Brigo Francesco, Lattanzi Simona, Igwe Stanley C, Behzadifar Masoud, Bragazzi Nicola Luigi
Department of Neurology, Franz Tappeiner Hospital, Merano, Italy.
Neurological Clinic, Marche Polytechnic University, Ancona, Italy.
Cochrane Database Syst Rev. 2020 Jul 24;7(7):CD001416. doi: 10.1002/14651858.CD001416.pub5.
The majority of people with epilepsy have a good prognosis, and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop dug-resistant epilepsy, especially those with focal seizures. In this review, we summarised the evidence from randomised controlled trials (RCT) of zonisamide, used as an add-on treatment for focal epilepsy uncontrolled by one or more concomitant antiepileptic drug. This is an updated version of the Cochrane review previously published in 2018.
To evaluate the efficacy and tolerability of zonisamide, when used as an add-on treatment for people with focal epilepsy uncontrolled by one or more concomitant antiepileptic drugs.
For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE Ovid (September 2019). In addition, we contacted Eisai Limited (makers and licensees of zonisamide) and experts in the field, to seek any ongoing or unpublished studies.
Randomised controlled trials, in which add-on zonisamide was compared with placebo or another antiepileptic drug in people with focal epilepsy, uncontrolled by one or more concomitant antiepileptic drugs.
Two review authors independently selected trials for inclusion, extracted data, assessed for risk of bias using the Cochrane 'Risk of bias' tool, and assessed the certainty of the evidence, using the GRADE approach. The primary outcome was at least a 50% reduction in total seizure frequency; the secondary outcomes were (1) tolerability; and (2) adverse effects. We used an intention-to-treat approach for our primary analyses. We estimated summary risk ratios (RRs) for each outcome. We displayed a summary of the estimates of effects and certainty of the evidence for each outcome in a 'Summary of findings' table.
We did not find any new studies since the last version of this review. We included eight studies (1636 participants) from previous versions of this review. The overall RR with 95% confidence interval (CI) for at least a 50% reduction in seizure frequency for 300 mg to 500 mg/day of zonisamide compared to placebo was 1.90 (95% CI 1.63 to 2.22; 7 trials, 1371 participants; moderate-certainty evidence). The RR for 50% reduction in seizure frequency compared to placebo for any dose of zonisamide (100 mg to 500 mg/day) was 1.86 (95% CI 1.60 to 2.17; 7 trials, 1429 participants; moderate-certainty evidence). The number needed to treat for an additional beneficial outcome was six (95% CI 4.1 to 6.8). Two trials provided evidence of a dose-response relationship for this outcome. The RR for treatment withdrawal for 300 mg to 500 mg/day of zonisamide compared to placebo was 1.59 (95% CI 1.18 to 2.13; 6 trials, 1099 participants; moderate-certainty evidence), and for 100 mg to 500 mg/day was 1.44 (95% CI 1.08 to 1.93; 6 trials, 1156 participants; moderate-certainty evidence). The number needed to treat for an additional harmful outcome was 15 (95% CI 9.3 to 36.7). The following adverse effects were more likely to be associated with zonisamide than with placebo: ataxia (RR 3.85, 99% CI 1.36 to 10.93; 4 trials, 734 participants; low-certainty evidence); somnolence (RR 1.52, 99% CI 1.00 to 2.31; 8 trials, 1636 participants; moderate-certainty evidence); agitation (RR 2.35, 99% CI 1.05 to 5.27; 4 trials, 598 participants; low-certainty evidence); and anorexia (RR 2.74, 99% CI 1.64 to 4.60; 6 trials, 1181 participants; low-certainty evidence). Across the eight studies, we rated risk of bias domains at low or unclear risk of bias, apart from two studies, which we rated at high risk of attrition bias. Five of the eight studies were sponsored by the drug companies that produced zonisamide.
AUTHORS' CONCLUSIONS: When used as an add-on treatment in people with focal epilepsy, uncontrolled by one or more concomitant antiepileptic drugs, moderate-certainty evidence found that zonisamide was more successful than placebo at reducing the frequency of seizures by at least 50%. We were unable to identify minimum effective and maximum tolerated doses. The included trials evaluated a maximum stable-dose phase of 18 weeks, so results cannot be used to confirm longer periods of efficacy in seizure control. The results cannot be extrapolated to monotherapy, or to people with other seizure types or epilepsy syndromes.
