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.     

A double-blind, placebo-controlled study of topiramate in adult patients with refractory partial epilepsy

PURPOSE: The efficacy and safety of topiramate (TPM) as adjunctive therapy in the treatment of adult Chinese patients with refractory partial epilepsy were investigated in a randomized, double-blind, placebo-controlled study. METHODS: A total of 46 patients who had four or more complex partial seizures with or without secondary generalization within an 8-week baseline phase were enrolled. Patients were assigned randomly to receive TPM (n = 23) or placebo (n = 23). TPM or placebo was titrated to target doses of 300 mg/d for 6 weeks and maintained at stabilized levels for another 8 weeks. Concomitant antiepileptic drugs remained at constant previous levels during the trial. RESULTS: In all, 41 patients completed the trial (TPM group, n = 20; placebo group, n = 21). The proportion of patients with a > or =50% reduction from baseline in complex partial seizures was 11 of 23 (47.8%) in the TPM group and 3 of 23 (13.0%) in the placebo group (p = 0.01). In addition, patients treated with TPM had significantly better investigator (p = 0.014) and patient (p = 0.0005) global assessment scores than patients in the placebo group. Adverse events were mostly mild and transient, with no significant differences between treatment groups. Two patients with TPM therapy complained of weight loss. Routine blood cell counts and other laboratory results showed no significant changes from baseline in either treatment group. CONCLUSIONS: TPM 300 mg/d is effective and well tolerated as treatment for refractory partial epilepsy in adults.     

Clinical Efficacy of Topiramate as Add-On Therapy in Refractory Partial Epilepsy: The European Experience

Summary: In three randomized, double-blind, placebo-controlled add-on European trials, target daily topiramate (TPM) dosages of 400, 600, and 800 mg/day (200, 300, and 400 mg bid) were evaluated in adults with refractory partial seizures with or without becoming secondarily generalized. Median reductions from baseline in monthly seizure rate were 41% with TPM 400 mg/day vs. 1% with placebo ( n = 0.065), 46% with TPM 600 mg/day compared to -12% (a 12% increase) with placebo ( p ≤ 0.005), and 36% with TPM 800 mg/day versus –18% (an 18% increase) with placebo ( p ≤ 0.001). Differences between TPM and placebo with respect to percent responders (percent of patients demonstrating a 50% or greater reduction in seizures) significantly favored TPM ( p ≤ 0.05) at all three target dosages. Significant reductions in secondarily generalized tonic-clonic seizures compared to placebo were also observed with 400 mg/day ( p = 0.002) and 800 mg/day ( p < 0.05) of TPM. TPM appears to be a promising new antiepileptic drug for use as adjunctive therapy in adults with refractory partial epilepsy.     

Topiramate as Adjunctive Therapy in Refractory Partial Epilepsy: Pooled Analysis of Data from Five Double-Blind, Placebo-Controlled Trials

Summary: A pooled analysis of data from five similarly designed double-blind, placebo-controlled trials of topiramate (TPM) as add-on therapy in patients with partial epilepsy was performed. The pooled analysis allowed evaluation of efficacy end points and response to treatment for a number of study subgroups not statistically evaluable in the individual study analyses due to limited sample sizes. The five trials included 534 patients, 360 who received TPM at target dosages of 200-1,000 mg daily and 174 who received placebo. In the intent-to-treat pooled analysis, TPM was significantly ( p ≤ 0.01) superior to placebo in reducing total seizures by ≥ 75% or by 100%. When seizure types were evaluated independently, TPM significantly ( p ≤ 0.001) reduced the frequency of simple partial, complex partial, and secondarily generalized seizures. TPM was significantly ( p ≤ 0.001) better than placebo regardless of gender, patient age, baseline seizure rate, and concomitant AEDs. The efficacy of TPM in partial epilepsy is consistent across efficacy end points and across strata defined by study population characteristics.     

Topiramate in medically intractable partial epilepsies: double-blind placebo-controlled randomized parallel group trial. Korean Topiramate Study Group

Summary: Purpose: To evaluate the efficacy and safety of topiramate (TPM) as add-on therapy in medically intractable partial epilepsies. Methods: 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. Results: 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. Conclusions: 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.     

Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial

OBJECTIVE: To evaluate the efficacy and safety of 500 mg bid and 1500 mg bid levetiracetam as adjunctive therapy for refractory partial seizures in a double-blind, randomized, placebo-controlled, parallel-group, multicenter trial. METHODS: The authors studied patients with uncontrolled partial seizures (minimum 12 per 12 weeks), regardless of whether they became secondarily generalized, for 38 weeks. A 12-week baseline was followed by random assignment to adjunctive therapy with placebo (n = 95), levetiracetam 1000 mg/day (n = 98), or levetiracetam 3000 mg/day (n = 101). Upward titration over 4 weeks was followed by 14 weeks of fixed dose treatment, and concluded with an 8-week medication withdrawal period or entering a follow-up study. RESULTS: Of 294 patients randomized, 268 completed the study. Partial seizure frequency during the entire evaluation period (primary efficacy variable) was lower with levetiracetam compared to placebo (p /=10%), mostly mild to moderate in severity, with incidences higher than placebo were asthenia, dizziness, flu syndrome, headache, infection, rhinitis, and somnolence. CONCLUSION: Adjunctive therapy with levetiracetam was effective and well tolerated in controlling partial seizures.     

