Defining success in clinical trials – profiling pregabalin, the newest AED

The efficacy and safety of pregabalin as adjunctive therapy for patients with partial epilepsy with or without secondary generalization has been established by four randomized, 12-week, double-blind, placebo-controlled trials ( n  = 1396) and four long-term open-label studies ( n  = 1480). Patients in the three fixed-dose trials were ≥12 years of age, had ≥6 partial seizures and no 4-week seizure-free period during the 8-week baseline period. Seventy-three per cent of patients were taking ≥2 concomitant antiepileptic drugs. Responder rates across the effective doses (150–600 mg/day) ranged from 14% to 51% and demonstrated a significant dose–response relationship. The most common adverse events were central nervous system related, generally mild or moderate, transient, and tended to be dose related. The fourth placebo-controlled trial compared a fixed dose of pregabalin 600 mg/day with a flexible-dose regimen (150–600 mg/day). Responder rates were greater for both the fixed dose (45.3%, P  < 0.001) and flexible dose (31.3%, P  < 0.001) when compared with placebo (11.0%). Compared with the fixed-dose group, the flexible-dose patients had a lower incidence of adverse events and study discontinuations. In long-term open-label trials, the efficacy of pregabalin was maintained with respect to 50% responder rates suggesting no obvious tolerance developing over 2 years. Seizure-free rates were 8.9% and 5.8% for the last 6 months and 1 year of pregabalin treatment, respectively. Long-term open-label pregabalin treatment was well tolerated.     

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.     

Pregabalin for the management of partial epilepsy

Pregabalin is one of the latest antiepileptic drugs introduced for the treatment of partial epilepsy. Its efficacy and safety as adjunctive therapy in refractory partial epilepsy have been established in four double-blind placebo-controlled trials (n = 1396) and 4 long-term open-label studies (n = 1480). In 3 fixed-dose trials, the proportion of patients with a ≥50% reduction in seizure frequency across the effective dose-range (150–600 mg/day) ranged between 14% and 51%, with a clear dose-response relationship. Suppression of seizure activity could be demonstrated as early as day 2. The most frequently reported CNS-related adverse events included dizziness, somnolence, ataxia and fatigue, were usually mild or moderate, and tended to be dose related. In long-term studies, weight gain was reported as an adverse event by 24% of patients. When pregabalin dose was individualized to according to response within the 150 to 600 mg/day dose range, tolerability was considerably improved compared with use of a high-dose, fixed-dose regimen (600 mg/day) without titration. In long-term studies up to 4 years, no evidence of loss efficacy was identified. During the last year on pregabalin, 3.7% of patients were seizure-free. Pregabalin appears to be a useful addition to the therapeutic armamentariun for the management of refractory partial epilepsy.     

Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: A randomized placebo-controlled trial

Purpose:   To evaluate efficacy and safety of adjunctive treatment with rufinamide 1600 mg twice daily in subjects aged ≥16 years with refractory partial seizures.
Methods:   This double-blind, placebo-controlled, randomized, parallel-group, multicenter trial included an 8-week baseline phase and a 13-week double-blind phase. Treatment was initiated with rufinamide 400 mg twice daily or placebo; rufinamide was titrated to 1600 mg twice daily. Percentage change in partial seizure frequency was the primary outcome measure. Secondary outcome measures included total partial seizure frequency and the percentage of subjects experiencing a ≥50% reduction in partial seizure frequency.
Results:   Three hundred thirteen subjects were randomized; 156 subjects received rufinamide and 157 received placebo. Rufinamide-treated subjects experienced a 20.4% median reduction in partial seizure frequency relative to baseline, while placebo-treated subjects had an increase of 1.6% (p = 0.02). Exclusion of subjects taking carbamazepine in a post hoc analysis resulted in a reduction of 29.2% versus 0.7% in the placebo group (p = 0.05), whereas the treatment difference in subjects taking carbamazepine was not significant. Of rufinamide-treated subjects, 28.2% experienced a ≥50% decrease in partial seizure frequency versus 18.6% of placebo-treated subjects (p = 0.04). The most common adverse events associated with rufinamide treatment were dizziness, nausea, diplopia, and ataxia; they occurred primarily during the titration phase.
Discussion:   Adjunctive therapy with rufinamide 3200 mg/day compared with matching placebo demonstrated efficacy and was generally well tolerated in adults with partial seizures. Further study of this agent in adults with partial seizures taking a range of baseline AEDs is warranted.     

