safety window, and its ability to cross the blood-brain barrier have the potential to improve quality of life in pediatric epilepsy. 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 aim of the present study was to verify the clinical efficacy of melatonin (MLT) in children, adolescents and young adults with wake-sleep disorder and mental retardation, most of them on chronic anticonvulsant therapy for epileptic seizures, by means of a randomized, double-blind, placebo-controlled cross-over trial. Twenty-five patients (16 males, nine females), aged from 3.6 to 26 years (mean 10.5 years), all affected with mental retardation mostly with epileptic seizures, were randomized to oral synthetic fast-release MLT or placebo. Melatonin was initiated at the daily dose of 3 mg, at nocturnal bedtime. In case of inefficacy, MLT dose could be titrated up to 9 mg the following 2 weeks at increments of 3 mg/week, unless the patient was unable to tolerate it. The analysis of all the sleep logs disclosed a significant treatment effect of melatonin on sleep latency (P = 0.019). Melatonin was well tolerated in all patients and no side effects were reported. In conclusion, our study supports the efficacy of MLT in young patients with mental disabilities and epileptic seizures in improving the wake-sleep disorders such as time to fall asleep. Overall, MLT appeared to influence the seizure frequency poorly, though there may be occasional seizure worsening or improving. Such a dual effect requires further studies in young epileptic patients. The need for new antiepileptic drugs (AEDs) and more sensitive methods of assessing their efficacy is well recognized. This study was designed to evaluate the efficacy and safety of lamotrigine (LTG), a potential new AED and to develop and test new outcome measures. A health-related quality of life (HRQL) model was developed which contains previously validated measures of anxiety, depression, happiness, overall mood, self-esteem, and mastery and a specifically designed seizure severity scale with patient- and caregiver-based components. This HRQL model was used in a randomized, placebo-controlled, double-blind, cross-over study of LTG in 81 patients with refractory partial seizures. Seizure frequency was the primary measure and seizure severity and the HRQL were secondary measures of efficacy. The reduction in seizure frequency with LTG, relative to placebo, was 29.7% [95% confidence interval (CI) 17.8%, 39.9%] for total seizure count, 33.4% (95% CI 14.8%, 47.9%) for complex partial seizures (CPS) and 20.3% (95% CI 0.3%, 36.2%) for secondarily generalized tonic-clonic seizures (GTCS). However, although 41 patients elected to continue with LTG, only 11 experienced at least 50% reduction in total seizures, indicating that other factors influenced their decision. The score with LTG, relative to placebo, was significantly lower for the ictal (p = 0.017) and caregivers (p = 0.035) subscales of the seizure severity scale and significantly higher for happiness (p = 0.003) and mastery (p = 0.003). Simple correlation and multiple-regression analyses indicate that the effects on seizure frequency, seizure severity, and psychological variables appear to be independent of each other. This study indicates that LTG is effective in reducing seizure frequency and has additional favorable effects on seizure severity, mood, and perceived internal control. Some of the scales used indicate the potential of secondary measures of efficacy to enhance the sensitivity of trials of new AEDs. This randomized, double-blind, placebo-controlled UK trial evaluated the effect of topiramate as add-on therapy on seizure frequency, seizure severity, and quality of life in patients with epilepsy and intellectual disability. There were three phases: 4 weeks baseline, 18 weeks titration to 200-400 mg topiramate/day (adults) or 5-9 mg/kg/day (children), 12 weeks maintenance. Recruitment was low (88/120); analyses were underpowered. Seizure frequency varied enormously (median 17.7, maximum 1706.2). There was no significant difference in reduction in mean total seizure frequency or number of responders between the groups. Topiramate reduced seizure frequency by >30% from baseline (placebo 1%); post hoc analyses showed a trend toward significance (R ratio, P=0.052). There were no significant differences between the groups with respect to mean seizure severity or other outcome measures. Topiramate was generally well tolerated; body weight (P=0.015) and systolic blood pressure (P=0.043) were reduced. The study suggests that topiramate reduces seizure frequency in patients with epilepsy and intellectual disability without the added burden of behavior effects, and was potentially advantageous to physical well-being. 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. The antiepileptic effect of lamotrigine (LTG) was assessed in a double-blind, placebo-controlled crossover trial in 24 adult patients with refractory partial seizures. LTG or placebo was added to existing antiepileptic drugs (AEDs). The dose of LTG varied from 75 to 400 mg daily. Three patients did not complete the trial. One was withdrawn from the trial with ataxia, tiredness, dyspnea, and diplopia while receiving LTG and died 18 days later of invasive carcinoma involving the liver. A second patient was withdrawn during baseline for contravening admission criteria, and a third received LTG in error during both treatment periods. Twenty-one patients (12 men and 9 women) completed the trial. An analysis of seizure counts in the 12-week treatment period with LTG showed a statistically significant reduction in seizures as compared with placebo for total seizures (p less than 0.002), partial seizures (p less than 0.002), and secondarily generalized seizures (p less than 0.05). The analysis of total seizure days showed a significant reduction during LTG treatment (p less than 0.002). There were no statistically significant changes in plasma concentrations of phenytoin (PHT), carbamazepine (CBZ), primidone (PRM), or phenobarbital (PB) between the two treatment periods. The most common adverse events reported during the trial were diplopia, drowsiness, tiredness, ataxia, and headache, but although these were more frequent during LTG treatment, the differences from placebo were not statistically significant. No hematological or biochemical changes were noted. 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.
Included studies were of poor methodologic quality, and did not systematically evaluate seizure frequency and adverse events, so that it was impossible to summarize data in a meta-analysis. It is not possible to draw any conclusion about the role of melatonin in reducing seizure frequency or improving quality of life in patients with epilepsy.