大多数癫痫患者预后良好，使用单一抗癫痫药物即可很好地控制癫痫发作，但高达30%的患者会发展为难治性癫痫，尤其是局灶性癫痫患者。在本综述中，我们总结了唑尼沙胺作为一种添加治疗药物，用于治疗一种或多种联合抗癫痫药物无法控制的局灶性癫痫的随机对照试验（RCT）证据。这是对先前于2018年发表的Cochrane综述的更新版本。
评估唑尼沙胺作为添加治疗药物，用于治疗一种或多种联合抗癫痫药物无法控制的局灶性癫痫患者的疗效和耐受性。
为了进行最新更新，我们检索了Cochrane研究注册库（CRS网络版）和MEDLINE Ovid（2019年9月）。此外，我们联系了唑尼沙胺的制造商和授权方卫材株式会社（Eisai Limited）以及该领域的专家，以查找任何正在进行或未发表的研究。
随机对照试验，其中将添加唑尼沙胺与安慰剂或另一种抗癫痫药物，用于治疗一种或多种联合抗癫痫药物无法控制的局灶性癫痫患者。
两位综述作者独立选择纳入试验，提取数据，使用Cochrane“偏倚风险”工具评估偏倚风险，并使用GRADE方法评估证据的确定性。主要结局是总癫痫发作频率至少降低50%；次要结局是（1）耐受性；（2）不良反应。我们对主要分析采用意向性分析方法。我们估计了每个结局的汇总风险比（RR）。我们在“结果总结”表中展示了每个结局的效应估计和证据确定性的总结。
自本综述的上一版本以来，我们未发现任何新的研究。我们纳入了本综述先前版本中的八项研究（1636名参与者）。与安慰剂相比，唑尼沙胺每日300毫克至500毫克时，癫痫发作频率至少降低50%的总体RR及95%置信区间（CI）为1.90（95%CI 1.63至2.22；7项试验，1371名参与者；中等确定性证据）。与安慰剂相比，任何剂量的唑尼沙胺（每日100毫克至500毫克）癫痫发作频率降低50%的RR为1.86（95%CI 1.60至2.17；7项试验，1429名参与者；中等确定性证据）。为获得额外有益结局所需治疗的人数为6（95%CI 4.1至6.8）。两项试验提供了该结局的剂量反应关系证据。与安慰剂相比，唑尼沙胺每日300毫克至500毫克时因治疗而停药的RR为1.59（95%CI 1.18至2.13；6项试验，1099名参与者；中等确定性证据），每日100毫克至500毫克时为1.44（95%CI 1.08至1.93；6项试验，1156名参与者；中等确定性证据）。为获得额外有害结局所需治疗的人数为15（95%CI 9.3至36.7）。以下不良反应与唑尼沙胺的关联比与安慰剂的关联更可能：共济失调（RR 3.85，99%CI 1.36至10.93；4项试验，734名参与者；低确定性证据）；嗜睡（RR 1.52，99%CI 1.00至2.31；8项试验，1636名参与者；中等确定性证据）；激越（RR 2.35，99%CI 1.05至5.27；4项试验，598名参与者；低确定性证据）；以及厌食（RR 2.74，99%CI 1.64至4.60；6项试验，1181名参与者；低确定性证据）。在八项研究中，除两项研究我们评定为高失访偏倚风险外，我们对偏倚风险领域评定为低或不清楚的偏倚风险。八项研究中有五项由生产唑尼沙胺的制药公司赞助。
当作为添加治疗药物用于一种或多种联合抗癫痫药物无法控制的局灶性癫痫患者时，中等确定性证据表明，唑尼沙胺在将癫痫发作频率至少降低50%方面比安慰剂更成功。我们无法确定最低有效剂量和最大耐受剂量。纳入的试验评估了最长18周的最大稳定剂量阶段，因此结果不能用于确认更长时间的癫痫控制疗效。结果不能外推至单药治疗，或其他癫痫发作类型或癫痫综合征的患者。
