Long-term open multicentre, add-on trial of vigabatrin in adult resistant partial epilepsy. The Canadian Vigabatrin Study Group.

Vigabatrin (VGB) has been shown in a number of clinical trials with varying designs to be effective and well-tolerated as both add-on therapy and monotherapy in epilepsy with partial seizures with or without secondary generalization as well as in infantile spasms. The present study is an open, long-term (1 year) extension of a randomized double-blind placebo-controlled multicentre Canadian trial of VGB in resistant partial adult epilepsy. The present study was designed to examine the safety and long-term efficacy of VGB. Completers of the preceding double-blind study had their dose of VGB titrated to 4 g/day over 3 weeks. Patients were evaluated every 2-4 weeks and at week 14 were allowed to continue only if they achieved a 50% seizure reduction compared with pre-VGB baseline. In addition to neurological and physical examinations, safety was assessed by a cognitive psychosocial test battery, visual and somatosensory evoked potentials and MRI scans. Ninety-seven of 100 eligible patients entered the study, 53 of whom completed the 52 weeks. Fifty-eight percent of the patients had a greater than 50% seizure reduction in seizures vs. pre-VGB baseline. Seizure reductions of 56% and 45%, respectively, were seen in the VGB and placebo groups from the preceding study. Fifty-four percent of patients were judged by the investigators to have experienced at least a moderate therapeutic effect. Discontinuations were 29% for lack of efficacy and 12% for adverse effects. There was a mean weight gain of 3.7 +/- 0.2 kg by end of study. Neurologica/psychiatric side effects were the most common reason for withdrawal including three behavioral reactions attributed to the drug which required temporary hospitalization. There were no abnormalities on laboratory or special tests and there was a tendency for improvement on most tests of cognitive function and mood. Vigabatrin, as an add-on agent, is well-tolerated and can be of long-term benefit in a substantial proportion of patients with intractable partial epilepsy.     

Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group

PURPOSE: To evaluate the efficacy and tolerability of levetiracetam (LEV, Keppra) as add-on therapy in patients with refractory partial seizures. METHODS: In this European multicenter, double-blind, randomized, placebo-controlled trial, LEV (500 or 1,000 mg twice daily) was compared with placebo as add-on therapy in 324 patients with uncontrolled simple or complex partial seizures, or both, with or without secondary generalization. After enrollment, three parallel groups were assessed during a baseline period of 8 or 12 weeks, followed by a 4-week titration interval and a 12-week evaluation period. RESULTS: LEV significantly decreased partial seizure frequency compared with placebo. A reduction in seizure frequency of > or =50% occurred in 22.8% of patients in the 1,000-mg group and 31.6% of patients in the 2,000-mg group, compared with 10.4% of patients in the placebo group. Administration of LEV did not affect plasma concentrations of concomitant antiepileptic drugs or alter vital signs or laboratory parameters. No significant difference in the incidence of adverse events was observed between treatment groups (70.8% for the 1,000-mg group and 75.5% for the 2,000-mg group), or between the LEV and placebo groups (73.2% for placebo group). The most commonly reported adverse effects in the LEV group were asthenia, headache, and somnolence. CONCLUSIONS: The antiepileptic efficacy and tolerability of LEV (1,000 mg/d and 2,000 mg/d, administered in two divided doses) as add-on therapy was established in patients with refractory partial seizures in this clinical study.     

Vigabatrin in complex partial seizures: a long-term study

The efficacy and safety of oral vigabatrin (VGB) as add-on therapy in the long-term treatment of poorly controlled epilepsy were evaluated in 19 patients with complex partial seizures, either with or without secondary generalization. The study was run with a single-blind, placebo-controlled, crossover design, and included 2 months of placebo and 13-15 months of treatment with VGB, at doses ranging from 1 to 4 g/day. Of the 14 patients who completed the trial, 2 were seizure free, in 5 seizure frequency dropped by more than 75% and in another 5 by more than 50% with respect to baseline. The decrease in seizure frequency in the group as a whole was significant at all observation points of the trial. Three patients were not entered into the long-term phase due to lack of improvement (an increase in seizure frequency was observed in one of them), and 2 were excluded later because improvement disappeared leading to unauthorized changes in comedication. Side effects were mild and never caused discontinuation of treatment. In conclusion, VGB showed a remarkable efficacy and safety in the long-term treatment of complex partial seizures.     

