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

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

Intravenous lacosamide as replacement for oral lacosamide in patients with partial-onset seizures

PURPOSE: This multicenter, double-blind, double-dummy, randomized, inpatient trial evaluated the safety, tolerability, and pharmacokinetics of intravenous lacosamide as replacement for oral lacosamide in patients with partial-onset seizures. METHODS: Patients were enrolled from an ongoing open-label extension trial of oral lacosamide and randomized (2:1) to either intravenous lacosamide and oral placebo or intravenous placebo and oral lacosamide. During the 2-day inpatient treatment period, patients received twice-daily doses of lacosamide equivalent to their current daily dose of oral lacosamide. The first 30 patients enrolled received infusions with 60-min durations and the next 30 received infusions with 30-min durations. RESULTS: Of 60 patients randomized, 59 completed the trial. Treatment-emergent adverse events (AEs) were reported by 16 patients and included dizziness, headache, back pain, somnolence, and injection site pain. The tolerability profile of intravenous lacosamide was consistent with that of oral lacosamide. All AEs were considered mild or moderate in intensity, and no serious AEs or AEs leading to withdrawal were reported. CONCLUSIONS: Intravenous lacosamide, administered as 60- or 30-min twice-daily infusions, showed a similar safety and tolerability profile to oral lacosamide when used as replacement therapy. Results from this trial support further investigation of intravenous lacosamide at shorter infusion durations.     

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.     

Randomized, controlled clinical trial of zonisamide as adjunctive treatment for refractory partial seizures

PURPOSE: This study was designed to evaluate efficacy and safety of zonisamide (ZNS) as adjunctive treatment for patients with refractory partial seizures. METHODS: This randomized, double-blind, placebo-controlled study was conducted at four epilepsy treatment centers. It included a baseline phase (8 to 12 weeks) and a double-blind treatment phase (12 weeks). Initially, patients randomized to ZNS treatment were given a 7-mg/kg/d dosage. When investigators found that adverse effects could be reduced by gradually introducing ZNS, patients were allowed to begin treatment at lower doses (100 mg or approximately 1.5 mg/kg/d) titrated over several weeks to a maximum of 400 to 600 mg/d. Primary and secondary efficacy measures were the median percentage reduction from baseline in seizure frequency and the proportion of patients achieving a > or =50% reduction from baseline (responder rate). Patient and physician global assessments also served as indicators of efficacy. Safety was assessed primarily by treatment-emergent adverse events. RESULTS: ZNS-treated patients had a 28.9% reduction in seizure frequency, which differed significantly from the 4.7% increase in placebo-treated patients. The responder rate for ZNS-treated patients was 26.9%, compared with 16.2% for placebo-treated patients. At study's end, 66.2% of ZNS-treated patients and 12.3% of placebo-treated patients considered their condition improved; similarly, physicians assessed 63.6% of ZNS-treated patients and 10.8% of placebo-treated patients as improved. The most frequently reported adverse events with ZNS treatment included somnolence, irritability, dizziness, nausea, and fatigue. CONCLUSIONS: As adjunctive treatment, ZNS was generally well tolerated and significantly improved seizure control among patients with refractory partial seizures.     

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.     

Once-daily extended-release levetiracetam as adjunctive treatment of partial-onset seizures in patients with epilepsy: A double-blind, randomized, placebo-controlled trial

Purpose:   Double-blind randomized trial to assess efficacy and tolerability of once-daily extended-release levetiracetam (LEV XR) tablets (2 × 500 mg) as add-on therapy in patients (12–70 years old) with partial-onset seizures (POS) refractory to one to three antiepileptic drugs.
Methods:   After an 8-week prospective baseline-period, eligible patients were randomized (1:1) to once-daily LEV XR 1,000 mg/day or placebo for 12 weeks. Evaluations included changes from baseline in POS-frequency/week, responders (≥50% reduction in POS-frequency/week), seizure-freedom, adverse events, laboratory tests, physical and neurologic examinations, vital signs, body-weight, and 12-lead electrocardiogram.
Results:   Of 188 patients screened, 158 were randomized (intention-to-treat population): LEV XR (n = 79) or placebo (n = 79). Seventy-one (89.9%) LEV XR and 72 (91.1%) placebo patients completed the trial. Median POS-frequency/week reduction was 46.1% on LEV XR and 33.4% on placebo. Estimated reduction with LEV XR over placebo was 14.4% (p   =   0.038). Thirty-four (43%) LEV XR and 23 (29.1%) placebo patients experienced ≥50% reduction in POS-frequency/week. Eight (10.1%) patients receiving LEV XR and one (1.3%) receiving placebo were free of POS during the 12-week treatment period. Forty-one (53.2%) LEV XR and 43 (54.4%) placebo patients reported ≥1 adverse event. Adverse events reported with an incidence >5% and seen more often with LEV XR than with placebo were somnolence, influenza, irritability, nasopharyngitis, dizziness, and nausea .
Discussion:   Once-daily LEV XR 1,000 mg was effective and well-tolerated as adjunct therapy in patients with POS. Ten percent of patients randomized to LEV XR experienced freedom from POS. These results support the clinical value of this new LEV XR formulation.     

