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.     

Lacosamide as adjunctive therapy for partial‐onset seizures: A randomized controlled trial

Purpose: To evaluate the efficacy and safety of lacosamide (400 and 600 mg/day) as adjunctive treatment in patients with uncontrolled partial‐onset seizures taking one to three concomitant antiepileptic drugs (AEDs). Methods: This multicenter, double‐blind, placebo‐controlled trial randomized patients 1:2:1 to placebo, lacosamide 400 mg, or lacosamide 600 mg/day. After an 8‐week baseline period, patients began treatment with placebo or lacosamide 100 mg/day, were force‐titrated weekly (100 mg/day increments) to the target dose, and entered a 12‐week maintenance period. Results: A total of 405 patients were randomized and received trial medication. Most (82.1%) were taking two to three concomitant AEDs. Median percent reductions in seizure frequency per 28 days from baseline to maintenance (intention‐to‐treat, ITT) were 37.3% for lacosamide 400 mg/day (p = 0.008) and 37.8% for lacosamide 600 mg/day (p = 0.006) compared to 20.8% for placebo, with responder rates of 38.3% and 41.2%, respectively, compared to placebo (18.3%, p < 0.001; ITT). Patients randomized to lacosamide showed large reductions in secondarily generalized tonic–clonic seizures, with median percent reductions in seizure frequency of 59.4% for lacosamide 400 mg/day and 93.0% for lacosamide 600 mg/day compared to 14.3% for placebo, and responder rates of 56.0% and 70.2% compared to placebo (33.3%). Dose‐related adverse events included dizziness, nausea, and vomiting. Discussion: Adjunctive treatment with lacosamide 400 and 600 mg/day reduced seizure frequency for patients with uncontrolled partial‐onset seizures. Lacosamide 400 mg/day provided a good balance of efficacy and tolerability; lacosamide 600 mg/day may provide additional benefit for some patients as suggested by secondary efficacy analyses, including response in patients with secondarily generalized tonic–clonic seizures.     

Wednesday July 5, 200617:30–19:00Hall 1Schwarz Pharma & Valeant Pharmaceuticals International Satellite SymposiumWhat's around the corner: AEDs in late development

¹ E. Ben-Menachem (   ¹ Neurologkliniken, Sahlgrenska Universitetssjukhuset, Goteberg, Sweden )
Lacosamide is in Phase 3 of clinical development for the adjunctive treatment of epilepsy and neuropathic pain. Currently the mode of action (MOA) is under investigation since it has been previously demonstrated that lacosamide does not share a MOA with other currently marketed antiepileptic drugs (AEDs). The drug can be administered orally or intravenously. Results from pharmacokinetic studies suggest that lacosamide has a low potential for drug-drug interactions, and it appears that lacosamide has a minimal risk for affecting the pharmacokinetics of commonly prescribed concomitant AEDs for the treatment of epilepsy.
In a double-blind, randomized, placebo-controlled, multicenter trial for the treatment of partial seizures (SP667), lacosamide was administered orally in doses of 200 mg, 400 mg and 600 mg divided in 2 daily doses. In this trial, lacosamide demonstrated a statistically significant reduction in seizure frequency over placebo. Moreover, the 50% responder rate (defined as patients with at least a 50% reduction in seizure frequency) was statistically significant.
A further trial (SP616) investigated the safety, tolerability and pharmacokinetics of IV lacosamide as replacement for oral lacosamide in patients with partial-onset seizures. The nature of AEs reported following 60- and 30 minute infusions of lacosamide was consistent with AEs reported following oral administration of lacosamide.
Dose-related adverse events include dizziness, nausea, fatigue, ataxia, vision abnormal, diplopia, and nystagmus.
The currently available results justify the further development of lacosamide for the treatment of epilepsy.     