多中心双盲、随机、安慰剂对照评价左乙拉西坦添加治疗难治性部分性癫(癎)发作的疗效及安全性

目的 评价左乙拉西坦(LEV)添加用药治疗难治性部分性癫(癎)发作的临床疗效及安全性.方法 随机、双盲、安慰剂对照、多中心平行设计添加治疗,确诊为有癫(癎)部分性发作的202例癫(癎)患者,平均年龄(32.8±12.7)岁,随机分配入LEV治疗组(n=102)与安慰剂组(n=100).在回顾8周基线期的癫(癎)发作频率后,进入逐量加药期.初始用药剂量为0.5 g,每日2次,2周后增加至1.0 g,每日2次服用,4周后加量至1.5 g,每日2次,随后维持该剂量治疗12周,最后逐渐减量并转入LEV开放治疗期.主要评价指标为16周治疗期内每周癫(癎)发作频率的比较、得出药物治疗发作频率减少50%有效率、安全性和药物不良反应.结果 在16周治疗期内,LEV组每周癫(癎)发作频率明显减少,较安慰剂组减少26.8%;每周发作频率较基线期下降数在LEV组与安慰剂组的组间差异为42.2%;部分性发作频率减少50%有效率为55.9%,与安慰剂组比的OR值为3.6;有11例治疗后完全无发作,两组相比均有显著统计学意义(P＜0.001).LEV组的主要不良事件为嗜睡、头晕、无力及血小板减少,但与安慰剂组比差异无统计学意义.结论 LEV添加用药治疗成人难治性部分性癫(癎)发作,可以显著减少癫(癎)发作频率,安全性良好.     

多中心、随机、双盲、安慰剂对照评价唑尼沙胺添加治疗癫(癎)部分性发作的疗效和安全性

目的 评价唑尼沙胺作为添加治疗癫(癎)部分性发作的疗效和安全性.方法 确诊为有癫(癎)部分性发作的217例癫(癎)患者,随机分配入唑尼沙胺治疗组(n=111)与安慰剂组(n=106)进行随机、双盲、安慰剂对照、多中心平行设计添加治疗.在3个月回顾性基线期后,给予患者初始剂量唑尼沙胺(100 mg/片)或安慰剂每次1片,每日1次口服,4周内递增至每次2片,每日2次.分别在治疗0、2、4、8、12和16周时进行随访.主要疗效指标为治疗结束后与基线期比较发作次数减少的中位百分比;次要疗效指标为发作次数减少大于50%的比例.同时观察研究药物的安全性与不良反应情况.结果 总发作次数减少率中位数在唑尼沙胺组为33.33%,安慰剂组为0;唑尼沙胺组总发作次数减少>50%者38例(34.23%),安慰剂组21例(19.81%),差异有统计学意义(χ3=5.7159,P=0.0168).唑尼沙胺组治疗后无发作13例(11.71%),有效25例(22.52%),临床有效率为34.23%;安慰剂组无发作5例(4.72%),有效16例(15.09%),临床有效率为19.81%,2组间比较差异有统计学意义(U=2.4701,P=0.0135).唑尼沙胺组与安慰剂组比较,其不良反应发生率差异无统计学意义,唑尼沙胺组较常见的不良反应有思睡、乏力、食欲下降、胃肠道不适、失眠和便秘.结论 唑尼沙胺作为部分性癫(癎)发作的添加药物有确定的疗效,安全耐受性较好,具有一定临床应用价值.     

Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures

Summary: Purpose: To evaluate pregabalin (PGB), 150 mg/day, and PGB, 600 mg/day, as an add‐on treatment for patients with refractory partial seizures concurrently treated with one to three anticonvulsants (AEDs). Methods: An international (13 countries), multicenter (45 centers), 12‐week, double‐blind, randomized study in which patients with partial seizures received placebo (n = 96); PGB, 150 mg/day (n = 99); or PGB, 600 mg/day (n = 92); given 3 times a day (t.i.d.). The primary efficacy criterion was reduction in seizure frequency during treatment as compared with baseline, as measured by RRatio, the symmetrical percentage change in seizure rates determined from daily seizure diaries. The RRatio between the 8‐week baseline (pretreatment phase) and the 12‐week treatment period were compared between each of the PGB groups and the placebo group by using an analysis of variance analysis of the intent‐to‐treat population. Results: PGB, 150 mg/day and 600 mg/day, were both significantly more effective than placebo in reducing the RRatio [–11.5 (p = 0.0007) and –31.4 (p ≤ 0.0001), respectively, vs. 0.9]. These RRatio values correspond to seizure‐frequency reductions from baseline of –1.8, 20.6, and 47.8% for placebo, 150 mg/day, and 600 mg/day, respectively. PGB efficacy was significantly dose related (p ≤ 0.0001). Secondary efficacy variables corroborated the findings of the primary analysis. Significantly more patients were responders (≥50% reduction in seizure frequency) in the PGB, 600 mg/day (43.5%), group than in the placebo group (6.2%) (p ≤ 0.001). PGB was well tolerated. Dose‐related, treatment‐emergent adverse events (≥10%), mostly mild or moderate in intensity, were somnolence, dizziness, ataxia, diplopia, and weight gain. The withdrawal rate due to adverse events was 10% of patients at 150 mg/day and 18.5% of patients at 600 mg/day, compared with 6.2% of patients receiving placebo. Conclusions: PGB, 150 mg/day and 600 mg/day, is highly effective and well‐tolerated add‐on therapy in patients with partial seizures.     

Gabapentin as add-on therapy in children with refractory partial seizures: a 24-week, multicentre, open-label study

The efficacy and safety of gabapentin as add-on therapy for refractory partial seizures in 237 children, aged 3 to 12 years were evaluated over a 6-month period. All children received gabapentin at 24 to 70 mg/kg/day. Efficacy variables included the percent change in seizure frequency and the responder rate (defined as those patients who showed >50% reduction in seizure frequency). For all partial seizures, the median percent change in seizure frequency was -34% and the overall responder rate was 34%. Simple partial seizures showed a median reduction of -53%; complex partial seizures, -38%; and secondarily generalized tonic-clonic seizures, -35%. Thirteen patients (5%) withdrew during the 6-month period because of adverse events. Concurrent antiepileptic medication remained unchanged in 185 patients (78%), was decreased in 27 (11%), and increased in 25 (11%) patients. This 6-month follow-up study has demonstrated that gabapentin was well tolerated and appeared to show a sustained efficacy in a large population of children with refractory partial and secondarily generalized tonic-clonic seizures.     

A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children. Lamictal Pediatric Partial Seizure Study Group

OBJECTIVE: To compare the safety and efficacy of add-on lamotrigine and placebo in the treatment of children and adolescents with partial seizures. BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Lamotrigine was effective for the adjunctive treatment of partial seizures in children and demonstrated an acceptable safety profile.     

Eslicarbazepine acetate: a double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures

