Efficacy and safety of levetiracetam in children with partial seizures: an open-label trial

PURPOSE: To assess the efficacy and safety of levetiracetam (LEV) as adjunctive therapy in children with treatment-resistant partial-onset seizures. METHODS: Children (aged 6-12 years) with treatment-resistant partial-onset seizures receiving one standard antiepileptic drug (AED) were eligible. After a 4-week baseline period, children received LEV in a 6-week titration phase (target dose, 40 mg/kg/day) followed by an 8-week evaluation phase. Seizure frequency during the evaluation period with individualized LEV doses (20-40 mg/kg/day) were compared with the 4-week baseline seizure frequency. Plasma concentrations of LEV and other AEDs were determined to evaluate potential drug interactions. RESULTS: Twenty-four subjects enrolled and received LEV; 23 entered the evaluation phase, and 22 completed the evaluation phase. Compared with their baseline seizure frequency, 12 (52%) of 23 subjects entering the evaluation phase had their seizure frequency decrease by >50%. Two subjects remained seizure free during the entire evaluation period. LEV did not significantly affect plasma concentrations of any concomitant AED during this study, and no alteration of mean clinical laboratory values was observed. The most commonly reported adverse events were headache, infection, anorexia, and somnolence. CONCLUSIONS: This open-label study of adjunctive LEV therapy (at 20-40 mg/kg/day) suggests that LEV is effective, safe, and well tolerated in children ages 6-12 years with treatment-resistant partial-onset seizures. A randomized, placebo-controlled, double-blind trial of LEV adjunctive therapy in children with treatment-resistant partial-onset seizures is needed and ongoing to confirm these open-label findings.     

A double-blind, randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children. Topiramate YP Study Group

OBJECTIVE: To evaluate the efficacy and safety of topiramate 6 mg/kg/day in children (age 2 to 16 years) as adjunctive therapy for uncontrolled partial-onset seizures with or without secondarily generalized seizures in a multicenter, randomized, double-blind, placebo-controlled trial. METHODS: Patients with at least six partial-onset seizures during the 8-week baseline phase were treated with either topiramate (n = 41) or placebo (n = 45) for 16 weeks. RESULTS: Topiramate-treated patients had a greater median percent reduction from baseline in average monthly partial-onset seizure rate than placebo-treated patients (33.1% versus 10.5%, p = 0.034), a greater proportion of treatment responders (i.e., patients with a > or = 50% seizure rate reduction; 16 of 41 [39%] versus 9 of 45 [20%], p = 0.080), and patients with a > or = 75% seizure rate reduction (7 of 41 [17%] versus 1 of 45 [2%], p = 0.019), and better parental global evaluations of improvement in seizure severity (p = 0.019). Emotional lability (12% versus 4%), fatigue (15% versus 7%), difficulty with concentration or attention (12% versus 2%), and forgetfulness/impaired memory (7% versus 0%) were more frequent among topiramate-treated than placebo-treated patients. Most treatment-emergent adverse events were mild or moderate in severity. No topiramate-treated patients discontinued the study due to adverse events. CONCLUSIONS: Topiramate was safe and effective in the treatment of partial-onset seizures in children.     

Topiramate in older patients with partial-onset seizures: a pilot double-blind, dose-comparison study