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.     

Pregabalin in generalized anxiety disorder: a placebo-controlled trial

OBJECTIVE: Current drug therapies for generalized anxiety disorder have limitations. In a controlled trial, the novel agent pregabalin was studied for the treatment of patients with generalized anxiety disorder. METHOD: In this double-blind study, patients with DSM-IV generalized anxiety disorder were randomly assigned to receive pregabalin (150 mg/day or 600 mg/day), lorazepam (6 mg/day), or placebo. A 1-week placebo lead-in was followed by 4 weeks of treatment and then a 1-week dose taper. The primary efficacy measure was the Hamilton Anxiety Rating Scale score at endpoint. RESULTS: A total of 276 patients were randomly assigned to a treatment group and received at least one dose of their assigned medication. Fewer patients given lorazepam (59%, N=40 of 68) completed the trial than did those given placebo (73%, N=50 of 69), 600 mg/day of pregabalin (71%, N=50 of 70), or 150 mg/day or pregabalin (90%, N=62 of 69). The mean baseline-to-endpoint decreases in total Hamilton anxiety scale score in the patients given 150 mg/day of pregabalin (-9.2), 600 mg/day of pregabalin (-10.3), and lorazepam (-12.0) were significantly greater than the decrease in those given placebo (-6.8). As early as the week 1 observation, pregabalin significantly reduced the total Hamilton anxiety scale score compared with placebo. The most frequent adverse events reported for pregabalin and lorazepam were somnolence and dizziness. There were no serious adverse events reported by patients given pregabalin, and no withdrawal syndrome was associated with pregabalin treatment. CONCLUSIONS: These results indicate that pregabalin is an effective, rapidly acting, and safe treatment for generalized anxiety disorder. In short-term treatment, pregabalin does not appear to have the withdrawal symptoms associated with the benzodiazepines.     

Rapid onset of seizure suppression with pregabalin adjunctive treatment in patients with partial seizures

Purpose:  To determine the time at which pregabalin demonstrates seizure-suppressing activity when given as adjunctive treatment to patients with refractory partial seizures.
Methods:  Data from four similar 12-week, randomized, double-blind, placebo-controlled, parallel-group trials in patients with refractory partial seizures were pooled to provide an adequate sample to compare the proportion of patients free of seizures on each study day between pregabalin (combined 150–600 mg/day groups) and placebo (combined groups). A generalized estimating equation (GEE) statistical model was used to perform pairwise comparisons on each study day. In several pregabalin dosage groups the dosage was escalated during days 1–7, whereas in others pregabalin was initiated at a fixed dosage without escalation.
Results:  The proportion of patients free of seizures on any treatment day was greater in the combined pregabalin groups compared with baseline. Differences were not observed between the placebo group and baseline. A significantly greater proportion of patients were free of seizures in the combined pregabalin 150–600 mg/day and the pregabalin 600 mg/day fixed-dosage groups compared with the placebo groups from treatment day 2 onward (p < 0.05). From day 8 (coinciding with completion of the 1-week dosage-escalation period in two studies) onward, the proportion of patients free of seizures per day in the pregabalin groups remained relatively constant.
Discussion:  This exploratory analysis of a refractory population using a rigorous endpoint demonstrates that pregabalin rapidly reduced the frequency of partial seizures. At the dosing schemes most commonly used in placebo-controlled trials, significant seizure-suppressing activity was observed after only 2 days of treatment.     

