Abstracts

Double-blind studies of TPM monotherapy in newly diagnosed epilepsy have explored various TPM dosages: 50 vs. 500 mg/day; 50 vs. 400 mg/day and 100 vs. 200 mg/day, with the latter also comparing TPM with carbamazepine (CBZ) and valproate (VPA). We focus on results from two of these trials that confirm 100 mg/day TPM as the target dose in patients with previously untreated epilepsy.
A dose-controlled study enrolled patients with newly diagnosed epilepsy or patients who had relapsed while off antiepileptic drugs (AEDs). Patients had 1 or 2 partial-onset (POS) or primary generalized tonic-clonic seizures (GTCS) in the 3-mo retrospective baseline. Patients were randomized to double-blind treatment with 50 or 400 mg/day TPM, which continued 6 mos after last patient randomized or 1^st POS or GTCS occurred. Based on the titration schedule, patients randomized to TPM 400 were receiving TPM 100 starting Wk 2 of double-blind treatment; patients in the control group were receiving TPM 25. The other study compared TPM 100 and 200 with CBZ 600 and VPA 1250 in adults and children with newly diagnosed epilepsy. No restrictions were placed on seizure type/syndrome or baseline seizure frequency. Investigators selected CBZ or VPA as preferred AED for each patient, who was then randomized to the investigators[rsquo] selection or to 1 of 2 TPM doses. Patients continued double-blind treatment until 6 mos after last patient randomized or until investigators decided a change in AED regimen was needed.
In the dose-controlled study, 234 and 236 patients were assigned to TPM 50 and TPM 400, respectively. Time to 1^st seizure was the primary efficacy analysis, truncating the follow-up period at various treatment intervals, starting at Day 14. Kaplan-Meier analysis of time to 1^st seizure showed a significant treatment effect (P=0.046) favoring TPM 100 vs TPM 25 at Day 14. The between-group difference increased over time as target or maximally tolerated doses were achieved and maintained (P=0.0002 at study end). In the AED comparison study, 210, 199, 126 and 78 patients were assigned to TPM 100, TPM 200, CBZ 600 and VPA 1250, respectively. 6-month seizure-free rates were 49% for TPM 100 and 44% for the other groups. Efficacy data showed no difference between TPM 100 and 200, with TPM being at least as effective as CBZ and VPA. However, TPM 100 was better tolerated than TPM 200, CBZ or VPA. Discontinuations due to adverse events were TPM 100, 19%; TPM 200, 28%; CBZ, 25% and VPA, 23%.
Based on the dose-controlled study, 100 mg/day TPM is an effective dose, and, based on the comparative study, at least as effective and well-tolerated as CBZ and VPA. Thus, 100 mg/day TPM is the recommended initial target dose for previously untreated epilepsy patients.
[Supported by: Johnson [amp] Johnson Pharmaceutical Research [amp] Development]