Purpose: Pharmacokinetics of antiepileptic drugs (AEDs) can be altered by age-related changes in physiology, thereby altering clinical effects, especially tolerability, in older adults. We compared two dosages of topiramate (TPM) in a pilot study of patients ≥60 years of age with partial-onset seizures.
Methods: In this 24-week, double-blind, randomized, parallel-group study, patients with one or more seizures in previous 6 months were randomized to treatment with 50 or 200 mg/day TPM. TPM was initiated as monotherapy or added to one AED and titrated by 25 mg/day per week to target or maximum tolerated dose as the concomitant AED, if any, was withdrawn.
Results: Thirty-eight patients were randomized to the 50 mg/day TPM (mean age, 68 years) and 39–200 mg/day TPM (69 years). Seizure control was similar with the two dosages when TPM could be used as monotherapy, whereas 200 mg TPM was more effective than 50 mg in patients requiring adjunctive therapy. The overall incidence of adverse events was similar for the two dosages—66% with 50 mg and 62% with 200 mg TPM. Most common adverse events were somnolence (TPM 50, 13%; TPM 200, 8%), dizziness (13% vs. 8%), and headache (13% vs. 5%). Of 10 (13%) patients reporting a cognitive-related adverse event, six patients were assigned to the 50-mg group. A total of 14 patients (18%; seven in each group) discontinued TPM due to adverse events.
Conclusions: This pilot study supports the practice of using low-to-moderate dosages of AEDs in older adults.     

A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group

BACKGROUND AND OBJECTIVE: Topiramate is effective as adjunctive treatment of partial-onset seizures in adults. The efficacy and safety of topiramate as adjunctive therapy for the treatment of primary generalized tonic-clonic (PGTC) seizures were investigated in a randomized, double-blind, placebo-controlled study. METHODS: Eighty patients, 3 to 59 years old, who experienced three or more PGTC seizures during an 8-week baseline phase were randomly assigned to treatment with either topiramate (n = 39) or placebo (n = 41). Topiramate was titrated to target doses of approximately 6 mg/kg/day over 8 weeks and maintained for another 12 weeks. RESULTS: The median percentage reduction from baseline in PGTC seizure rate was 56.7% for topiramate patients and 9.0% for placebo patients (p = 0.019). The proportion of patients with 50% or higher reduction in PGTC seizure rate was 22/39 (56%) and 8/40 (20%) for the topiramate and placebo groups, respectively (p = 0.001). The median percentage reduction in the rate of all generalized seizures was 42.1% for topiramate patients and 0.9% for placebo patients (p = 0.003). The proportions of patients with 50% or higher reductions in generalized seizure rate were 18/39 (46%) and 7/41 (17%) for the topiramate and placebo groups, respectively (p = 0.003). The most common adverse events were somnolence, fatigue, weight loss, difficulty with memory, and nervousness. Treatment-limiting adverse events occurred in one patient in the topiramate group (anorexia and weight loss) and one in the placebo group (granulocytopenia and thrombocytopenia). CONCLUSION: Topiramate is well-tolerated and effective for the adjunctive treatment of PGTC seizures.     

Randomized dose-controlled study of topiramate as first-line therapy in epilepsy

OBJECTIVES: To evaluate the efficacy and tolerability of topiramate as monotherapy, using a dose-controlled study design. MATERIALS AND METHODS: We conducted a multinational, randomized, double-blind trial in adults and children (> or =6 years old) with epilepsy that was not being treated when randomized to 400 or 50 mg/day topiramate as target maintenance dosages. In addition to > or =2 lifetime unprovoked seizures, patients had to have one or two partial-onset seizures or generalized-onset tonic-clonic seizures in the 3-month retrospective baseline. The primary efficacy end point was time to first seizure; a secondary efficacy measure was the seizure-free rate at 6 months and 1 year. Double-blind treatment continued until 6 months after the last patient was randomized. RESULTS: Kaplan-Meier survival analyses for time to first seizure (intent-to-treat, n = 470) favored 400 mg/day over 50 mg/day (P = 0.0002) as a target maintenance dosage. The first evaluation point with a significant difference (P = 0.046) favoring the higher dose was at day 14 when patients were receiving 100 or 25 mg/day. The probability of being seizure-free at 6 months was 83% in patients randomized to 400 mg/day and 71% in those randomized to 50 mg/day (P = 0.005). Seizure-free rates at 12 months were 76% and 59%, respectively (P = 0.001). Differences favoring the higher dose were significant in patients with partial-onset seizures (P = 0.009) and in those with generalized-onset tonic-clonic seizures (P = 0.005). The most common dose-related adverse events were paresthesia, weight loss, and decreased appetite. Discontinuations due to cognitive-related adverse events were 2% in the 50-mg group and 7% in the 400-mg group. Overall, 7% and 19%, respectively, discontinued with adverse events during the median treatment duration of 9 months. CONCLUSION: Topiramate is effective as monotherapy in adults and children. Because a therapeutic effect emerges during titration, clinicians should adjust dosages in step-wise fashion with intermediate stopping points, e.g., 100 mg/day, to evaluate patient response and achieve the optimal maintenance dosage.     

