Abstracts

RATIONALE: A superiority design showing a significant difference between treatments is the highest standard for proof of efficacy and a requirement for drug approval in some countries. One approach to safely achieving such a standard for AED monotherapy in newly diagnosed epilepsy is to directly compare two doses [ndash] a modestly effective dose and one presumed to be a maximally effective dose, using a seizure-related endpoint to protect patients. However, such a design has yet to be successful in newly diagnosed epilepsy. We undertook a multicenter double-blind study comparing 50 and 400 mg/day TPM in adults and children with newly diagnosed epilepsy, using time to 1st seizure as the primary endpoint.
METHODS: Children ([gte]25 kg) and adults with newly diagnosed epilepsy ([lte]3 mos); (1-2 partial or GTC seizures during 3-mo retrospective baseline) were eligible, as were untreated patients with recurrent epilepsy. Although temporary/emergency use of 1 AED before study entry was allowed, the AED was withdrawn during a 7-day open-label run-in with 25 mg/day TPM. After randomization to 50 or 400 mg/day TPM, patients continued double-blind treatment until their 1st seizure or the study ended 6 mos after the last randomization. Because statistical power in a survival analysis depends on the number of patients who have seizures, study enrollment continued until 108 patients had their 1st seizure. Patients exiting due to a seizure could enter the open-label extension.
RESULTS: 470 patients were randomized to TPM 50 (N=234) or TPM 400 (N=236). Median age was 22 (6-83) yrs; 32% were [lt]16 yrs of age and 50% were female. Median time since epilepsy diagnosis was 1 mo. Kaplan-Meier estimates for time to 1st seizure showed a highly significant (P=0.0002) treatment effect favoring TPM 400. Covariate analyses showed no interaction with age, gender, region, baseline weight, baseline seizure type, baseline AED use, or time since epilepsy diagnosis. With TPM 400, the estimated seizure-free rate at 6 mos was 83% vs. 71% for TPM 50 (P=0.005), at 1-yr, 76% and 59% (P=0.001), respectively. The most common adverse events were paresthesia, 23%; headache, 19%; upper respiratory infection, 16%; dizziness, 13%; somnolence, 12%; weight loss, 11%; fatigue, 11% and loss of appetite, 10%. During treatment up to 786 days (median, 266 days), 11% withdrew due to adverse events (TPM 50, 6%; TPM 400, 17%).
CONCLUSIONS: TPM is the first AED to show, in a randomized double-blind trial, a strongly significant dose-response effect as monotherapy in adults and children with newly diagnosed epilepsy. This study demonstrates the feasibility of safely achieving the highest standard for proof of AED efficacy as initial therapy in this population. The 6-mo and 1-yr seizure-free rates for both doses compare very favorably with the 6-mo and 1-yr seizure-free rates (6 mos, 35-48%; 1 yr, 53-61%) reported in double-blind studies with other AEDs in newly diagnosed epilepsy. In this study, TPM 400 was selected to show superiority over TPM 50. In a comparative study of likely initial target doses in newly diagnosed epilepsy, TPM 100 mg was at least as effective as 600 mg carbamazepine and 1250 mg valproate, but better tolerated. The study reported here confirms the usefulness of TPM as first-line therapy in newly diagnosed epilepsy.
[Supported by: Johnson & Johnson Pharmaceutical Research & Development]; (Disclosure: Consulting - SANOFI, Admirall Prodesfarma, Lilly, Wyeth, Yamanouchi, Novartis, Ortho-McNeil Pharmaceutical/Johnson & Johnson, Pfizer/Parke-Davis, UCB, Honoraria - SANOFI, Novartis, Ortho-McNeil Pharmaceutical/Johnson & Johnson, Pfizer/Parke-Davis, UCB)