Elsevier

The Lancet Neurology

Volume 10, Issue 10, October 2011, Pages 881-890
The Lancet Neurology

Articles
Efficacy and safety of pregabalin versus lamotrigine in patients with newly diagnosed partial seizures: a phase 3, double-blind, randomised, parallel-group trial

https://doi.org/10.1016/S1474-4422(11)70154-5Get rights and content

Summary

Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Funding

Pfizer Inc.

Introduction

New onset epilepsy (mostly partial seizures) develops in about 50 people per 100 000 each year.1 Guidelines recommend to begin treatment in these patients with a single antiepileptic drug, with the goal of achieving complete seizure freedom and minimum adverse effects.2 Only about 50% of newly diagnosed adult patients are able to tolerate, and become seizure-free with, the first antiepileptic drug.3 Therefore, additional efficacious and safe monotherapy options are needed. None of the newer antiepileptic drugs developed as adjunctive treatments have shown superior efficacy compared with established drugs when used as monotherapy against partial seizures,4, 5 although lamotrigine fared better than carbamazepine because of greater tolerability6, 7 and is currently approved as monotherapy in Europe and the USA. Few randomised head-to-head comparisons of new antiepileptic drugs have been reported. In a double-blind trial,8 gabapentin seemed to be as effective as lamotrigine monotherapy, although gabapentin was inferior to lamotrigine in a subsequent larger but open-label study.9

Pregabalin is a new antiepileptic drug with additional analgesic and anxiolytic properties. Similar to gabapentin, it binds to the α2δ subunits of neuronal voltage-gated calcium channels, but with greater affinity.10, 11 It is generally well tolerated and has many desirable properties for monotherapy use, including high bioavailability, linear pharmacokinetics, and low risk of drug interactions.12 In placebo-controlled studies, pregabalin 150–600 mg/day consistently showed efficacy as adjunctive therapy in patients with partial seizures.13 Pregabalin (300–600 mg/day) also compared favourably with lamotrigine (300–400 mg/day) as adjunctive therapy.14 We examined whether pregabalin was efficacious as monotherapy for partial seizures in newly diagnosed patients, using lamotrigine as the comparator.

Section snippets

Study design and patients

This phase 3, double-blind, randomised, parallel-group, non-inferiority study was undertaken at 105 centres, mostly in Europe and Asia, in patients with partial seizures. The study complied with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice Guidelines, was approved by a local research ethics committee in every centre, and written informed consent was obtained from all patients.

Eligible patients were diagnosed with focal epilepsy (at least two

Results

Patient recruitment began in August, 2006, and the last patient completed the efficacy assessment phase in December, 2009. The ITT population consisted of 660 patients (330 pregabalin; 330 lamotrigine), among whom 314 in the pregabalin group and 308 in the lamotrigine group entered the efficacy assessment phase. In the per-protocol population (321 pregabalin; 322 lamotrigine), 305 and 300 patients, respectively, entered the efficacy assessment phase. Baseline characteristics are presented in

Discussion

We compared the efficacy and tolerability of pregabalin and lamotrigine as monotherapy for newly diagnosed partial seizures. The study allowed flexible dosing to better reflect clinical practice and was adequately powered to test the non-inferiority hypothesis in accordance with ILAE stipulations to achieve the highest level of evidence.17 The study also complied with European regulations for such pivotal trials in adopting a randomised, double-blind, dose-ranging design, and a seizure-free

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