Lacosamide and epilepsy

We will review all available studies on the use of lacosamide in the treatment of partial-onset seizures. The available evidence includes two open-label studies and three randomized controlled trials evaluating the safety and efficacy of oral lacosamide. One open-label study and one randomized controlled trial evaluating the safety and tolerability of intravenous lacosamide was also identified. Lacosamide was found to be efficacious with significant reduction in seizure frequency dosed 400-600 mg daily. Moreover, its adverse drug effects were mild and infrequently reported in the literature. Findings suggest that lacosamide is an effective agent for adjunctive treatment of refractory partial-onset seizures.     

Lacosamide

Lacosamide is a new chemical entity being investigated as an adjunctive treatment for epilepsy, as well as monotherapy for diabetic neuropathic pain. Lacosamide appears to have a dual mode of action: selective enhancement of sodium channel inactivation and modulation of collapsin response mediator protein-2. Rapidly and completely absorbed after oral administration, lacosamide has an elimination half-life of approximately 13 hours and a low potential for drug interactions. Additionally, lacosamide exhibits linear, dose-proportional pharmacokinetics with low intra- and interpatient variability. Randomized controlled trials of adjunctive lacosamide (200, 400, and 600 mg/day) have demonstrated statistically significant reduction in median seizure frequency compared with placebo. In addition, 50% responder rates for lacosamide (400 and 600 mg/day) were statistically superior to placebo. The most frequently reported adverse events (≥10% of lacosamide-treated patients) included dizziness, headache, and nausea. A double-blind, double-dummy randomized trial of intravenous lacosamide (30- and 60-minute infusion) as replacement for oral lacosamide showed that the safety and tolerability profiles were comparable for intravenous and oral lacosamide. The efficacy and safety results from completed clinical trials, as well as the favorable pharmacokinetic profile, suggest that lacosamide may represent a significant advance in antiepileptic drug therapy.     

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 focal epilepsy: an open‐label trial evaluating the impact of flexible titration and dosing on safety and seizure outcomes

Aims. To evaluate the safety and effectiveness of lacosamide in a real‐life setting with the use of a flexible dose titration schedule and individualised maintenance doses up to the maximum approved dose of 400 mg/day. Methods. Adults with a diagnosis of focal seizures, with or without secondary generalization, were enrolled in this open‐label Phase IV trial (NCT01235403). Lacosamide was initiated at 100 mg/day (50 mg bid) and uptitrated over a 12‐week period to 200, 300 or 400 mg/day, based on safety and seizure control. Although dose increases were to be in increments of 100 mg/day, intermediate doses were permitted at each escalation step for one week for patients known to be particularly sensitive to starting new AEDs. After receiving a stable, effective dose for three weeks, patients entered the 12‐week maintenance period. Primary outcomes were incidence of treatment‐emergent adverse events (TEAEs) and withdrawal due to TEAEs. Seizure outcomes, all secondary, were median focal seizure frequency, ≥50% reduction in focal seizure frequency, and seizure freedom. Results. One hundred patients with a mean age of 44 years were enrolled and 74 completed the trial. The incidence of TEAEs was 64.0% (n=100), with the most frequently reported (≥5% of patients) being dizziness, headache, and asthenia. Fourteen patients withdrew due to TEAEs, most frequently due to dizziness (six patients; 6.0%), vomiting (two patients; 2%), and tremor (two patients; 2%). Among patients with baseline and maintenance phase seizure data (n=75), median reduction in focal seizure frequency from baseline was 69.7% and the ≥50% responder rate was 69.3%. Among 74 patients who completed the maintenance phase, 21 (28.4%) were seizure‐free. Conclusion. Flexible lacosamide dosing in this open‐label trial was associated with a favourable tolerability and safety profile; the nature of the TEAEs was consistent with that observed in previous pivotal trials. Treatment with lacosamide was also associated with effective seizure control.     