Time course of adverse events in patients with localization-related epilepsy receiving topiramate added to carbamazepine

PURPOSE: To explore the time course of treatment-emergent adverse events (AEs) during topiramate (TPM) adjunctive therapy. METHODS: Post hoc analyses were performed by using data from a large (264 subjects) multicenter, double-blind, placebo-controlled trial in which 200 mg/day TPM was added to carbamazepine (CBZ) with or without another antiepileptic drug (AED) in adults with treatment-resistant partial-onset seizures. The daily incidence and mean duration of the most common (> or =5% incidence) AEs were calculated for patients completing the 12-week study. RESULTS: The daily incidence of somnolence, headache, loss of appetite, nervousness, fatigue, dizziness, upper respiratory tract infection, and vertigo peaked during titration and declined to rates similar to that of placebo after the target TPM dose had been reached. In contrast, the daily incidence of paresthesia increased during titration and was maintained for the study duration. Relatively few patients had cognitive symptoms (9% with TPM, 5% with placebo), but these were the most common AEs associated with treatment discontinuation. Patient/investigator reports of weight loss increased gradually over the course of the trial, corresponding with the pattern of change in weight measured at study visits. CONCLUSIONS: This study demonstrates that most of the more common AEs with TPM adjunctive therapy are transient. Patients can be counseled that most AEs emerging when TPM is initially added to CBZ can be expected to diminish with continued therapy.     

Efficacy and safety of levetiracetam 1000-3000 mg/day in patients with refractory partial-onset seizures: a multicenter, open-label single-arm study

PURPOSE: To evaluate the efficacy and tolerability of levetiracetam as add-on therapy in patients with refractory partial-onset seizures in a protocol designed to reflect clinical practice. METHODS: All patients in this open-label, single-arm study entered an 8-week baseline period followed by a 4-week titration period and a 12-week maintenance period. Patients initially received levetiracetam 1000 mg/day (administered bid) and could increase to 2000 mg/day after 2 weeks, and to 3000 mg/day after another 2 weeks, to obtain adequate seizure control. During the 12-week maintenance period, the dose of levetiracetam could not be increased but could be decreased once if tolerability warranted. Seizure count and adverse events were recorded by patients in a diary. Quality of life and global evaluation of disease evolution were also evaluated. RESULTS: Ninety-nine patients were enrolled and 91 completed the study. A steady dose was maintained over the last 8 weeks of treatment or longer in 84 patients, with 89.3% of these patients receiving 3000 mg/day, 9.5% receiving 2000 mg/day, and 1.2% receiving 1000 mg/day. A 35.9% median percent reduction from baseline in weekly frequency of partial-onset seizures was observed over the entire treatment period. The median partial-onset seizure count decreased from 2.3 per week during the baseline period to 1.3 per week over the treatment period. A total of 42.4% of patients were responders (> or = 50% reduction from baseline in weekly seizure frequency) over the treatment period; two patients were seizure-free from the first day of treatment throughout the treatment period. The most frequent drug-related adverse events were fatigue (27.3% of patients), somnolence (11.1%), headache (8.1%), and dizziness (8.1%). CONCLUSION: Levetiracetam as add-on therapy at doses up to 3000 mg/day effectively reduced the frequency of partial-onset seizures in patients with refractory epilepsy and was well-tolerated in this study, bridging conditions of placebo-controlled clinical trials and clinical practice.     

