Efficacy and safety of pregabalin versus lamotrigine in patients with newly diagnosed partial seizures: a phase 3, double-blind, randomised, parallel-group trial. A comparison of pregabalin, lamotrigine, and placebo as adjunctive therapy in patients with refractory partial-onset seizures. Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group. 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. A randomized open-label study of gabapentin and lamotrigine in adults with learning disability and resistant epilepsy. Pregabalin add-on therapy using a flexible, optimized dose schedule in refractory partial epilepsies: a double-blind, randomized, placebo-controlled, multicenter trial. Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures. Double-blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant generalised epilepsy.
Efficacious and safe monotherapy options are needed for adult patients with newly diagnosed epilepsy. As an adjunctive treatment for partial seizures, pregabalin compares favourably with lamotrigine and is an effective, approved treatment. We studied the efficacy and safety of pregabalin as monotherapy, using a design that complied with European regulatory requirements and International League Against Epilepsy guidelines.
                This phase 3, double-blind, randomised, non-inferiority study compared the efficacy and tolerability of pregabalin and lamotrigine monotherapy in patients with newly diagnosed partial seizures at 105 centres, mostly in Europe and Asia. Randomisation to treatment groups (1:1 ratio) was by a computer-generated pseudorandom code (random permuted blocks), with patients sequentially assigned numbers by telephone. Investigators, site staff, and patients were masked to the assigned treatment. After randomisation, patients were titrated to either 75 mg oral pregabalin or 50 mg oral lamotrigine twice daily during a 4-week dose-escalation phase, followed by a 52-week efficacy assessment phase during which the daily dose could be increased as needed to a maximum of 600 mg and 500 mg, respectively. The primary efficacy endpoint was the proportion of patients who remained seizure-free for 6 or more continuous months during the efficacy assessment phase; analysis included all patients who were randomly assigned to treatment groups and received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT00280059.
                660 patients were randomly assigned to treatment groups (330 pregabalin, 330 lamotrigine), of whom 622 entered the efficacy assessment phase (314 pregabalin, 308 lamotrigine). Fewer patients in the pregabalin group than in the lamotrigine group became seizure-free for 6 or more continuous months (162 [52%] vs 209 [68%]; difference in proportion, -0·16, 95% CI -0·24 to -0·09). The overall incidence of adverse events was similar between the groups and consistent with that in previous studies; dizziness (55 [17%] vs 45 [14%] patients), somnolence (29 [9%] vs 14 [4%]), fatigue (27 [8%] vs 19 [6%]), and weight increase (21 [6%] vs 7 [2%]) were numerically more common in the pregabalin group than in the lamotrigine group.
                Pregabalin has similar tolerability but seems to have inferior efficacy to lamotrigine for the treatment of newly diagnosed partial seizures in adults. Inferior efficacy of pregabalin might have been attributable to limitations in the study design, as treatment doses might have not been optimised adequately or early enough.
                Pfizer Inc.
                Copyright © 2011 Elsevier Ltd. All rights reserved. This study assessed the comparative efficacy of pregabalin for refractory partial seizures.
                Four-hundred and thirty-four patients with partial seizures were randomized to pregabalin, lamotrigine, or placebo as adjunctive therapy for 17 weeks of double-blind treatment. In phase I (11 weeks), pregabalin was titrated over 1 week and lamotrigine over 5 weeks to fixed dosages of 300mg/day for both. In phase II (6 weeks), patients not yet seizure-free were increased to pregabalin 600mg/day or lamotrigine 400mg/day.
                During phase I, there was a nonsignificant trend toward a greater reduction in seizures with pregabalin versus placebo and lamotrigine. Across the 17 weeks of treatment, pregabalin showed a median percentage reduction from baseline in seizure frequency of -20.0% (p=.001) versus placebo, and -9.7% (p=.080) versus lamotrigine. The responder rate (> or =50% reduction in seizure frequency) for pregabalin exceeded that of placebo (36% vs 21%; p=.007) and lamotrigine (36% vs 24%; p=.04). Adverse events were consistent with the known safety profiles of pregabalin and lamotrigine.
                Pregabalin was demonstrated to be noninferior to lamotrigine in the treatment of refractory partial seizures. Overall conclusions were complicated by an unusually large and heterogeneous placebo response.
                Copyright 2010. Published by Elsevier B.V. To evaluate the efficacy, tolerability, and safety of two pregabalin regimens administered as adjunctive therapy to that of placebo in patients with medically refractory partial epilepsy.