Pregabalin in partial seizures: a pragmatic 21‐week,open‐label study (PREPS)

Background and purpose: Pregabalin has demonstrated efficacy in controlled trials as adjunctive treatment in patients with refractory seizures. Methods: This open‐label, 21‐week study in adults with at least two partial seizures in the last 2 months, who were inadequately controlled with one to three antiepileptic drugs, evaluated pregabalin 150–600 mg/day (dosed twice daily). The study comprised a prospective or retrospective 8‐week baseline phase, and 9‐week dose optimization and 12‐week maintenance periods. The primary assessment was the mean percentage change in 28‐day seizure frequency between baseline and end‐point (last 12 weeks of treatment, last observation carried forward, modified intention‐to‐treat population). Results: Four hundred and seventy‐six patients from Europe were included in this study (51% men; mean age/epilepsy duration 40.1/24.1 years). The median baseline seizure frequency was 5.5/28 days. Amongst the patient population, 78% completed the 21‐week treatment period; 7% discontinued for lack of efficacy and 12% because of adverse events (AEs). The mean last pregabalin dose was 359 mg/day. The mean (95% CI) reduction in seizure frequency was 36% (31%; 41%). The median reduction was 33%, and 39% of patients had a ≥50% reduction in seizure frequency. There were 19% and 8% of patients free of seizures during their last 4 and 12 weeks of treatment, respectively. The three most common AEs were dizziness (17%), somnolence (13%) and weight increase (13%). Conclusions: This open‐label study of pregabalin demonstrated efficacy that was consistent with that observed in previous controlled epilepsy trials. Pregabalin was well tolerated. The AE profile was also consistent with that reported in previous trials.     

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.     

Clinical Science

Christian E. Elger , Martin J. Brodie , Henning Anhut , Caroline M. Lee , and Jeannette A. Barrett
Pregabalin is an antiepileptic medication introduced in many countries in 2004–2005 for the treatment of partial epilepsy in adults, when administered in combination with other antiepileptic drugs (AEDs). Clinical trials traditionally employ fixed doses throughout, while in clinical practice, the dose of most AEDs is adjusted gradually, with the dual aim of enhancing tolerability and allowing for optimum effective dosing. The current study included a novel flexible dose regimen in which patients were started on the lowest effective dose of 150 mg/day of pregabalin, followed by a stepwise increase in dose for those patients with inadequate seizure control, up to 600 mg/day. The study goal was to compare the stepwise regimen in terms of both efficacy in seizure reduction and tolerability with a fixed high dose regimen of 600 mg/day. To be eligible for the 12-week study, patients (n = 341) had to be receiving at least one other AED and still experiencing at least four partial seizures in the previous 6 weeks. Both pregabalin regimens were highly effective at reducing the frequency of seizures, with reductions of 35% for flexible dose, and 49% for fixed dose, compared to 11% for placebo. Both regimens were well tolerated, with most side effects being mild or moderate. However, 76% of the patients completed the study in the flexible dose group, versus 58% for the fixed dose group, and more had side effects in the fixed dose group. In conclusion, there appears to be a treatment advantage to adjusting the dose of pregabalin within the therapeutic range of 150–600 mg/day, according to the patient's optimal efficacy and tolerability.     

Adjunctive pregabalin therapy in mentally retarded, developmentally delayed patients with epilepsy

This retrospective study evaluated the efficacy and tolerability of adjunctive pregabalin (PGB) therapy in mentally retarded, developmentally delayed patients. The primary efficacy measure was the change in the median frequency of seizure days per week between the baseline (8 weeks prior to initiating PGB) and treatment (12 weeks of titration and maintenance) periods. Inclusion criteria were: documented epilepsy treated with antiepileptic drug, at least one seizure during the baseline period, and lack of prior exposure to PGB. Seven patients (four female, three male, mean age=43) with multiple seizure types (generalized tonic-clonic, tonic, partial, and atypical absence) met the inclusion criteria. The mean dose of PGB was 293 mg/day (range=150-350 mg/day). PGB was efficacious, resulting in a significant reduction in the median frequency of seizure days/week between baseline and treatment (1.38 vs 0.50, P=0.018). The 50% responder rate was 71%. The adverse effects at last follow-up (mean 13 months) included weight gain, myoclonus, and sedation.     

