Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures
Biton V, Sackellares JC, Vuong A, Hammer AE, Barrett PS and Messenheimer JA;
Commented by , 20 Feb 2006
Background
The overwhelming majority of placebo-controlled studies in epilepsy are conducted in patients with partial seizures, with or without secondary generalization (ref. 1). Very few trials investigated antiepileptic drugs (AEDs) in patients with primary generalized tonic-clonic seizures (PGTCS).
Aim
To investigate the potential efficacy of lamotrigine as adjunctive therapy in refractory PGTCS.
Methods
- In a double-blind randomised parallel-group trial, 58 patients received lamotrigine and 59 placebo. Clinical characteristics were similar in the two groups
- Eligible patients (age range 2-53 years) had at least 3 PGTCS during an 8-week baseline. Patients with Lennox-Gastaut syndrome were excluded.
- Dose escalation lasted 7-12 weeks. Maintenance phase was 12 weeks.
- Primary endpoint was median % reduction in PGTCS frequency in treatment period versus baseline.
Results
- Median reduction in PGTCS frequency was 66% on lamotrigine and 34% on placebo (p=0.006). For all generalized seizure types, median seizure frequency reduction was 47% on lamotrigine and 16% on placebo (p=0.004).
- Responder rates (% of patients with > or = 50% seizure reduction) for PGTCS seizures and for all seizures were 64% and 48% respectively on lamotrigine versus 39% and 34% respectively on placebo (p<0.05).
- At maintenance, mean lamotrigine dosage for age groups >12 years was 189 mg/day for patients on valproate, 233 mg/day for those on valproate plus an enzyme inducer and 393 mg/day for those on enzyme inducers without valproate.
- Tolerability was generally good. Discontinuations for adverse events were 9% on lamotrigine and 3% on placebo. There was only one (non-serious) rash on lamotrigine.
Professor Perucca's comments
Although lamotrigine is widely regarded as a broad-spectrum drug with efficacy against PGTCS in addition to partial and other generalized seizure types (ref. 2; ref. 3; ref. 4; ref. 5; ref. 6; ref. 7; ref. 8; ref. 9), there have been few controlled studies in PGTCS patients. Active control monotherapy studies in newly diagnosed epilepsy did include subgroups with PGTCS (ref. 10; ref. 11; ref. 12), but these were small and diagnostic criteria uncertain.
To my knowledge, this is the second placebo-controlled trial of lamotrigine in refractory PGTCS. The first, which is remarkably not cited, used a cross-over design in 21 patients with various generalized epilepsies: 50% of these showed a > or = 50% decrease in PGTCS compared with placebo (ref. 13). Those results have now been corroborated in a larger and more powerful study.
Studies in PGTCS are difficult to perform: 38 active centers (!) were required to assess 117 patients, and additional centers failed to recruit. Reasonable inclusion criteria were used in that repeat EEGs were required to exclude focal epileptic activity; however, a 24-h EEG was not required when generalized paroxisms were not detected by routine EEG.
A disappointing feature is that no effort was made to provide a syndromic classification, which should have been known since all patients had long-standing epilepsy. This leaves some uncertainty about the type of epilepsies that were actually enrolled, and the applicability of the findings.
An interesting observation is the high placebo response, also seen in a similar trial with topiramate (ref. 14). This is probably due to spontaneous fluctuation in seizures that, overall, occur infrequently, and to the partial use of a retrospective baseline (which may enhance regression to the mean).
During the 12-week maintenance, 49% of patients on placebo had at least a 50% reduction in PGTCS, and 17% were completely free from all seizures (compared with 72% and 28% on lamotrigine). At global impression, 71% of patients felt improved on placebo, compared with 88% on lamotrigine, a non-significant difference. These findings emphasize the need for caution when interpreting uncontrolled trial results in this condition.
There have been reports of lamotrigine aggravating myoclonic seizures in some epilepsies (ref. 15; ref. 16; ref. 17; ref. 18; ref. 19; ref. 20; ref. 21), including idiopathic generalized epilepsies (ref. 19; ref. 20; ref. 21), but there was no evidence for this in this study. A >50% increase in all seizures occurred in 9% of patients on lamotrigine and 25% on placebo (highlighting the fact that seizure aggravation may occur spontaneously), but no details were given about proportions of patients in whom specifically myoclonic seizures emerged or worsened.
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