A study of topiramate pharmacokinetics and tolerability in children with epilepsy

The pharmacokinetic and safety profile of topiramate as adjunctive therapy was assessed in pediatric patients with epilepsy in an open-label, 4-week, single-center study. Six children from each of the following age groups were enrolled: 4-7 years, 8-11 years, and 12-17 years. Patients received topiramate 1 mg/kg/day for 1 week, with subsequent progressive weekly increases in dosage to 3, 6, and then 9 mg/kg/day or 800 mg/day, whichever was less. Topiramate oral plasma clearance (CL/F) was independent of dose, and steady-state plasma concentrations increased in proportion to dose. Weight-normalized topiramate CL/F was higher (P = 0.003) in pediatric patients receiving enzyme-inducing concomitant antiepileptic drugs (AEDs) (mean = 70.1 mL/minute/70 kg) than in those not receiving enzyme-inducing AEDs (mean = 33.1 mL/minute/kg). Topiramate CL/F in children was approximately 50% greater than that observed in adults regardless of the type of concomitant AED therapy. Thus steady-state plasma topiramate concentrations for the same mg/kg dose will be approximately 33% lower in pediatric patients than in adult patients. The most frequently reported treatment-emergent adverse events considered related to topiramate therapy included anorexia, fatigue, and nervousness, and no patient discontinued therapy. This study indicates that, in children 4-17 years of age, topiramate has linear pharmacokinetics, 50% higher clearance than in adults, and is generally well tolerated.     

Retigabine as adjunctive therapy in adults with partial-onset seizures: Integrated analysis of three pivotal controlled trials

We assessed the efficacy and tolerability of retigabine (RTG; international non-proprietary name)/ezogabine (EZG; US adopted name) as adjunctive therapy in adults with partial-onset seizures in an integrated analysis of three trials. Studies 205, 301 (NCT00232596), and 302 (NCT00235755) were randomized, double-blind, placebo-controlled studies in adults having ≥4 partial-onset seizures per 28 days and receiving 1-3 antiepileptic drugs with/without vagus nerve stimulator. Patients underwent titration to RTG/EZG 600, 900, or 1200mg/day or to placebo followed by 8 or 12 weeks maintenance. For efficacy analyses, placebo was compared with RTG/EZG 600 and 900mg/day in Studies 205 and 302, and RTG/EZG 1200mg/day in Studies 205 and 301. Responder rates (≥50% reduction in baseline seizure frequency) were 35% and 45% for RTG/EZG 600 and 900mg/day, respectively (placebo=21%; p<0.001), and 50% for RTG/EZG 1200mg/day (placebo=24%, p<0.001). Reductions in 28-day total partial-seizure frequency (medians: placebo=14%; 600mg/day=26%, p=0.003; 900mg/day=37%, p<0.001; placebo=15%; 1200mg/day=39%, p<0.001) were significantly greater with all RTG/EZG doses vs. placebo from baseline to the double-blind phase, and similarly during the maintenance phase. The most commonly reported (>10%) treatment-emergent adverse events were dizziness, somnolence, headache, and fatigue. RTG/EZG demonstrated efficacy and was generally tolerated as adjunctive therapy in adults with partial-onset seizures in this integrated analysis.     

Randomized controlled trial of zonisamide for the treatment of refractory partial-onset seizures.