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.     

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.     

Efficacy and tolerability of adjunctive brivaracetam in adults with uncontrolled partial‐onset seizures: A phase IIb,randomized, controlled trial

Purpose: To evaluate the efficacy and tolerability of adjunctive brivaracetam (BRV), a novel high‐affinity synaptic vesicle protein 2A ligand that also displays inhibitory activity at neuronal voltage‐dependent sodium channels, in adult epilepsy patients with uncontrolled partial‐onset seizures. Methods: A phase IIb, double‐blind, randomized, placebo‐controlled, parallel‐group, dose‐ranging study (N01114; NCT00175929) was conducted in patients aged 16–65 years. To be included in the study, patients were required to have experienced four or more partial‐onset seizures during a 4‐week prospective baseline, despite treatment with 1–2 concomitant antiepileptic drugs. Patients were randomized in a ratio of 1:1:1 to receive BRV 50 mg/day (BRV50), 150 mg/day (BRV150), or placebo. A 3‐week up‐titration period was followed by a 7‐week maintenance period (total treatment period of 10 weeks). Key Findings: A total of 157 patients were randomized (intent‐to‐treat [ITT] population; BRV50 n = 53, BRV150 n = 52, placebo n = 52) and overall 148 (94.3%) completed the study. The percent reduction in baseline‐adjusted partial‐onset seizure frequency/week over placebo during the 7‐week maintenance period (primary efficacy outcome) did not reach statistical significance (14.7% for BRV50 [p = 0.093] and 13.6% for BRV150 [p = 0.124]). However, during the entire 10‐week treatment period a statistically significant difference was observed for both BRV groups (17.7% for BRV50 [p = 0.026] and 16.3% for BRV150 [p = 0.043]). The median percent reduction from baseline in partial‐onset seizure frequency/week during the maintenance period was 38.2% for BRV50 (p = 0.017) and 30.0% for BRV150 (p = 0.113) versus 18.9% in the placebo group. During the treatment period, this was 34.9% for BRV50 (p = 0.004) and 28.3% for BRV150 (p = 0.070) compared with 16.3% for placebo. Fifty percent responder rates during the maintenance period were 23.1% for placebo compared with 39.6% for BRV50 (odds ratio [OR] 2.17, p = 0.077) and 33.3% for BRV150 (OR 1.66, p = 0.261). During the treatment period, 50% responder rates were 17.3% for placebo compared with 35.8% for BRV50 (OR 2.69, p = 0.038) and 30.8% for BRV150 (OR 2.15, p = 0.114). Nine patients were free from partial‐onset seizures during the 10‐week treatment period (five patients [9.4%] in the BRV50 group and three [5.8%] in the BRV150 group compared with one patient [1.9%] in the placebo group). Treatment‐emergent adverse events (TEAEs) reported during the treatment period were mostly mild‐to‐moderate with similar incidence across treatment groups (BRV50 36/53, 67.9%; BRV150 35/52, 67.3%; placebo 37/52, 71.2%). The most frequently reported TEAEs in BRV groups were headache, fatigue, nasopharyngitis, nausea, somnolence, and dizziness, although nausea had a higher incidence in the placebo group. Significance: In this double‐blind, placebo‐controlled, phase IIb study of adjunctive BRV (50 and 150 mg/day) in adults with uncontrolled partial‐onset seizures, the primary efficacy analysis did not reach statistical significance; however, statistically significant differences compared with placebo were observed on several secondary efficacy outcomes. BRV was well tolerated.     

