Randomized controlled clinical trial of zonisamide as adjunctive treatment for refractory partial seizures
Sackellares JC, Ramsay RE, Wilder BJ, Browne TR III and Shellenberger MK;
Commented by , 16 Jun 2004
Background
Zonisamide is a second generation antiepileptic drug (AED) already available in Japan and the U.S., but not yet licensed in Europe.
Aim
To assess the efficacy and tolerability of zonisamide as adjunctive therapy in refractory partial seizures.
Methods
In a double-blind parallel-group U.S. trial, 152 adults with refractory partial seizures receiving up to 2 concomitant AEDs were randomized to adjunctive therapy with zonisamide or placebo.
Zonisamide was given b.i.d. at 7 mg/kg/day (400-600 mg/day), but a later amendment allowed to initiate at lower doses (1.5 mg/day) with titration to 400-600 mg/day or plasma levels between 20 and 30 mcg/mL.
The primary efficacy endpoint was the median % reduction in seizure frequency during the 12-week treatment compared with an 8-12 week prospective baseline.
Results
Zonisamide was associated with a median 28.9% reduction in seizure frequency compared with a 4.7% increase on placebo (p<0.001).
A >50% seizure reduction occurred in 26.9% of patients on zonisamide and in 16.2% of those on placebo (p=0.11).
Of 78 patients randomized to zonisamide, 12 (15%) withdrew due to adverse events, compared with 1 out of 74 (1%) in the placebo group. Most common drug-related adverse events were somnolence, irritability, dizziness, nausea and fatigue.
Comment
Zonisamide acts through a variety of mechanisms including blockade of sodium channels (ref. 1), T-type calcium channels (ref. 2), and carbonic anhydrase (ref. 3), as well as enhancement of hippocampal GABA release (ref. 4).
Zonisamide was approved in Japan in 1989, but placebo-controlled trials were only completed in the 90s. The first was conducted in Europe and showed a median reduction in complex partial seizures of 27.7% compared with a 3.9% increase on placebo (ref. 5).
Of the two U.S. trials, the latest gave the best results (40.5% seizure reduction compared with a 9% reduction on placebo) and was rapidly published (ref. 6). In the present study, seizure reduction was less prominent (28%) and, unlike other studies, 50% responder rates did not differ statistically from placebo.
There is no clear explanation of why responses varied so much across trials. This highlights the difficulties of comparing AEDs based on results from different trials, without direct head-to head comparisons.
In any case, efficacy data for zonisamide are comparable with those of other second-generation AEDs and emphasize the modest therapeutic impact of these agents in refractory epilepsies (ref. 7). Significantly, no information was given on seizure-free rate, which is the ultimate goal of epilepsy therapy.
In an early metanalysis, zonisamide did not stand out for a particularly favourable tolerability profile (ref. 8). In the present publication, information on tolerability was less than desirable, and no comparison was included of adverse event rates in the two groups. It should be noted, however, that side effects may be overestimated in regulatory clinical trials due to suboptimal flexibility in dosing and titration schedules.
It is difficult to make inferences from this trial about the value of zonisamide in the treatment of epilepsy. Preliminary data suggest that zonisamide has broad spectrum efficacy and could be particularly valuable in some refractory generalized epilepsies (ref. 9), though well designed trials in the latter have not yet been performed.
References
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