OBJECTIVE: To explore the efficacy and safety of eslicarbazepine acetate (BIA 2-093), a new antiepileptic drug, as adjunctive therapy in adult patients with partial epilepsy. METHODS: A multicenter, double-blind, randomized, placebo-controlled study was conducted in 143 refractory patients aged 18-65 years with >or=4 partial-onset seizures/month. The study consisted of a 12-week treatment period followed by a 1-week tapering off. Patients were randomly assigned to one of three groups: treatment with eslicarbazepine acetate once daily (QD, n=50), twice daily (BID, n=46), or placebo (PL, n=47). The daily dose was titrated from 400 mg to 800 mg and to 1,200 mg at 4-week intervals. The proportion of responders (patients with a >or=50% seizure reduction) was the primary end point. RESULTS: The percentage of responders versus baseline showed a statistically significant difference between QD and PL groups (54% vs. 28%; 90% CI =-infinity, -14; p=0.008). The difference between the BID (41%) and PL did not reach statistical significance (90% CI =-infinity, -1; p=0.12). A significantly higher proportion of responders in weeks 5-8 was found in the QD group than in the BID group (58% vs. 33%, respectively, p=0.022). At the end of the 12-week treatment, the number of seizure-free patients in the QD and BID groups was 24%, which was significantly different from the PL group. The incidence of adverse events was similar between the treatment groups and no drug-related serious adverse events occurred. CONCLUSION: Eslicarbazepine acetate was efficacious and well tolerated as an adjunctive therapy of refractory epileptic patients.     

Losigamone add-on therapy in partial epilepsy: a placebo-controlled study

OBJECTIVES: To evaluate the efficacy and tolerability of losigamone (LSG). PATIENTS AND METHODS: 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). RESULTS: 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. CONCLUSIONS: LSG proved to be an effective and well tolerated anticonvulsant drug for the treatment of chronic partial seizures.     

A double-blind, placebo-controlled evaluation of the efficacy and safety of loreclezole as add-on therapy in patients with uncontrolled partial seizures

Sixty-two patients with uncontrolled partial seizures participated in a 12-week, double-blind, placebo-controlled add-on-trial. Thirty-two patients received loreclezole and 30 a placebo as add-on therapy. Loreclezole was targeted at a plasma level of 1-2 mg/l. In spite of an antiepileptic therapy, usually with 2 or 3 antiepileptic drugs, these patients had at least 4 seizures a month during the baseline period. At the end of the treatment phase with loreclezole and placebo, individual responses varied widely. The median change in the daily seizure frequency was not significantly different in the 2 groups. However, when individual responses are considered, 6 patients in the verum group (19%) experienced a seizure reduction of 50% or more, compared with no patients in the placebo group. During the trial, only mild adverse events were reported in both the loreclezole and the placebo group, nor were any clinically relevant abnormalities seen in the haematological and biochemical analysis. The efficacy and safety of higher loreclezole plasma concentrations were studied in a long-term follow-up trial, the results of which are presented in the following article.     

Vigabatrin therapy for refractory complex partial seizures: review of major European trials

Complex partial seizures (CPS) are a form of localization-related seizures associated with serious comorbidities and risks. CPS can be difficult to treat and may remain refractory to treatment with antiepileptic drugs (AEDs). Refractory CPS (rCPS) can be hazardous because of the potential for severe dysfunction and bodily harm, sometimes with fatal consequences. Control of seizure activity is critical to the clinical management of CPS. Vigabatrin is a unique AED approved in both Europe and the United States as adjunctive therapy for adult patients with rCPS who have responded inadequately to several alternative treatments. This review focuses on appropriately controlled studies of vigabatrin conducted in Europe. Several double-blind studies randomized those with rCPS to treatment with vigabatrin vs placebo, and two evaluated durability of response to long-term, open-label vigabatrin. Endpoints included seizure frequency, treatment satisfaction, and adverse events (AEs). Efficacy outcomes demonstrated that vigabatrin add-on therapy significantly reduced the frequency of seizures. Long-term studies indicated durability of response and tolerability of vigabatrin therapy for up to several years. Treatment satisfaction data indicated a preference for vigabatrin vs placebo for both physicians and study participants. Vigabatrin was well-tolerated with generally mild AEs considered common to AEDs. Vision effects were not formally monitored in these studies. In European trials, vigabatrin was efficacious as adjunctive therapy for rCPS.     