Adjunctive levetiracetam in infants and young children with refractory partial-onset seizures

Purpose:   To evaluate the efficacy and tolerability of adjunctive levetiracetam in very young children (aged 1 month to <4 years) with partial-onset seizures inadequately controlled with one or two antiepileptic drugs.
Methods:   This multicenter, double-blind, randomized, placebo-controlled study consisted of a 48-h inpatient baseline video-EEG (electroencephalography) and a 5-day inpatient treatment period (1-day up-titration; 48-h evaluation video-EEG in the last 2 days). Children who experienced at least two partial-onset seizures during the 48-h baseline video-EEG were randomized to either levetiracetam [40 mg/kg/day (age 1 to <6 months); 50 mg/kg/day (age ≥6 months to <4 years] or placebo.
Results:   Of 175 patients screened, 116 patients were randomized [60 levetiracetam; 56 placebo; intent-to-treat (ITT) population], and 111 completed the study. The responder rate in average daily partial-onset seizures frequency (48-h video-EEG monitoring; primary efficacy variable) was 43.1% for levetiracetam [modified ITT (mITT) = 58] versus 19.6% for placebo (mITT = 51; p=0.013), with odds ratio for response 3.11 [95% confidence interval (CI), 1.22–8.26]. The median percent reduction from baseline in average daily partial-onset seizure frequency was 43.6% for levetiracetam and 7.1% for placebo with a median difference between treatment groups of 39.2% (95% CI, 17.5–62.2; p   <   0.001). In general, levetiracetam was well tolerated. Treatment-emergent adverse events were reported by 55.0% levetiracetam- and 44.6% placebo-treated patients (ITT population). The most frequently reported adverse events were somnolence (13.3% levetiracetam, 1.8% placebo) and irritability (11.7% levetiracetam, 0% placebo).
Discussion:   Adjunctive levetiracetam is an efficacious and well-tolerated treatment for partial-onset seizures in infants and young children.     

Adjunctive pregabalin for uncontrolled partial-onset seizures: findings from a prospective audit

Stephen LJ, Parker P, Kelly K, Wilson EA, Leach V, Brodie MJ. Adjunctive pregabalin for uncontrolled partial‐onset seizures: findings from a prospective audit.
Acta Neurol Scand: 2011: 124: 142–145.
© 2011 John Wiley & Sons A/S. Aims – Pregabalin (PGB) was licensed in Europe as an add‐on antiepileptic drug (AED) for the treatment of partial‐onset seizures in 2004. This audit assessed the response to adjunctive PGB in patients with uncontrolled seizures. Methods – PGB was titrated in 135 patients [73 men; 62 women, aged 18–76 (median 44 years) until one of the following occurred: ≥6 months’ seizure freedom, ≥50% or <50% seizure reduction over 6 months; PGB withdrawal because of adverse effects, lack of efficacy or both. Results – Of the 135 patients, 14 (10.4%) became seizure‐free for ≥6 months (median PGB dose 300 mg/day; range 75–600 mg). A ≥ 50% seizure reduction occurred in 33 (24.4%) patients; 20 (14.8%) had <50% reduction. PGB was withdrawn in 68 (50.4%) (40 adverse effects, seven lack of efficacy and 21 both). Commonest problems resulting in withdrawal were sedation (n = 18), weight gain (n = 14) and ataxia (n = 9). There was a positive correlation between increasing dose and weight gain (r = 0.42, P = 0.045). Conclusions – Add‐on PGB benefited 50% of patients, but only 10% achieved 6 months’ seizure freedom. Adverse effects, most commonly sedation, dose‐related weight gain and ataxia, led to drug discontinuation by 45%. Prospective audits of novel AEDs are a useful adjunct to randomized, controlled trials in managing epilepsy.     