                A multicenter, double-blind, randomized, parallel-group, placebo-controlled trial was performed. Following a prospective 8-week baseline phase, patients were randomized to 12 weeks of double-blind treatment with placebo or pregabalin 600 mg/day administered twice daily (BID) or three times daily (TID). Primary efficacy was measured as change in seizure frequency from baseline of either pregabalin regimen compared with placebo. Secondary efficacy comparisons included the proportion of patients experiencing > or =50% reduction in seizure frequency (responder rate) and median percentage change from baseline in seizure frequency. Safety/tolerability assessments included adverse events (AEs), physical and neurologic examinations, and clinical laboratory evaluation. Efficacy and safety analyses were performed on the intent-to-treat (ITT) population.
                Pregabalin treatment resulted in seizure frequency reductions: 53% for pregabalin TID (p < or = 0.0001) and 44% for pregabalin BID (p < or = 0.0001) compared with a 1% increase for placebo. Responder rates were 49% for pregabalin TID and 43% for pregabalin BID compared with 9% for placebo (p < or = 0.001). Both pregabalin regimens were similar in efficacy and tolerability. The most common AEs were dizziness, somnolence, and ataxia.
                Pregabalin administered at 600 mg/day is safe, generally well tolerated, and efficacious as adjunctive therapy for the treatment of patients with partial seizures, with or without secondary generalizations. This dose can be administered on a twice daily or three times daily schedule with similar efficacy and tolerability results. Lamotrigine has been licensed widely as adjunctive therapy for partial and secondary generalised seizures. Use of the drug as monotherapy was investigated in a double-blind, randomised, parallel-group comparison with carbamazepine in newly diagnosed epilepsy. After 4 weeks of planned, fixed dose escalation, doses were adjusted according to efficacy, adverse events, and plasma concentrations. 151 of 260 patients (131 lamotrigine, 129 carbamazepine) in eight UK centres completed the 48-week trial. No differences in efficacy between the drugs were found for partial seizures with or without secondary generalisation or for primary generalised tonic-clonic seizures. The proportion of patients maintained seizure-free during the last 24 weeks of treatment was almost the same in both groups (39% lamotrigine, 38% carbamazepine). More patients with primary generalised tonic-clonic seizures (47% both groups) than those presenting with a focal onset (35%, 37%) were fully controlled. Overall, fewer patients on lamotrigine than on carbamazepine withdrew because of adverse events (15 vs 27%). The commonest side-effect leading to withdrawal with either drug was rash (9%, 13%). Sleepiness was less common in lamotrigine than in carbamazepine recipients (12 vs 22%, p < 0.05). More lamotrigine than carbamazepine recipients (65 vs 51%, p = 0.018) completed the study (hazard ratio 1.57 [95% CI 1.07-2.31]). Lamotrigine and carbamazepine showed similar efficacy against partial onset seizures and primary generalised tonic-clonic seizures in newly diagnosed epilepsy. Lamotrigine, however, was better tolerated. 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.
                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.
                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.
                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. The aim of this study was to evaluate the efficacy and safety of gabapentin in patients with learning disabilities and resistant epilepsy, comparing the effects of gabapentin with lamotrigine on efficacy, behaviour and mood. An open-label, randomized, parallel group, multicentre add-on study comparing gabapentin with lamotrigine in 109 patients with drug-resistant localization-related epilepsy and learning disabilities was conducted: 39 patients were randomized to gabapentin and 44 to lamotrigine. The study population had a range of learning disabilities and severe partial epilepsy. The percentage of patients achieving a greater than or equal to 50% reduction in seizure frequency on gabapentin was 50%, (mean reduction in seizures was 51%). Compared to 48.6% of lamotrigine patients, no statistically significant treatment differences could be identified. The safety profile of both drugs was consistent with that seen in previous clinical trials. Carer-rated visual analogue scales detected significant improvements (P< 0.05) for the gabapentin-treated patients in seizure severity, attention, general health and sleeping pattern, while for lamotrigine seizure severity improved significantly. For learning disabled patients with resistant epilepsy, gabapentin and lamotrigine provide safe and effective treatment, with positive benefits on behaviour. To evaluate the efficacy and safety of pregabalin (PGB) as adjunctive therapy, using a flexible-dosing schedule in Korean patients with refractory partial-onset seizures.
                This randomized, double-blind (DB), placebo-controlled trial consists of a 6-week baseline, a 12-week DB treatment, and a 1-week taper phase. Patients having recurrent partial seizures (>or=4 seizures during baseline phase) under adequate pharmacotherapy were recruited to be randomized to PGB or placebo (PLC) in a 2 to 1 ratio. Starting dose was 150 mg/day, increased every 2 weeks by 150-mg/day increments up to maximum dose of 600 mg/day. The primary efficacy parameter was response ratio (RRatio) for all partial seizures.