Vigabatrin for refractory complex partial seizures: multicenter single-blind study with long-term follow-up

The irreversible GABA transaminase inhibitor vigabatrin (VGB) was given in a single-blind fashion to 89 patients with complex partial seizures (CPS) refractory to conventional drugs. The median number of CPS per month decreased from 11.0 to 5.0 after addition of VGB, and 51% of patients had a 50% or greater decrease in CPS frequency (p less than 0.001). Side effects (principally drowsiness, ataxia, and headache) occurred mainly during the initiation of therapy and decreased during therapy. After 12 weeks on VGB, side effects significantly interfered with functioning in only 13% of patients, and the efficacy:toxicity ratio warranted continued administration in 74% of patients. Coadministration of VGB resulted in a mean decrease of 20% in phenytoin serum concentration (p less than 0.001). Sixty-six patients with a favorable response to VGB during the single-blind study have been followed for a median of 16.7 months on VGB. No serious systemic or neurologic toxicity has been detected, and most patients have retained their initial favorable CPS control.     

Pregabalin add-on treatment in patients with partial seizures: a novel evaluation of flexible-dose and fixed-dose treatment in a double-blind, placebo-controlled study

PURPOSE: To evaluate pregabalin as add-on therapy for patients with partial seizures administered as fixed dose or as flexible dose adjusted to optimal seizure reduction and tolerability. METHODS: Patients receiving antiepileptic drugs (98.8% between 1 and 3 AEDs; 1.2% on more than 3 AEDs) and experiencing > or =4 partial seizures during the 6-week baseline period and no 4-week seizure-free interval were randomized (1:2:2) to placebo (n = 73), pregabalin fixed dose (600 mg/day BID; n = 137), or pregabalin flexible dose (n = 131; 150 and 300 mg/day for 2 weeks each; 450 and 600 mg/day for 4 weeks each, BID) for 12 weeks. Dosage could be adjusted based on tolerability and maintained when a 4-week seizure-free period was achieved. Primary efficacy parameter was reduction in seizure frequency from baseline. RESULTS: Both pregabalin regimens significantly reduced seizure frequency compared with placebo, by 35.4%, for flexible dose (p = 0.0091) and 49.3% for fixed dose (p = 0.0001) versus 10.6% for placebo, and the fixed-dose group was superior to the flexible-dose group (p = 0.0337). Most adverse events were mild or moderate. Discontinuation rates due to adverse events were 6.8% (placebo), 12.2% (pregabalin flexible dose), and 32.8% (pregabalin fixed dose). Patients receiving pregabalin fixed dose discontinued due to adverse event earlier than other groups. CONCLUSIONS: Pregabalin administered twice daily, either as fixed (600 mg/day), or as flexible (150-600 mg/day) dose, was highly effective and generally well-tolerated as add-on therapy for partial seizures with or without secondary generalization. Lower incidence of adverse events and discontinuations were achieved in patients receiving pregabalin when dosing was individualized to optimize efficacy and tolerability.     

Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in Chinese patients with refractory partial-onset seizures

Purpose:   To evaluate efficacy and tolerability of levetiracetam (LEV; Keppra^®) as add-on therapy in Chinese patients with refractory partial-onset seizures.
Methods:   In this multicenter, double-blind, randomized, placebo-controlled trial, 206 patients aged 16–70 years with uncontrolled partial-onset seizures were randomized to receive LEV (n =103) or placebo (n =103); 202 patients (LEV, n =102; placebo, n = 100) comprised the intent-to-treat population. An 8-week historical baseline period confirmed eligibility according to seizure count. The 16-week treatment period consisted of a 4-week up-titration period (LEV, 1,000–3,000 mg/day in two equal divided doses) followed by a 12-week maintenance period. Efficacy assessments were based on weekly frequency of partial-onset seizures during the 16-week treatment period.
Results:   LEV significantly decreased weekly partial-onset seizure frequency over placebo by 26.8% (p  < 0.001). Median percentage reductions in weekly partial-onset seizure frequency from historical baseline were 55.9% for LEV and 13.7% for placebo (p  < 0.001). The ≥50% responder rates were 55.9% for LEV, compared with 26.0% for placebo (p  < 0.001). Freedom from partial-onset seizures during treatment period was achieved by 11 LEV patients (10.8%) and 2 placebo patients (2.0%) (p = 0.012). Adverse events were reported by 65 LEV-treated patients (63.1%) and 62 placebo-treated patients (60.2%); most were of mild-to-moderate intensity. The most common adverse events were somnolence (LEV, 17.5%; placebo, 17.5%), decreased platelet count (LEV, 9.7%; placebo, 9.7%), and dizziness (LEV, 7.8%; placebo, 13.6%).
Discussion:   Add-on LEV was effective and well-tolerated in Chinese patients with refractory partial-onset seizures.     