Review of Controlled Trials of Gabitril (Tiagabine): A Clinician's Viewpoint

Summary: A recent problem for doctors has been the choice of which new antiepileptic drug (AED) to select for treatment of pharmacoresistant epilepsy. This article summarizes the clinical experience to date regarding the efficacy and safety of tiagabine (TGB; Gabitril) as adjunctive therapy in patients with partial-onset seizures. In its early Phase II development, TGB was evaluated in two multicenter pilot studies. Each had an open-label enrichment phase followed by a treatment phase with randomized, double-blind, two-period, cross-over phases. Between 24 and 50% of patients experienced reductions in seizure rates of ≥50%, depending on the type of partial seizure. In Phase III, three double-blind, parallel group, placebo-controlled adjunctive studies determined the efficacy of TGB in patients with refractory partial seizures. The first was a dose-response study employing doses of TGB-HCl of 16, 32 or 56 mg/day. Significant reductions in seizure rates were found with 32 and 56 mg/day. The second and third studies evaluated the efficacy of dosing TGB twice, three times, and four times daily, all of which showed similar efficacy. TGB efficacy in partial seizures was supported in several open trials, and no tolerance to efficacy was noted in long-term continuation studies. Tolerability was documented in all trials. Most adverse events were mild or moderate and transient, occurring during dose titration. They were clearly dose-related. No relevant changes in hematologic and biochemical tests, vital signs, or body weight were attributable to TGB. TGB appears to be an effective new drug for partial seizures with an acceptable safety profile.     

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.     

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.     

Clobazam in the treatment of Lennox-Gastaut syndrome

Purpose:   This randomized, double-blind, dose-ranging study evaluated safety and efficacy of clobazam (CLB) as adjunctive therapy for drop seizures in patients with Lennox-Gastaut syndrome (LGS).
Methods:   Sixty-eight patients with LGS aged 2–26 years were administered CLB (low dose = target 0.25 mg/kg/day; high dose = target 1.0 mg/kg/day). The study consisted of 4-week baseline, 3-week titration, and 4-week maintenance periods, followed by a 3-week taper or continuation in an open-label study. Seizure frequency was recorded in a diary by the parent/caregiver throughout the study.
Results:   Weekly drop seizure rates were significantly reduced from baseline in both the high-dose and low-dose groups; the reduction was significantly greater in the high-dose group. A significantly greater proportion of patients in the high-dose group experienced reductions in drop seizures of ≥25%, ≥50%, and ≥75% compared to the low-dose group; more patients in the high-dose group experienced a 100% reduction, but the difference was not significant. Nondrop seizures were also reduced in a dose-dependent manner. In both investigator and parent/caregiver global evaluations, patients in the high-dose group showed significantly greater improvements in overall symptoms compared to low-dose CLB. Adverse events were generally mild or moderate, and were similar between dose groups. Five serious adverse events were reported in four patients, but in no case was CLB discontinued.
Conclusions:   Clobazam was well tolerated and reduced drop seizure rates; high-dose CLB was more effective than low-dose CLB. Other seizure types were also reduced.     

An open-label, add-on study of pregabalin in patients with partial seizures: A multicenter trial in Greece

Introduction

Pregabalin efficacy and safety as an adjunctive treatment for partial seizures was evaluated using an open-label, flexible-dose.

Study design

In 98 adults with refractory partial epilepsy taking 1–3 anti-epileptic drugs with ≥2 seizures during an 8-week baseline period.

Methods

Pregabalin was increased to ≤600 mg/day during a 9-week dose optimization period with dosage maintained for 12 additional weeks. Primary endpoint was the percentage change in partial seizure frequency between the 8-week baseline and 12-week observation period.