BACKGROUND: Zonisamide is a sulfonamide antiepilepsy drug with sodium and calcium channel-blocking actions. Experience in Japan and a previous European double-blind study have demonstrated its efficacy against partial-onset seizures. METHODS: A randomized, double-blind, placebo-controlled trial enrolling 203 patients was conducted at 20 United States sites to assess zonisamide efficacy and dose response as adjunctive therapy for refractory partial-onset seizures. Zonisamide dosages were elevated by 100 mg/d each week. The study design allowed parallel comparisons with placebo for three dosages and a final crossover to 400 mg/d of zonisamide for all patients. The primary efficacy comparison was change in seizure frequency from a 4-week placebo baseline to weeks 8 through 12 on blinded therapy. RESULTS: At 400 mg/d, zonisamide reduced the median frequency of all seizures by 40.5% from baseline, compared with a 9% reduction (p = 0.0009) with placebo treatment, and produced a > or =50% seizure reduction (responder rate) in 42% of patients. A dosage of 100 mg/d produced a 20.5% reduction in median seizure frequency (p = 0.038 compared with placebo) and a dosage of 200 mg/d produced a 24.7% reduction in median seizure frequency (p = 0.004 compared with placebo). Dropouts from adverse events (10%) did not differ from placebo (8.2%, NS). The only adverse event differing significantly from placebo was weight loss, though somnolence, anorexia, and ataxia were slightly more common with zonisamide treatment. Serum zonisamide concentrations rose with increasing dose. CONCLUSION: Zonisamide is effective and well tolerated as an adjunctive agent for refractory partial-onset seizures. The minimal effective dosage was 100 mg/d, but 400 mg/d was the most effective dosage.     

Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial

Purpose:   To evaluate the efficacy and safety of lacosamide (200 and 400 mg/day) when added to one to three concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures.
Methods:   This multicenter, double-blind, placebo-controlled trial randomized patients (age 16–70 years) with partial-onset seizures with or without secondary generalization to placebo, lacosamide 200, or lacosamide 400 mg/day. The trial consisted of an 8-week baseline, a 4-week titration, and a 12-week maintenance period.
Results:   Four hundred eighty-five patients were randomized and received trial medication. Among these, 87% were taking two or more concomitant AEDs. Median percent reduction in seizure frequency per 28 days from baseline to maintenance period (intent-to-treat, ITT) was 20.5% for placebo, 35.3% for lacosamide 200 mg/day (p   =   0.02), and 36.4% for 400 mg/day (p   =   0.03). In the per protocol population, the reductions were 35.3% for lacosamide 200 mg/day (p   =   0.04) and 44.9% for 400 mg/day (p   =   0.01) compared to placebo (25.4%). The 50% responder rate for lacosamide 400 mg/day (40.5%) was significant (p   =   0.01) over placebo (25.8%), but was not for 200 mg/day (35.0%). In the per protocol population, the 50% responder rate for lacosamide 400 mg/day (46.3%) was significant (p   <   0.01) compared with the placebo responder rate (27.5%). Dose-related adverse events (AEs) included dizziness, nausea, and vomiting. Clinically relevant changes in the mean plasma concentrations of commonly used AEDs were not observed.
Discussion:   Results of this trial demonstrated the efficacy and tolerability of adjunctive lacosamide 200 and 400 mg/day and support that lacosamide may be an advantageous option for the treatment of partial-onset seizures in patients with epilepsy.     

Prospective assessment of levetiracetam pharmacokinetics during dose escalation in 4- to 12-year-old children with partial-onset seizures on concomitant carbamazepine or valproate