                A total of 178 patients (119 in PGB, 59 in PLC) were assigned to the study. Median daily doses of PGB and PLC were 367 and 420 mg/day, respectively. RRatio least squares (LS) mean was -35.8 in the PGB group and -23.2 in the PLC group, with estimated difference in RRatios being -12.6 [95% confidence interval (CI): -22.7 to -2.5, p = 0.015] in the intent-to-treat (ITT) population. Analysis of secondary efficacy measures showed a general trend favoring PGB over PLC. Seventy-seven patients (64.7%) in the PGB group and 18 patients (30.5%) in the PLC group developed adverse events (AEs) related to the study drug. Seven patients (5.9%) in the PGB group discontinued the study prematurely because of AEs. In the post hoc analysis, a significant weight gain (>or=7% of baseline body weight) was found in 24.8% of patients taking PGB, which was more frequent in patients with a lower body mass index (BMI <or=20).
                PGB was effective and easily tolerable as add-on treatment in an Asian population with refractory partial-onset seizures. To evaluate the efficacy and tolerability of adjunctive lamotrigine in primary generalized tonic-clonic (PGTC) seizures in a randomized, double-blind, placebo-controlled trial.
                Patients with a diagnosis of epilepsy with PGTC seizures who were receiving one or two antiepileptic drugs at study entry were eligible. Patients with partial seizures were excluded on the basis of seizure history and screening EEGs. The study comprised a baseline phase, an escalation phase during which study medication was titrated to a target dose, and a 12-week maintenance phase during which doses of lamotrigine/placebo and concomitant antiepileptic drugs were maintained.
                Of the 121 randomized patients ages 2 to 55 years, 117 (58 lamotrigine, 59 placebo) entered the escalation phase and received study medication. During the escalation and maintenance phases combined, median percent reduction in PGTC seizure frequency was 66.5% with lamotrigine compared with 34.2% with placebo (p = 0.006). The corresponding numbers for lamotrigine and placebo were 60.6% and 32.8% (p = 0.038) during the escalation phase and 81.9% and 43.0% (p = 0.006) during the maintenance phase. During the maintenance phase, 72% of lamotrigine-treated patients compared with 49% of placebo-treated patients experienced a > or = 50% reduction in frequency of PGTC seizures (p = 0.014). A similar pattern of results was observed for all generalized seizures. The most common drug-related adverse events were dizziness (5% lamotrigine, 2% placebo), somnolence (5% lamotrigine, 2% placebo), and nausea (5% lamotrigine, 3% placebo).
                Adjunctive lamotrigine is effective in the treatment of primary generalized tonic-clonic seizures and has a favorable tolerability profile. Lamotrigine (LTG) is recognised as effective add-on therapy for focal epilepsies, but this is the first double-blind, placebo-controlled, crossover study in treatment-resistant generalised epilepsy.
                The study consisted of 2 x 8-week treatment periods followed by a 4-week washout period. Patients received doses of either 75 or 150 mg daily, depending on their concomitant antiepileptic drugs (AEDs). Long-term continuation was offered at the end of the study with open-label LTG.
                Five centres in Australia recruited 26 patients who were having absence, myoclonic, or generalized tonic-clonic seizures or a combination of these. Twenty-two patients completed the study. There was a significant reduction in frequency of both tonic-clonic and absence seizure types with LTG. A 350% decrease in seizures was observed for tonic-clonic seizures in 50% of cases and for absence seizures in 33% of evaluable cases. Rash was the only adverse effect causing discontinuation. Twenty-three of 26 opted for open-label LTG, with 20 still receiving LTG for a mean of 26 months. In these 20, 80% had > or =50% seizure reduction and five (25%) were seizure free.
                This study shows that LTG is effective add-on therapy in patients with refractory generalised epilepsies. Statistically significant reduction in seizures in both absence and tonic-clonic seizure types was seen even with low doses of LTG.
Pregabalin seems to have similar tolerability but inferior efficacy in comparison to lamotrigine for newly diagnosed partial seizures. However, considering the limitations in the study design (such as the short-term follow-up and the low initial target dose selection), the results should be interpreted with caution. The available data were too limited to draw any conclusions between pregabalin and gabapentin. The result indicated that the treatment effects were influenced by the study regions. The clinical disadvantage of pregabalin was more prominent in Asia when compared with lamotrigine. We should determine whether pregabalin has ethnic differences in the treatment of epilepsy in the future. This review does not inform any treatment policy for patients with generalized onset tonic-clonic seizures. Further long-term trials are needed to investigate the genuine effectiveness of pregabalin as monotherapy.