Risperidone as add-on therapy in behavioural disturbances in mental retardation: a double-blind placebo-controlled cross-over study

A double-blind placebo-controlled cross-over trial was carried out to evaluate the efficacy and safety of the combined serotonin-dopamine antagonist risperidone in mentally retarded patients with persistent behavioural disturbances. After an observation period of 1 week, risperidone 4–12 mg or placebo was administered during 3 weeks as add-on treatment to the existing medication, followed by a 1-week single-blind placebo wash-out, and another 3 weeks of double-blind treatment with the cross-over medication. Thirty-seven patients participated in the trials; 30 completed the study. Risperidone was significantly superior to placebo in its effect on the Aberrant Behaviour Checklist and the Clinical Global Impression. The Extrapyramidal Symptom Rating Scale did not show any differences between risperidone and placebo. Two patients experienced hypotension at the start of the risperidone administration. Sedation and drowsiness were the most frequently reported treatment-emergent adverse events. The results of this trial warrant further investigation into the therapeutic assets of risperidone in this indication, as add-on therapy and as monotherapy.     

Treatment of partial seizures with gabapentin: double-blind, placebo-controlled, parallel-group study

This double-blind study was conducted to evaluate the efficacy and safety of gabapentin 1200 mg/day and 1800 mg/day (t.i.d.) compared to placebo as an adjunctive therapy in patients with refractory epilepsy. Patients were included when they had partial seizures at least eight times during a 12-week baseline period despite treatment with one to two antiepileptic drugs. After baseline, eligible patients were randomized to gabapentin 1200 mg/day, 1800 mg/day, or placebo for 12-week treatment. The primary end-point, response ratio, was derived from seizure frequencies during treatment and baseline period based upon the seizure daily record by a patient. Of the 209 randomized patients, 86 received gabapentin 1200 mg/day, 41 received gabapentin 1800 mg/day, and 82 received placebo. A statistically significant difference was found between each of the two gabapentin groups and placebo for the primary efficacy end-point, response ratio (P < 0.005) with definite dose-response (P < 0.001). More gabapentin patients reported moderate to marked improvement in seizure frequency and intensity/duration of each seizure than placebo patients. Treatment-related adverse events were reported by approximately 65% of patients receiving gabapentin compared to approximately 46% of patients receiving placebo; somnolence and dizziness were the most common events. Gabapentin 1200 mg/day and 1800 mg/day significantly reduced the frequency of refractory seizures compared to placebo. Favorable tolerability of gabapentin was confirmed also in a Japanese population, consistent with previous global studies.     

A randomized, double-blind, placebo-controlled, parallel-group study of rufinamide as adjunctive therapy for refractory partial-onset seizures