Results

Pregabalin treatment was associated with a significant reduction in partial seizure frequency: median percent change in partial seizure frequency from baseline to 12 weeks was −33% and −22% in patients with a baseline seizure frequency of ≤3 and >3 per 28 days, respectively. The 50% and 75% responder rates were 41.94% (95% CI: 31.91–51.96) and 30.11% (95% CI: 20.78–39.43), respectively. Nineteen percent of subjects were seizure-free throughout the last 12 weeks. Pregabalin administration resulted in a significant reduction in anxiety (mean reduction in Hospital Anxiety and Depression Scale scores of 1.68 units, 95% CI: −2.60 to −0.76). Most patients were much improved or very much improved on Patient Global Impression of Change (53.8%) and Clinical Global Impression of Change (53.8%). The most frequently self-reported adverse events (AEs) were mild or moderate somnolence (20.4%) and dizziness (5.1%) with a low AE discontinuation rate (5.1%).

Conclusions

The efficacy and side-effect profile of pregabalin were similar to previous pregabalin double-blind, controlled studies. Additionally, pregabalin, as an add-on treatment for partial epilepsy, exhibits significant anti-anxiety properties.     

Efficacy of gabapentin as adjunctive therapy in a large, multicenter study. The Steps Study Group.

The objective of this study was to determine the efficacy of gabapentin as adjunctive therapy in doses required to achieve the most effective seizure control. There were 2016 patients with partial seizures requiring adjunctive therapy who received gabapentin at doses up to 3600 mg/day in this open-label, multicenter, 16-week study. Of the 1055 patients evaluable for efficacy, 573 received gabapentin < or =1800 mg/day and 482 received > 1800 mg/day as the highest dose received. For the overall efficacy evaluable population, the percentage of patients achieving at least a 50% reduction in seizure frequency was 76.0%; 46.4% of the patients were seizure free. Patients whose highest gabapentin dose did not require > 1800 mg/day had, at baseline, fewer seizures and were receiving fewer concomitant antiepileptic drugs (AEDs) at baseline than those patients requiring > 1800 mg/day. This suggests that patients requiring higher doses of gabapentin were more refractory to drug treatment at the start of the study. Gabapentin was well tolerated at all doses in this study. The results of the study demonstrate that gabapentin is effective as adjunctive therapy in patients with partial seizures whose seizures are inadequately controlled by traditional AEDs.     

Efficacy and safety of retigabine/ezogabine as adjunctive therapy in adult Asian patients with drug-resistant partial-onset seizures: A randomized,placebo-controlled Phase III study

PurposeThe purpose of this study was to evaluate the efficacy and safety of adjunctive retigabine/ezogabine (RTG/EZG) therapy in Asian adults with partial-onset seizures.MethodsA Phase III, randomized, double-blind, placebo-controlled, parallel-group study was conducted at 26 centers in Asia. Eligible patients were randomized in a 1:1:1 ratio to receive RTG/EZG 600 mg/day (200 mg 3 times daily), RTG/EZG 900 mg/day (300 mg 3 times daily), or placebo. The study consisted of an 8-week screening/baseline phase, followed by a 16-week treatment phase (4-week titration phase and 12-week maintenance phase).ResultsThe study was terminated early because of emerging safety information on RTG/EZG (i.e., retinal pigmentation and skin/mucosal discoloration) from long-term trials. Of 132 patients screened and 76 randomized, 75 (placebo, n = 25; RTG/EZG 600 mg/day, n = 26; RTG/EZG 900 mg/day, n = 24) received at least 1 dose of the study drug and were included in the safety and intent-to-treat populations. The responder rate (≥ 50% reduction in 28-day total partial-onset seizure frequency) was 31% with RTG/EZG 600 mg/day and 17% with RTG/EZG 900 mg/day versus 0% with placebo. Median percent change from baseline in 28-day total partial-onset seizure frequency during the maintenance phase was − 33.90% and − 22.46% with RTG/EZG 600 and 900 mg/day, respectively, versus − 22.21% with placebo. No new safety concerns were identified.ConclusionsInsufficient data were obtained to permit definitive conclusions. However, the results appear to be broadly in line with those from previous studies that included primarily Caucasian patients.     