Intravenous lacosamide as short‐term replacement for oral lacosamide in partial‐onset seizures

Purpose : Lacosamide is a new antiepileptic drug effective for adjunctive treatment of partial‐onset seizures. We evaluated the safety and tolerability of an intravenous (i.v.) formulation of lacosamide (200–800 mg/day) infused over 10, 15, and 30 min as short‐term replacement for oral lacosamide in patients with partial‐onset seizures. Methods : This multicenter, open‐label, inpatient trial enrolled 160 patients from ongoing open‐label, long‐term trials who were taking stable doses of oral lacosamide and up to three concomitant antiepileptic drugs (AEDs). Serial cohorts of patients were converted from oral lacosamide treatment to the same intravenous doses infused over progressively shorter infusion durations: 30, 15, and 10 min for 2–5 days. A data monitoring committee (DMC) reviewed safety data for each cohort. The safety of intravenous lacosamide was assessed from adverse events (AEs), laboratory variables, electrocardiography findings, and physical/neurologic examinations. Results : A total of 160 patients received lacosamide 200–800 mg/day, i.v., for 2–5 days, of which 69% received 400–800 mg/day doses. The most common AEs (reported by ≤10% of patients) were headache, dizziness, and somnolence. There was no increase in frequency or severity of AEs with shorter durations of infusion or increased days of exposure. AEs were similar, but more frequent, with higher doses (≥400 mg/day). Injection‐site events were rare and did not appear to be linked to infusion doses or rates. Lacosamide plasma concentrations were linearly related to dose across the cohorts. Discussion : This comprehensive evaluation supports the safety of an intravenous lacosamide infusion duration as short as 15 min for short‐term (2–5 days) replacement for patients temporarily unable to take oral lacosamide.     

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.     

Long-term safety and efficacy in patients with uncontrolled partial-onset seizures treated with adjunctive lacosamide: results from a Phase III open-label extension trial

Purpose: To evaluate the long‐term (up to 5 years exposure) safety and efficacy of lacosamide as adjunctive therapy in patients with uncontrolled partial‐onset seizures taking one to three concomitant antiepileptic drugs (AEDs) in open‐label extension trial SP756 (NCT00522275). Methods: Patients who completed the double‐blind trial SP754 (NCT00136019) were eligible to participate in this open‐label extension trial (SP756). At the conclusion of trial SP754, patients had transitioned to lacosamide 200 mg/day. Subsequent dosage adjustments of lacosamide (100–800 mg/day) and/or concomitant AEDs were allowed to optimize tolerability and seizure reduction. Treatment‐emergent adverse events (TEAEs), vital signs, body weight, clinical laboratory data, electrocardiography studies, and seizure frequency were evaluated. Key Findings: A total of 308 patients received open‐label lacosamide and 138 patients (44.8%) completed the long‐term trial. The median modal dose (defined as the daily lacosamide dose a patient received for the longest duration during the treatment period) was 500 mg/day. The percentages of patients with lacosamide exposure >1, >2, >3, or >4 years were 75%, 63%, 54%, and 29%, respectively. Primary reasons for discontinuation were lack of efficacy (26%) and adverse events (11%). Common TEAEs (≥15%) were dizziness, headache, contusion, nausea, convulsion, nasopharyngitis, fall, vomiting, and diplopia. TEAEs that led to discontinuation in ≥1.0% of patients were dizziness (1.6%) and convulsion (1.0%). The median percent reductions from baseline of trial SP754 in 28‐day seizure frequency were 53.4%, 55.2%, 58.1%, and 62.5%, respectively, for 1‐, 2‐, 3‐, and 4‐year completers. The ≥50% responder rates were 52.8%, 56.5%, 58.7%, and 62.5% for 1‐, 2‐, 3‐, and 4‐year completers, respectively. Seven of eight patients on lacosamide monotherapy for ≥12 months were deemed 50% responders. Of patients exposed to lacosamide ≥2 years, 3.1% remained seizure‐free for a period ≥2 years. Significance: Long‐term (up to 5 years) lacosamide treatment was generally well tolerated. The safety profile of lacosamide observed in this trial is consistent with that established in previous double‐blind, placebo‐controlled trials. Although the open‐label trial design limits the analysis of efficacy, long‐term reduction in seizure frequency and maintenance of efficacy was observed.     

Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study

Lacosamide is a new antiepileptic drug that is currently approved by the US Food and Drug Administration (FDA) for adults 17 years or older for partial-onset seizures. The authors reviewed 21 pediatric patients (<17 years) with various seizure types who were started on oral lacosamide as part of a prospective add-on study as adjunctive therapy for refractory epilepsy. Five patients were excluded due to less than 3 months of meaningful follow-up. Maintenance dosages used ranged from 2.4 to 19.4 mg/kg/d. Eight of 16 (50%) patients had greater than 50% reduction in seizure frequency with adjunctive lacosamide therapy. Eight (50%) patients had generalized epilepsy including 4 with Lennox-Gastaut syndrome. Lacosamide was effective therapy for most seizure types but was particularly effective for partial-onset seizures. Lacosamide was effective in treating 5 of 8 (62.5%) localization-related epilepsies but only 2 of 8 (25%) generalized epilepsies, both Lennox-Gastaut syndrome patients with greater than 90% seizure reduction. None of these very refractory patients remained seizure free.     

Adjunctive lacosamide in clinical practice: sodium blockade with a difference?

Lacosamide (LCM) was licensed in the United Kingdom in 2008 for the adjunctive treatment of partial-onset seizures. It exerts its effect by enhancing sodium channel slow inactivation. This article reports preliminary outcomes with adjunctive LCM in the everyday clinical setting. To date, 113 patients (57 males, 56 females; aged range = 18–74 years, median = 39 years) with uncontrolled partial-onset seizures (monthly frequency range = 1–300, median = 4) have been included in the audit. Patients were taking 1–4 (median = 1) antiepileptic drugs (AEDs), having previously tried 1–12 (median 3) drug schedules. After 12 weeks on stable AED dosing, LCM was added, aiming at an initial target range of 200–400 mg/day. Review took place every 6–8 weeks until one of four endpoints was reached: seizure freedom for ≥ 6 months on a given LCM dose; ≥ 50% (responder) or < 50% (marginal benefit) seizure reduction over 6 months compared with baseline on the highest tolerated LCM dose; withdrawal of LCM because of lack of efficacy, side effects, or both. An endpoint has been reached by 65 (57.5%) patients so far. Seventeen (26.2%) have remained seizure free on a median daily LCM dose of 100 mg (range = 50–300 mg). Patients were more likely to become seizure free when LCM was used as a first add-on (15/36, 41.7%), compared with a later treatment schedule (1/27, 3.7%, P = 0.001). With appropriate dose manipulation, patients taking traditional sodium blockers (5/26, 19.2%) were as likely to become seizure free as those taking AEDs with other mechanisms of action only (11/37, 29.7%). Fifty percent or greater seizure reduction was achieved in an additional 16 (24.6%) patients (1 monotherapy); 18 (27.7%) reported marginal benefit. Two patients were established on LCM monotherapy (one seizure free, one responder). Patients remaining on LCM were as likely to also be taking sodium blockers only (23/27, 85.1%) as AEDs with other mechanisms (26/36, 72.2%). LCM was withdrawn in 14 patients (12.3% of ongoing patients, 21.5% of those at an endpoint; 10 for side effects, 4 for lack of efficacy). The most common side effects leading to withdrawal were sedation, ataxia, and dizziness. Of the 10 with side effects, only 2 patients took concomitant sodium blockers. Patients on sodium valproate were more likely to discontinue LCM (8/21, P = 0.018) than those also taking other AEDs; 5 of the 8 did so because of side effects and 3 because of lack of efficacy. In patients with partial-onset seizures, LCM is an effective and well-tolerated adjunctive AED when combined with appropriate doses of traditional sodium blockers, as well as agents with other mechanisms of action. Seizure freedom was more likely when LCM was used as a first add-on compared with a later treatment schedule. Patients also taking sodium valproate were significantly more likely to discontinue LCM compared with those taking other AEDs. These data suggest that the pharmacological effect of LCM differs importantly from that of AEDs that influence fast inactivation of the sodium channel.     

