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Summary: Purpose: This study was designed to evaluate efficacy and safety of zonisamide (ZNS) as adjunctive treatment for patients with refractory partial seizures.
Methods: This randomized, double-blind, placebo-controlled study was conducted at four epilepsy treatment centers. It included a baseline phase (8 to 12 weeks) and a double-blind treatment phase (12 weeks). Initially, patients randomized to ZNS treatment were given a 7-mg/kg/d dosage. When investigators found that adverse effects could be reduced by gradually introducing ZNS, patients were allowed to begin treatment at lower doses (100 mg or ∼1.5 mg/kg/d) titrated over several weeks to a maximum of 400 to 600 mg/d. Primary and secondary efficacy measures were the median percentage reduction from baseline in seizure frequency and the proportion of patients achieving a ≥50% reduction from baseline (responder rate). Patient and physician global assessments also served as indicators of efficacy. Safety was assessed primarily by treatment-emergent adverse events.
Results: ZNS-treated patients had a 28.9% reduction in seizure frequency, which differed significantly from the 4.7% increase in placebo-treated patients. The responder rate for ZNS-treated patients was 26.9%, compared with 16.2% for placebo-treated patients. At study's end, 66.2% of ZNS-treated patients and 12.3% of placebo-treated patients considered their condition improved; similarly, physicians assessed 63.6% of ZNS-treated patients and 10.8% of placebo-treated patients as improved. The most frequently reported adverse events with ZNS treatment included somnolence, irritability, dizziness, nausea, and fatigue.
Conclusions: As adjunctive treatment, ZNS was generally well tolerated and significantly improved seizure control among patients with refractory partial seizures.
Zonisamide (ZNS, 1,2-benzisoxazole-3-methane-sulfonamide) is a relatively new antiepileptic drug (AED) with multiple mechanisms of action, including blockage of voltage-sensitive sodium channels (1) and voltage-dependent T-type calcium channels (2), blockage of potassium-evoked glutamate response (3), reduction of glutamate-mediated synaptic excitation (4), facilitation of dopaminergic (5) and serotonergic (6) neurotransmission, scavenging of hydroxyl and nitric oxide radicals (7,8), increasing γ-aminobutyric acid (GABA) release from the hippocampus (9,10), and weak inhibition of carbonic anhydrase (11). Such mechanisms suggest that ZNS is a broad-spectrum treatment for epilepsy. Early pilot and open-label studies conducted in the United States characterized ZNS as effective (12,13). Studies conducted in Europe and Japan have confirmed the safety and efficacy of ZNS at dosages of 400 to 500 mg, administered once or twice daily (14,15). In addition, these studies have shown ZNS to be effective at the recommended starting dosage (100 mg/d). The second of two placebo-controlled clinical trials in the United States has shown that ZNS is both effective and well tolerated as an adjunctive treatment for refractory partial seizures (16).
This report presents data from the first of two placebo-controlled trials conducted in the United States. The study was a randomized, multicenter, double-blind trial examining the efficacy, safety, and tolerability of ZNS as an adjunctive treatment for refractory partial seizures at dosages of 400 to 600 mg/d.
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Results from this study confirm that ZNS improves seizure control in adults with partial seizures. As observed in the second pivotal United States, placebo-controlled study across all seizure categories, the decrease in seizure frequency seen with ZNS was significant relative to the slight increases or decreases seen with placebo (16). The second United States study showed a greater seizure frequency reduction in comparison with this study; however, this inconsistency is most likely related to protocol differences (i.e., length of time patients had been receiving treatment).
More than one fourth of patients qualified as responders to ZNS, compared with roughly one sixth of patients who responded to placebo treatment. Additionally, for complex partial seizures, responder rates were significantly greater in the ZNS group than in the placebo group. Although responder rates did not significantly differ between the ZNS and placebo groups for all partial seizures and all seizures, a greater numeric trend toward higher responder rates was noted in the ZNS group than in the placebo group, and p values for these categories (0.1141 for all partial seizures and 0.0796 for all seizures) were low, approaching statistical significance.
As further evidence of efficacy, most (66.2%) patients who received ZNS assessed their condition as markedly or slightly improved, compared with only 12.3% of placebo-treated patients. Physician ratings of the ZNS and placebo groups were similar to patient ratings.
These efficacy findings are consistent with those published earlier (12–14,16). In an open-label, historical-controlled study, for all partial seizures, a ZNS dosage of 500 mg/d was observed to yield a 52% reduction in seizure frequency and a responder rate of 41% (13). A European trial that used the same protocol as that in this study found that ZNS administered at a dosage of ∼7 mg/kg/d produced a 40.5% decrease in the frequency of all partial seizures, compared with a 9.0% increase for placebo-treated patients (14). The second pivotal clinical trial conducted in the United States found that ZNS at a dosage of 400 mg/d reduced the frequency of all partial seizures by 38% and yielded a responder rate of 42% (16).
Although findings from the second United States pivotal study hint at correlations among ZNS dosage, ZNS plasma levels, and response to treatment (16), the current study provides no evidence to support such relations. However, this study was not specifically designed or powered to detect dose–response relations, and a more detailed study is warranted.
In general, ZNS treatment was well tolerated, with adverse effects most often involving functions of the CNS. In evaluating the data, one important consideration is that all patients were receiving, in addition to ZNS or placebo, other AEDs that were capable of producing a variety of adverse events. The most frequently reported adverse events associated with ZNS treatment included dizziness, irritability, nausea, fatigue, somnolence, and ataxia. These adverse events are common among patients receiving AEDs.
Although treatment-emergent adverse events seemed to be evenly distributed across mild, moderate, and severe classifications, the risk for severe adverse events was clearly associated with initiation of treatment at 7 mg/kg/d. A gradual introduction of ZNS over a 2- to 4-week period improved tolerability and reduced the occurrence of adverse events. Furthermore, another study that followed up patients over a period of 20 weeks showed that adverse effects reported in the first few weeks of ZNS treatment subside over time (16).
Notably, the mean body weight of ZNS-treated patients tended to decrease during the study, as the body weight of placebo-treated patients increased slightly. This trend toward weight loss in ZNS-treated patients could have advantages in overweight patients but would require monitoring in patients at risk for unwanted weight loss.
Overall, this study showed that ZNS is well tolerated in most patients and effective as adjunctive treatment of refractory partial seizures.