PURPOSE: To assess the multiple-dose pharmacokinetics of levetiracetam and its major metabolite ucb L057 in children with partial-onset seizures and determine whether it is affected by adjunctive carbamazepine or valproate. To correlate levetiracetam concentrations in plasma and saliva and to assess its safety and clinical response. METHODS: Design was an open-label, multicenter study. Twenty-one children (4-12 years old) with epilepsy taking carbamazepine (13) or valproate (8) received adjunctive levetiracetam. Levetiracetam was initiated at 20 mg/(kg day) and titrated at 2-week intervals to 40 and then 60 mg/(kg day). Twelve-hour pharmacokinetics were determined at the end of each 2-week period. Efficacy was estimated from the partial seizure frequency per week and Global Evaluation Scale. RESULTS: Levetiracetam was rapidly absorbed following oral dosing, with median t(max) of 0.5 h. Dose proportional increases were observed for C(max) and AUC((0-12)) over the dose range; t(1/2) was 4.9 h. Pharmacokinetics of levetiracetam and ucb L057 were not markedly different with concomitant carbamazepine or valproate; clearance was only 7-13% faster and AUC was decreased by only 15-24% in those on carbamazepine compared to valproate. Levetiracetam did not affect trough carbamazepine or valproate. Concentration in saliva and plasma were strongly correlated. Seizure frequency declined by 50% or more in 43% of subjects in the intent-to-treat population (n=21) and in 56% of those with seizures at baseline (n=16). Marked or moderate improvement occurred in 80% and 75% of patients based on Global Evaluation Scale ratings by investigators and parents/guardians, respectively. Levetiracetam was well tolerated. CONCLUSION: Levetiracetam exhibits simple pharmacokinetics in children, with rapid absorption and dose-proportional kinetics. Small but not clinically relevant differences were observed between subjects receiving carbamazepine and valproate, suggesting significant dose adjustment is usually not necessary. This substantiates prior assessments that levetiracetam clearance is higher in children than adults, necessitating a higher dose in children on a mg/kg basis, and suggests it is useful add-on therapy for children with partial-onset seizures regardless of baseline therapy.     

Double-Blind, Placebo-Controlled Trial of Topiramate (600 mg Daily) for the Treatment of Refractory Partial Epilepsy

Summary: Purpose : 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.
Methods : 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.
Results : 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 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.
Conclusions : The results of the present trial indicate that TPM 600 mgiday is effective in the treatment of refractory partial-onset seizures with or without secondarily generalized seizures.     

Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures

PURPOSE: To evaluate the efficacy and safety of lacosamide when added to 1 or 2 antiepileptic drugs (AEDs) in adults with uncontrolled partial-onset seizures, and assess plasma concentrations of concomitant AEDs to determine any potential for drug interactions. METHODS: During this multicenter, double-blind, placebo-controlled trial, patients were randomized to placebo or lacosamide 200, 400, or 600 mg/day after an 8-week baseline period. Lacosamide was titrated in weekly increments of 100 mg/day over 6 weeks and maintained for 12 weeks. Results were analyzed on an intention-to-treat basis. RESULTS: Four hundred eighteen patients were randomized and received trial medication; 312 completed the trial. The median percent reduction in seizure frequency per 28 days was 10%, 26%, 39%, and 40% in the placebo, lacosamide 200, 400, and 600 mg/day treatment groups, respectively. The median percent reduction in seizure frequency over placebo was significant for lacosamide 400 mg/day (p=0.0023) and 600 mg/day (p=0.0084). The 50% responder rates were 22%, 33%, 41%, and 38% for placebo, lacosamide 200, 400, and 600 mg/day, respectively. The 50% responder rate over placebo was significant for lacosamide 400 mg/day (p=0.0038) and 600 mg/day (p=0.0141). Adverse events that appeared dose-related included dizziness, nausea, fatigue, ataxia, vision abnormal, diplopia, and nystagmus. Lacosamide did not affect mean plasma concentrations of concomitantly administered AEDs. CONCLUSIONS: In this trial, adjunctive lacosamide significantly reduced seizure frequency in patients with uncontrolled partial-onset seizures. Along with favorable pharmacokinetic and tolerability profiles, these results support further development of lacosamide as an AED.     