A multicenter randomized controlled trial on the clinical impact of therapeutic drug monitoring in patients with newly diagnosed epilepsy. The Italian TDM Study Group in Epilepsy

PURPOSE: To assess the clinical impact of monitoring serum concentrations of antiepileptic drugs (AEDs) in patients with newly diagnosed epilepsy. METHODS: One-hundred eighty patients with partial or idiopathic generalized nonabsence epilepsy, aged 6 to 65 years, requiring initiation of treatment with carbamazepine (CBZ), valproate (VPA), phenytoin (PHT), phenobarbital (PB), or primidone (PRM) were randomly allocated to two groups according to an open, prospective parallel-group design. In one group, dosage was adjusted to achieve serum AED concentration within a target range (10-20 microg/ml for PHT, 15-40 microg/ml for PB, 4-11 microg/ml for CBZ, and 40-100 microg/ml for VPA), whereas in the other group, dosage was adjusted on clinical grounds. Patients were followed up for 24 months or until a change in therapeutic strategy was clinically indicated. RESULTS: Baseline characteristics did not differ between the two groups. Most patients with partial epilepsy were treated with CBZ, whereas generalized epilepsies were most commonly managed with PB or VPA. PHT was used only in a small minority of patients. A total of 116 patients completed 2-year follow-up, and there were no differences in exit rate from any cause between the monitored group and the control group. The proportion of assessable patients with mean serum drug levels outside the target range (mostly below range) during the first 6 months of the study was 8% in the monitored group compared with 25% in the control group (p < 0.01). There were no significant differences between the monitored group and the control group with respect to patients achieving 12-month remission (60% vs. 61%), patients remaining seizure free since initiation of treatment (38% vs. 41%), and time to first seizure or 12-month remission. Frequency of adverse effects was almost identical in the two groups. CONCLUSIONS: Only a small minority of patients were treated with PHT, the drug for which serum concentration measurements are most likely to be useful. With the AEDs most commonly used in this study, early implementation of serum AED level monitoring did not improve overall therapeutic outcome. and the majority of patients could be satisfactorily treated by adjusting dose on clinical grounds. Monitoring the serum levels of these drugs in selected patients and in special situations is likely to be more rewarding than routine measurements in a large clinic population.     

Neurocognitive effects of adjunctive levetiracetam in children with partial-onset seizures: A randomized, double-blind, placebo-controlled, noninferiority trial

Purpose : Evaluate potential neurocognitive effects of adjunctive levetiracetam in children with inadequately controlled partial‐onset seizures (POS). Methods : Randomized, double‐blind, placebo‐controlled, noninferiority safety study. Children (4–16 years; IQ ≥65) with ≥1 POS during 4 weeks before screening despite taking 1–2 antiepileptic drugs (AEDs) were randomized (2:1) to levetiracetam (20–60 mg/kg/day) or placebo for 12 weeks. Results : Ninety‐nine patients were randomized with 98 (levetiracetam 64, placebo 34) in intent‐to‐treat (ITT) and 73 (levetiracetam 46, placebo 27) in per protocol (PP) populations. Primary cognitive assessment was the Leiter International Performance Scale–Revised Attention and Memory Battery with the memory screen composite score change from baseline as the primary endpoint. PP Least Square Mean [LSM (standard error)] were 5.36 (1.78) for levetiracetam; 5.17 (2.33) for placebo; difference [two‐sided 90% confidence interval (CI)] 0.19 (?4.69, 5.08). Levetiracetam was noninferior to placebo because the 90% CI lower bound was greater than the defined noninferiority margin (?9.0). There were no statistically significant differences between groups in Wide Range Assessment of Memory and Learning‐2 indexes and Leiter‐R Examiner’s Rating Scale scores. Median reductions from baseline in weekly POS frequency were 91.5% versus 26.5% for levetiracetam versus placebo; ≥50% responder rates: 62.5% versus 41.2%; seizure freedom rates: 46.9% versus 8.8% (ITT). Adverse events were reported by 89.1% levetiracetam‐treated and 85.3% placebo‐treated patients; those reported by ≥10% levetiracetam patients and more often with levetiracetam were headache, nasopharyngitis, fatigue, vomiting, somnolence, and aggression. Discussion : Neurocognitive effects were no different in pediatric patients with POS treated with adjunctive levetiracetam or placebo. Levetiracetam was effective and well tolerated.     

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.     

