* p < 0.05
PBO = placebo, DVPX = DEPAKOTE

Migraine

The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of DEPAKOTE in the prophylactic treatment of migraine headache.

Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception.

In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to DEPAKOTE or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase.

In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, DEPAKOTE to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on DEPAKOTE doses ranged from 500 to 2500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1087 mg/day resulting in a mean trough total valproate level of 72.5 µg/mL, with a range of 31 to 133 µg/mL.

The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the DEPAKOTE group (See Figure 2). These rates were significantly different.

In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three DEPAKOTE dose groups (500, 1000, or 1500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty-seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1000/1500 mg/day group and placebo group.

The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 µg/mL in the DEPAKOTE 500, 1000, and 1500 mg/day groups, respectively.

The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the DEPAKOTE 500, 1000, and 1500 mg/day groups, respectively, based on intent-to-treat results (See Figure 2). Migraine headache rates in the combined DEPAKOTE 1000/1500 mg group were significantly lower than in the placebo group.

Figure 2
Mean 4-week Migraine Rates

1 Mean dose of DEPAKOTE was 1087 mg/day.
2 Dose of DEPAKOTE was 500 or 1000 mg/day.

Epilepsy

The efficacy of DEPAKOTE in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials.

In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy) 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the “therapeutic range” were randomized to receive, in addition to their original antiepilepsy drug (AED), either DEPAKOTE or placebo. Randomized patients were to be followed for a total of 16 weeks. The following table presents the findings.

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