Adaptive behavior outcomes in infants treated with adjunctive topiramate

Data from two global studies (6-week open-label, phase 1 study; 20-day double-blind, phase 3 study) and their 1-year open-label extensions were pooled to assess long-term effects of adjunctive topiramate on adaptive behavior in infants with clinical or video-electroencephalographic evidence of refractory, partial-onset seizures. The primary safety and efficacy results of adjunctive topiramate treatment were reported previously. We report the changes in adaptive behavior of infants, based on Vineland Scales of Adaptive Behavior. Of 284 infants (mean [S.D.] age, 12 [6.3] months) enrolled, 89% (n = 252) manifested partial-onset seizures, and 41% (n = 116) manifested clinically relevant, symptomatic etiologies at pretreatment baseline. Overall, Vineland scores were below average at pretreatment baseline. The most frequently used concomitant antiepileptic drugs included valproic acid (59%), phenobarbital (31%), and carbamazepine (19%). The most common treatment-emergent cognitive and neuropsychiatric adverse events included anorexia (35%) and somnolence (27%). A clinically significant decline (approximately 15 points, or 1 S.D.) occurred in both Vineland Scales composite (mean change, -14.0) and domain standard scores from pretreatment baseline to open-label extension endpoint. However, individual domain raw scores increased, indicating that infants progressed in acquisitions of adaptive skill, but at a slower rate than the normative population.     

Dose-dependent safety and efficacy of zonisamide: a randomized, double-blind, placebo-controlled study in patients with refractory partial seizures

PURPOSE: To evaluate the safety and efficacy of zonisamide (ZNS) as adjunctive treatment in patients with refractory localization-related epilepsy. METHODS: This was a double-blind, placebo-controlled study of adjunctive ZNS in 351 patients with refractory partial seizures receiving a stable regimen of one to three antiepileptic drugs (AEDs). Patients were randomized to placebo or ZNS, 100 mg, 300 mg, or 500 mg/day (2:1:1:2) after a 12-week baseline. Dose titration was undertaken over a 6-week titration phase, which was followed by an 18-week fixed-dose assessment phase. Primary efficacy parameters were the differences between ZNS, 500 mg/day, and placebo in the change from baseline in frequency of complex partial (CP) seizures during the fixed-dose assessment phase and in the proportion of CP responders (> or =50% decrease from baseline in seizure frequency). Safety and tolerability also were assessed. RESULTS: Compared with placebo, the highest dose of ZNS (500 mg/day) resulted in a significantly greater decrease in CP seizure frequency from baseline (51.2% vs. 16.3%; p < 0.0001) and a significantly higher proportion of CP responders (52.3% vs. 21.3%; p < 0.001). Both ZNS, 500 mg/day, and 300 mg/day were statistically superior to placebo in reducing the frequency of "all seizures" and simple partial (SP) + CP seizures. For all seizures, a significant dose-response relation was observed (p < 0.0001).The most common adverse events were somnolence, headache, dizziness, and nausea during the titration phase and headache and pharyngitis during the fixed-dose assessment phase. CONCLUSIONS: ZNS provides dose-dependent, effective, and generally well-tolerated adjunctive therapy in patients with partial seizures.     

Safety and tolerability of dapsone for the treatment of patients with drug-resistant,partial-onset seizures: an open-label trial

Dapsone has shown anti-convulsive properties in animal models of epilepsy. In the present study, we tested the safety and tolerability of dapsone as adjunctive therapy in adult patients with drug-resistant partial-onset seizures. Twenty-two adult patients with drug-resistant partial-onset seizures were included. After a 3-month baseline period, patients received dapsone 100 mg per day, for a 3-month evaluation period. Plasma concentrations of anti-epileptic drugs (AEDs) did not significantly change during the study. No alteration of mean clinical laboratory values was observed. The reported adverse events were: mild methemoglobinemia (50%), headache (31.8%), paleness (27.3%) and somnolence (4.5%).Sixteen of 22 patients reduced their seizure frequency in more than 50% as a result of dapsone treatment. Three subjects remained seizure-free during the entire dapsone treatment period. This open-label study of adjunctive dapsone therapy at 100 mg/day suggests that dapsone is safe, and well-tolerated in adults with drug-resistant partial-onset seizures.     