The adverse event profile of lacosamide: A systematic review and meta‐analysis of randomized controlled trials

Purpose: Defining the tolerability and safety profile of recently marketed antiepileptic drugs, such as lacosamide (LCM), is a prerequisite for their optimal utilization in clinical practice. We aimed to identify any adverse event (AE) associated with LCM treatment by conducting a systematic review and meta‐analysis of all available randomized controlled trials (RCTs). We also evaluated the association of serious AEs with LCM, the proportion of study withdrawals due to intolerable AEs at different LCM doses, and whether the tolerability profile of LCM differs according to the disorder in which it was investigated. Methods: We searched MEDLINE and Cochrane CENTRAL to May 2011 for LCM RCTs. Additional studies were identified from reference lists of retrieved papers and from online clinical databases. We selected placebo‐controlled, double‐blind RCTs and investigated the therapeutic effects of oral LCM in adults with any condition. AEs were assessed for their association with LCM after identification/exclusion of synonyms, rare AEs, and non‐assessable AEs. We used risk differences to evaluate the association of any (99% confidence intervals [CIs]) or serious AEs (95% CIs) with LCM and to investigate dose–response relationships of identified AEs. Key Findings: Ten RCTs (three in pharmacoresistant epilepsy, four in neuropathic pain, one in migraine, one in fibromyalgia, and one in knee osteoarthritis) were included in our study. Their duration varied from 12–18 weeks. The total number of patients included was 3,148. No serious AE was significantly associated with LCM treatment. Of 21 identified AEs, 11 (52%) were found to be significantly associated with LCM. The number of AEs significantly associated with LCM increased with increasing dose: one at 200 mg/day (dizziness); six at 400 mg/day (dizziness, vertigo, abnormal coordination, abnormal vision, nausea, and vomiting); nine at 600 mg/day (dizziness, vertigo, ataxia, balance disorder, diplopia, fatigue, nausea, vomiting, and tremor). The proportion of AE‐related study withdrawals also significantly increased with increasing dose. LCM AEs tended to occur more frequently in patients with drug‐resistant epilepsy compared with patients with other disorders. Significance: A range of AEs suggestive of vestibulocerebellar dysfunction is significantly associated with LCM treatment and their incidence increases with increasing doses.     

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.     

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.     

Efficacy and Tolerance of Long-Term, High-Dose Gabapentin: Additional Observations

Summary: Gabapentin (GBP) has shown antiepileptic efficacy and good tolerance in clinical trials. Much remains to be learned about its clinical use. As a participating center in the US Gabapentin Study Group, we report observations that have practical implications for patient management. Twenty-three patients with intractable partial-onset seizures initiated open-label treatment after a blinded placebo-controlled add-on dose efficacy study. In the titration phase, GBP and concurrent antiepileptic drugs (AEDs) were adjusted to achieve optimal efficacy on maximally tolerated GBP doses. Nine patients had no significant improvement in seizure control and discontinued GBP. The remaining 14 patients were observed while treated long-term with stable-dose GBP and concurrent AEDs. Improvement was maintained as long as patients were followed: ≤4 years. The protocol-allowed upper dose limit, 2,400 mg/day, was well tolerated by 16 of 23 patients, indicating that higher doses may be tolerated. GBP discontinuation did not cause rebound increases in seizure frequency. The most common adverse events (AEs) (in 14 of 23) were similar to those induced by concurrent AEDs and responded to reduction of concurrent AEDs. Many patients reported positive psychostimulatory effects. These observations extend previous findings indicating that GBP is an effective and well-tolerated drug for treatment of partial-onset seizures.     

Lorazepam: a controlled trial in patients with intractable partial complex seizures

Lorazepam was studied in a double-blind, placebo-controlled, crossover trial in eight patients with frequent partial complex seizures refractory to therapy with a combination of standard anticonvulsant drugs. Concomitant antiepileptic drugs were maintained at therapeutic serum levels throughout the study, and concentrations of lorazepam were monitored. Following an 8-week baseline observation, patients were randomly assigned to placebo or lorazepam (1 mg BID). The dose was increased biweekly until seizures stopped or unacceptable side effects occurred. Eight weeks later, patients were crossed over, and the same escalating dose paradigm was followed. When seizure frequency during the last 2 weeks of each treatment was compared, seven of eight patients had fewer seizures on lorazepam, and the eighth had decreased seizure duration (a significant difference: p less than 0.01, two-tailed sign test). Blood level data suggest a narrow therapeutic window, with seizure improvement occurring at concentrations of 20-30 ng/ml and side effects at greater than 33 ng/ml. Lorazepam appears to be a useful adjunct in refractory partial complex seizure therapy. It should not be stopped abruptly, as an increase in seizure frequency may result.