A pooled analysis of adjunctive topiramate in refractory partial epilepsy

OBJECTIVES: To evaluate the impact of different dosages of topiramate (TPM) add-on to stable antiepileptic therapy for refractory partial epilepsy in adults. MATERIAL AND METHODS: Pooled intention-to-treat analysis of six similarly designed double-blind, placebo-controlled trials, including 481 patients treated with doses of TPM 200, 400, 600 and 800 mg/day, and 265 patients receiving placebo. RESULTS: Seizures were reduced by >/=50% from baseline in 41% of TPM-treated patients and 15% of placebo-treated patients (P < 0.001); 5 and 0.8%, respectively, were seizure-free (P < 0.003). TPM was significantly better than placebo regardless of gender, age, baseline seizure rate as well as number and type of concomitant antiepileptic drugs. Efficacy was statistically significant in favour of TPM at all dose levels: at least 50% seizure reduction was achieved in 40% of patients with 200 mg, 41% with 400 mg, 44% with 600 mg and 41% with 800 mg TPM when compared with 15% with placebo (P 相似文献   

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.     

Evaluation of adjunctive perampanel in patients with refractory partial‐onset seizures: Results of randomized global phase III study 305

Purpose: To assess the efficacy and safety of once‐daily doses of perampanel 8 and 12 mg when added to 1–3 concomitantly administered, approved antiepileptic drugs (AEDs) in patients with uncontrolled partial‐onset seizures. Methods: Study 305 was a multicenter, double‐blind, placebo‐controlled trial in patients aged 12 years and older with ongoing seizures despite prior therapy with at least two AEDs, and currently receiving 1–3 AEDs. Equal randomization to once‐daily oral perampanel 8 or 12 mg, or placebo was performed. Patients entered a 19‐week double‐blind treatment phase comprising a 6‐week titration period, with weekly 2‐mg dose increments, followed by a 13‐week maintenance period. Primary efficacy end points were the responder rate (proportion of patients who had a ≥50% reduction in seizure frequency during treatment per 28 days relative to baseline), and the percent change in seizure frequency per 28 days relative to pre‐perampanel baseline. A secondary end point was percent change in the frequency of complex partial plus secondarily generalized seizures. Adverse events (AEs) were monitored throughout the study. Key Findings: Three hundred eighty‐six patients were randomized and treated with study medication. Of these, 321 patients completed the study. The 50% responder rates (intent‐to‐treat analysis) were 14.7%, 33.3%, and 33.9%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg, with significant improvements over placebo for both perampanel 8 mg (p = 0.002) and 12 mg (p < 0.001). The median percent change from baseline in seizure frequency per 28 days (intent‐to‐treat analysis) was ?9.7%, ?30.5%, and ?17.6% for placebo, 8 mg, and 12 mg, respectively, with significant reductions compared with placebo for both 8 mg (p < 0.001) and 12 mg (p = 0.011). For complex partial seizures plus partial seizures that secondarily generalized, the median percent change in frequency was ?32.7% (8 mg), ?21.9 (12 mg), and ?8.1% (placebo), with significant reductions for both 8 mg (p < 0.001) and 12 mg (p = 0.005). The most frequent (occurring in ≥10% of patients in any treatment group) treatment‐emergent AEs were dizziness, somnolence, fatigue, and headache, with an apparent dose effect suggested for all except headache. Significance: This phase III trial demonstrated that adjunctive treatment with once‐daily perampanel at 8 mg and 12 mg was effective in improving seizure control in patients 12 years and older with refractory partial‐onset seizures. These study results also demonstrated that once‐daily doses of 8 mg and 12 mg were safe and acceptably tolerated in this study. Perampanel demonstrated a favorable risk/benefit ratio in this population.     

托吡酯单用及添加治疗癫痫302例临床分析

目的　观察托吡酯添加和单药治疗癫痫的临床疗效及不良反应 ,并探讨单药治疗的理想给药模式。方法　入组患者分为 3组 ,A组 10 2例采用托吡酯添加治疗 ,B组 2 0 0例采用托吡酯单药治疗 ,按初始剂量及加量速度不同 B组又分为 B1组、B2组。B1组 10 5例 ,妥泰初始剂量 2 5 mg/ d,增量 2 5 m g/ w至 2 0 0 m g/ d;B2组 95例 ,妥泰初始剂量 5 0 mg/ d,增量 5 0 m g/ w至 2 0 0 m g/ d。维持治疗 12周。记录发作情况及不良反应。结果　 A组总有效率及控制率分别为 6 0 .8%、2 4 .5 % ,B组总有效率及控制率为 76 .8%、4 1.5 % ,两组疗效差异有显著性意义 (P<0 .0 5 )。 B1组总有效率及控制率分别为 77.9%、4 1.9% ,B2组总有效率及控制率分别为 75 .8%、4 0 .0 % ,两组疗效差异无显著性意义 (P>0 .0 5 )。托吡酯对各型部分性发作及强直 -阵挛性发作的疗效差异无显著性意义 (P>0 .0 5 )。B2组不良反应高于 B1组 ,差异有显著性意义 (P<0 .0 5 )。结论　托吡酯添加及单药治疗癫痫具有良好的疗效 ,对发作频率较低的患者宜选用小剂量起始缓慢加量的治疗方法 ,对发作频率较高的患者可考虑予较大起始剂量并以较快速度加量以尽快控制发作