Dose-response effect of levetiracetam 1000 and 2000 mg/day in partial epilepsy

PURPOSE: To evaluate the efficacy, dose-response, tolerability, and withdrawal effects of levetiracetam (Keppra) as adjunctive therapy in adult patients with partial epilepsy. METHODS: In this European multicenter, double-blind, randomized, cross-over trial, levetiracetam 1000 or 2000 mg/day given in two divided doses was compared to placebo as add-on therapy in 324 patients with refractory partial seizures with or without secondary generalization. This trial consisted of six periods: an 8- or 12-week baseline, a treatment period A (4-week titration and 12-week evaluation), a treatment period B (4-week titration and 12-week evaluation), and a withdrawal period. During each evaluation period (A and B), patients received two of the three possible treatment regimens. RESULTS: This study provides additional information on dose-response effects and withdrawal phenomena and confirms the responder and seizure freedom rates previously reported in the parallel part of the study (Epilepsia 41 (2000) 1179-1186). Both doses of levetiracetam significantly decreased mean partial seizure frequency compared with placebo (P<0.001), and significantly more patients receiving levetiracetam had > or = 50 and > or = 75% reductions in partial seizure frequency (1000 mg, P=0.004 and P=0.043, respectively; 2000 mg P=0.001 and P<0.001, respectively). In addition, 5.5% (10/183) of patients receiving levetiracetam 1000 mg/day and 6.3% (11/175) of patients receiving levetiracetam 2000 mg/day were seizure-free during the corresponding evaluation period, compared with 1.2% (2/172) of patients on placebo. A within-patient comparison revealed a significantly greater responder rate for the higher levetiracetam dose (P=0.018). The most commonly reported adverse effects (> or = 5% and more frequent in one of the groups with levetiracetam) were headache, asthenia, infection, somnolence, pharyngitis, dizziness, and pain. No withdrawal-related adverse events were reported during the cross-titration period. CONCLUSIONS: Levetiracetam was effective and well-tolerated and decreased seizure frequency in a dose-dependent manner, with no evidence of typical withdrawal-related adverse events or rebound phenomena after withdrawal or down-titration.     

A randomised open-label study of tiagabine given two or three times daily in refractory epilepsy.

Efficacy and tolerability of tiagabine was evaluated in patients with non-controlled partial seizures in a multicentre, open-label, parallel group study. Tiagabine was administered either two (b.i.d.) or three times daily (t.i.d.) as adjunctive therapy and titrated stepwise to a target of 40 mg/day during a 12-week, fixed-schedule titration period; this was followed by a 12-week flexible continuation period. The primary efficacy endpoint was the proportion of patients completing the fixed-schedule titration period. A total of 243 patients were randomised and received treatment, 123 to b.i.d. and 120 to t.i.d. dosing. Fewer patients in the b.i.d. (76 and 62%) than in the t.i.d. (87 and 72%) group completed the fixed-schedule titration period (OR: 0.562; 95% CI: 0.309-1.008; P=0.0532). The median percentage decrease in all types of seizure (excluding status epilepticus) during the fixed schedule titration period was 33.4% for the b.i.d. and 23.8% for the t.i.d. groups (P=0.9634; Van Elteren's test). The proportion of responders was similar for the b.i.d. and t.i.d. groups. There were no significant differences between dosage regimens in the change in median seizure rates from baseline. Adverse events were more frequent during the titration than the continuation period. Most events were mild and related to the central nervous system. Although their incidence was similar between treatment groups, severity was more frequent in the b.i.d. group. Our results suggest that during titration tiagabine is better tolerated with t.i.d. dosing, but during long-term maintenance, a t.i.d. schedule is as effective and well tolerated as b.i.d.