Topiramate monotherapy in newly diagnosed epilepsy in children and adolescents

A double-blind, dose-controlled study evaluated topiramate as monotherapy in 470 patients with newly diagnosed (< or = 3 months) epilepsy or epilepsy relapse in the absence of therapy. In addition to having at least 2 lifetime-unprovoked seizures, patients had 1 or 2 partial-onset seizures or generalized-onset tonic-clonic seizures during a 3-month retrospective baseline. The trial included a large cohort (N = 151, 32%) of children and adolescents 6 to 15 years of age. Eligible patients were randomized to treatment groups in which topiramate was titrated to target maintenance dosages of either 400 mg/day (n = 77) or 50 mg/day (n = 74). Patients were followed for at least 6 months. Based on Kaplan-Meier analyses, the primary efficacy endpoint of time to first seizure favored the higher topiramate dose in both the overall population and the cohort of children/adolescents. The probability that children/adolescents remaining in the study were seizure free at 6 months was 78% in the 50-mg target dose group and 90% with the higher dose. At 12 months, the probability of being seizure free was 62% and 85%, respectively. The incidence of treatment-limiting adverse events was 4% in the 50-mg target dose group and 14% in the group assigned to 400 mg as a target dose. The most common adverse events, excluding typical childhood illnesses, were headache, appetite decrease, weight loss, somnolence, dizziness, concentration/attention difficulty, and paresthesia. As shown in this subset analysis, topiramate is effective and well tolerated as monotherapy in children and adolescents.     

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

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Adjunctive LEV therapy, 相似文献   

A placebo-controlled, random-assignment, parallel-group pilot study of adjunctive topiramate for patients with schizoaffective disorder, bipolar type

OBJECTIVES: This pilot study evaluated the efficacy and safety of adjunctive topiramate compared with placebo in the treatment of patients with a diagnosis of schizoaffective disorder, bipolar type (SAD-BT). METHODS: A sample of 48 adult patients with a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) diagnosis of SAD-BT (supported by the Structured Clinical Interview for DSM-IV Axis I Disorder, Patient Edition) were randomly assigned in a 2:1 ratio (favoring topiramate) to 8 weeks of double-blind treatment with topiramate (100-400 mg/day) or placebo. Patients who had achieved a > or =20% decrease from baseline in their Positive and Negative Syndrome Scale (PANSS) total scores were given the opportunity to continue for an additional 8 weeks of double-blind treatment. The dosage of the study medicine was continued unchanged from the earlier 8-week study period. At the end of the study period, the study medicine was tapered and discontinued over a 2-week period. Primary efficacy was assessed at 8 weeks using the mean change between treatment groups of the PANSS total scores in the intent-to-treat population of randomized patients. Several secondary measures were also assessed. Safety analyses included monitoring of adverse events, vital signs, electrocardiogram (ECG) and laboratory values. RESULTS: Even though both treatments reduced scores on various psychopathology rating scales, adjunctive topiramate treatment (nearly 275 mg/day) did not show increased efficacy relative to placebo on the primary outcome measure (PANSS scale) or any of the secondary outcome measures. Topiramate-treated patients lost significantly more body weight than placebo-treated patients, which led to a significant reduction in body mass index (BMI). Relative to adjunctive placebo, topiramate-treated patients experienced higher rates of paresthesia, sedation, word-finding difficulty, sleepiness, and forgetfulness, but these differences were not statistically significant. There were no clinically significant abnormalities in either the ECG or laboratory results. There were no serious adverse events in the study. Further, there was no worsening of the PANSS total scores (to > or =10% from baseline), and no significant differences between the treatments on worsening of total Montgomery-Asberg Depression Rating Scale (MADRS) scores [1/13 (7.7%) for placebo; 1/25 (4.0%) for topiramate]. CONCLUSIONS: This pilot study did not support clinical efficacy for adjunctive topiramate treatment in patients with SAD-BT. There were no major safety or tolerability issues in this study. Confirming the results of other studies, topiramate-treated patients did experience greater body weight loss and reduction in BMI.