Rational polytherapy with lacosamide in clinical practice: results of a Spanish cohort analysis RELACOVA

There has been little long-term success with polytherapy for patients with refractory partial-onset epilepsy. The rational combination of antiepileptic drugs based on their mechanism of action may help improve treatment efficacy and tolerability. Lacosamide, a novel sodium channel blocker (SCB), was investigated in 158 patients with partial-onset epilepsy in the prospective, multicenter, observational, RELACOVA cohort study conducted in Spain. After 12 months' treatment with lacosamide, 47% of patients were responders (≥50% reduction in seizure frequency) and 24% were seizure free. Lacosamide was well tolerated; dizziness was the most frequent adverse event. Efficacy was better (responder rate, 65% vs 38%; seizure free rate, 35% vs 17%) and there was a lower adverse event rate (33% vs 58%) in patients receiving non-SCBs (n=49) versus those receiving SCBs (n=104) as concomitant therapy at baseline. Further investigation of lacosamide combination therapy is warranted.     

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.     

The impact of background antiepileptic drugs on the efficacy and safety of pregabalin in treating partial-onset seizures: a post hoc analysis of combined clinical trials

Pregabalin is used as adjunctive treatment for partial-onset seizures and is often combined with multiple antiepileptic drugs (AEDs) from different classes. The objectives of this post hoc analysis were to evaluate the efficacy and safety of pregabalin when added to different AED regimens and to identify specific AED combinations that in conjunction with pregabalin yield high responder rates. Data from six double-blind, randomized studies of pregabalin in patients with partial-onset seizures were pooled for analysis (N=1775). When the treatment groups (placebo, 150mg, 300mg, 600mg, and flexible dose) were stratified by the number of concomitant AEDs (one, two or three or more), modeling results suggested that the magnitude of improvement on either ≥50% responder rate or mean response ratio remained consistent regardless of the number of concomitant AEDs. Adverse events were typical of pregabalin and, in general, did not vary as the number of concomitant AEDs increased. A cluster analysis was performed to identify possible combinations of AEDs that yielded high ≥50% responder rates. The majority of patients (>90%) fell within two clusters that yielded high responder rates, while <10% of the patients fell within two clusters that yielded low responder rates. Numerous AED combinations, ranging from 6 to 11, occurred within each cluster. In summary, pregabalin provided a consistent improvement in seizure reduction and comparable tolerability in patients with partial-onset epilepsy regardless of the number of concomitant AEDs.     

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.     

Low-dose topiramate in adults with treatment-resistant partial-onset seizures

OBJECTIVES: Based on dose predictions from animal and human volunteer studies, most patients enrolled in initial randomized controlled trials of topiramate as adjunctive therapy in adults with partial-onset seizures were randomized to >or= 600 mg/day topiramate. Subsequent experience suggests that dosage needs were overestimated. This double-blind, placebo-controlled study evaluated 200 mg/day topiramate in adults with treatment-resistant partial-onset seizures receiving a concurrent enzyme-inducing antiepileptic agent (carbamazepine). MATERIALS AND METHODS: After a 4-week baseline, 263 adults receiving carbamazepine who had at least three partial-onset seizures during the baseline period were randomized to placebo or one of two topiramate 200 mg/day treatment arms: topiramate escalated weekly 25 mg/day(8-week escalation) or 50 mg/day(4-week escalation). Therapy was then maintained for the remainder of the 12-week double-blind study. RESULTS: Median percent reduction in seizure frequency from baseline to study end was 44% with topiramate and 20% with placebo (P or=10% incidence in topiramate-treated patients) were somnolence, fatigue, paresthesia, nervousness and anorexia; 8% of topiramate-treated patients and 2% of placebo-treated patients discontinued because of adverse events. As a result of the low incidence of adverse events, differences between titration rates in terms of tolerability were not detected. CONCLUSION: Topiramate 200 mg/day is an appropriate target dose as adjunctive therapy in adults with treatment-resistant partial-onset seizures, even when receiving an enzyme-inducing agent; 100 mg/day also appears to be effective. A significant therapeutic effect may be seen in the second week of treatment with a dose of 100 mg/day.     

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.     

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.     

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.