Purpose: Efficacy and safety of adjunctive rufinamide (3,200 mg/day) was assessed in adolescents and adults with inadequately controlled partial‐onset seizures receiving maintenance therapy with up to three antiepileptic drugs (AEDs). Methods: This randomized, double‐blind, placebo‐controlled, parallel‐group, multicenter study comprised a 56‐day baseline phase (BP), 12‐day titration phase, and 84‐day maintenance phase (MP). The primary efficacy variable was percentage change in total partial seizure frequency per 28 days (MP vs. BP). Secondary efficacy outcome measures included ≥50% responder rate and reduction in mean total partial seizure frequency during the MP. Safety and tolerability evaluation included adverse events (AEs), physical and neurologic examinations, and laboratory values. Pharmacokinetic and pharmacodynamic assessments were conducted. Results: Three hundred fifty‐seven patients were randomized: 176 to rufinamide and 181 to placebo. Patients had a median of 13.3 seizures per 28 days during BP; 86% were receiving ≥2 AEDs. For the intent‐to‐treat population, the median percentage reduction in total partial seizure frequency per 28 days was 23.25 for rufinamide versus 9.80 for placebo (p = 0.007). Rufinamide‐treated patients were more than twice as likely to have had a ≥50% reduction in partial seizure frequency (32.5% vs. 14.3%; p < 0.001) and had a greater reduction in median total partial seizure rate per 28 days during the MP (13.2 vs. 5.2; p < 0.001). Treatment‐emergent AEs occurring at ≥5% higher incidence in the rufinamide group compared with placebo were dizziness, fatigue, nausea, somnolence, and diplopia. Conclusions: Adjunctive treatment with rufinamide reduced total partial seizures in refractory patients. AEs reported were consistent with the known tolerability profile of rufinamide.     

Vigabatrin therapy for refractory complex partial seizures: review of clinical trial experience in the United States

Vigabatrin is an antiepileptic drug used in more than 50 countries as adjunctive therapy for the treatment of refractory complex partial seizures (rCPS) in adults. First approved in the United Kingdom in 1989, vigabatrin was approved for use in the United States by the Food and Drug Administration in 2009. Although most clinical trials of vigabatrin have been conducted in Europe, three major trials, including two pivotal trials, were conducted in the United States. These trials have demonstrated efficacy and tolerability findings similar to those observed from the European trials. Results of the US trials have demonstrated vigabatrin to be an effective and generally well-tolerated therapy for rCPS in adults, with an optimal dosage of 3 g/day for most patients, and an onset of response generally within 2 weeks. This review focuses on the design and results of the three major US trials of vigabatrin in adults with rCPS.     

High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study

Summary. Increasing evidence has suggested that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of the paralysis in transgenic mice expressing a mutation in the superoxide dismutase gene found in certain forms of familial ALS. The current study, a double blind, placebo-controlled, randomised, stratified, parallel-group clinical trial, was designed to determine whether vitamin E (5000mg per day) may be efficacious in slowing down disease progression when added to riluzole. Methods. 160 patients in 6 German centres with either probable or definite ALS (according to the El Escorial Criteria) and a disease duration of less than 5 years, treated with riluzole, were included in this study and were randomly assigned to receive either alpha-tocopherol (5000mg per day) or placebo for 18 months. The Primary outcome measure was survival, calculating time to death, tracheostomy or permanent assisted ventilation, according to the WFN-Criteria of clinical trials. Secondary outcome measures were the rate of deterioration of function assessed by the modified Norris limb and bulbar scales, manual muscle testing (BMRC), spasticity scale, ventilatory function and the Sickness Impact Profile (SIP ALS/19). Patients were assessed at entry and every 4 months thereafter during the study period until month 16 and at a final visit at month 18. Vitamin E samples were taken for compliance check and Quality Control of the trial. For Safety, a physical examination was performed at baseline and then every visit until the treatment discontinuation at month 18. Height and weight were recorded at baseline and weight alone at the follow-up visits. A neurological examination as well as vital signs (heart rate and blood pressure), an ECG and VEPs were recorded at each visit. Furthermore, spontaneously reported adverse experiences and serious adverse events were documented and standard laboratory tests including liver function tests performed. For Statistical Analysis, the population to be considered for the primary outcome measure was an intent-to-treat (ITT) population which included all randomised patients who had received at least one treatment dose (n=160 patients). For the secondary outcome measures, a two way analysis of variance was performed on a patient population that included all randomised patients who had at least one assessment after inclusion. Results. Concerning the primary endpoint, no significant difference between placebo and treatment group could be detected either with the stratified Logrank or the Wilcoxon test. The functional assessments showed a marginal trend in favour of vitamin E, without reaching significance. Conclusion. Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol. Larger or longer studies might be needed. However, administration of this megadose does not seem to have any significant side effects in this patient population.