Double-Blind Placebo-Controlled Randomized Clinical Trial of Topiramate Add-On Therapy in Medically Intractable Partial Epilepsies

ABSTRACT

BACKGROUND: To evaluate the efficacy and safety of topiramate (TPM) as add-on therapy in medically intractable partial epilepsies. METHODS: This study was a multicenter double-blind placebo-controlled randomized parallel group trial consisting of 12 weeks of baseline phase, 10 weeks of titration phase, and 8 weeks of maintenance phase. The primary efficacy variable was the median seizure frequency reduction rate(MSFRR) and the other efficacy variables included responder rate, seizure free rate, and global evaluations by the patient and the physician. The patient should have partial epilepsies refractory to the maximally tolerable doses of one to two antiepileptic drugs(AEDs) and should have at least two or more episodes of clinical seizures every 4 weeks during the baseline phase. The target dose of study drugs was 600mg/day. The study drug was started at the initial dose of 50mg/day and increased by 50mg/day every week until 400mg/day was reached. Thereafter, the dose was increased by 100mg weekly over next two weeks. RESULTS: A total of 177 patients were randomized into TPM group(n=91) and placebo (PLC) group (n=86). Baseline median seizure frequencies were 5.60 episodes/4 weeks in TPM group and 5.59 episodes/4 weeks in PLC group. Among those who were randomized, 158 patients (TPM 78 patients, PLC 80 patients) were available for efficacy measurement by intention-to-treat analysis. The MSFRR was 63.6% for TPM and 17.9% for PLC, which was highly in favor of TPM (p=0.0001). The responder rate was 59.0% for TPM and 23.8% for PLC (p=0.001). Thirteen of 78 patients (16.7%) taking TPM became seizure free compared to 2 of 80 patients (2.5%) taking PLC (p=0.004). The global evaluation by the patient and the physician greatly favored TPM (p=0.001, p=0.001). The incidence of adverse events(AE) was higher in TPM(81.3%) than PLC (48.9%) with CNS-related AE being the most frequent. Among individual AE, anorexia (20.9%) and abdominal pain or discomfort (20.9%) were the most common AE in TPM group. AE precipitated early drop out in 7 patients taking TPM (7.6%) and 3 patients taking PLC(3.5%). No serious AE were observed. CONCLUSIONS: TPM was highly effective and safe as add-on therapy in medically intractable partial epilepsies. Slower titration of TPM seems to decrease the drop-out rate but the incidence of AE was still high. The AE profile of TPM in Asians was different from that in Caucasians.