Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
Department of Health Data Science, University of Liverpool, Liverpool, UK.
Health Technol Assess. 2021 Dec;25(75):1-134. doi: 10.3310/hta25750.
Levetiracetam (Keppra, UCB Pharma Ltd, Slough, UK) and zonisamide (Zonegran, Eisai Co. Ltd, Tokyo, Japan) are licensed as monotherapy for focal epilepsy, and levetiracetam is increasingly used as a first-line treatment for generalised epilepsy, particularly for women of childbearing age. However, there is uncertainty as to whether or not they should be recommended as first-line treatments owing to a lack of evidence of clinical effectiveness and cost-effectiveness.
To compare the clinical effectiveness and cost-effectiveness of lamotrigine (Lamictal, GlaxoSmithKline plc, Brentford, UK) (standard treatment) with levetiracetam and zonisamide (new treatments) for focal epilepsy, and to compare valproate (Epilim, Sanofi SA, Paris, France) (standard treatment) with levetiracetam (new treatment) for generalised and unclassified epilepsy.
Two pragmatic randomised unblinded non-inferiority trials run in parallel.
Outpatient services in NHS hospitals throughout the UK.
Those aged ≥ 5 years with two or more spontaneous seizures that require anti-seizure medication.
Participants with focal epilepsy were randomised to receive lamotrigine, levetiracetam or zonisamide. Participants with generalised or unclassifiable epilepsy were randomised to receive valproate or levetiracetam. The randomisation method was minimisation using a web-based program.
The primary outcome was time to 12-month remission from seizures. For this outcome, and all other time-to-event outcomes, we report hazard ratios for the standard treatment compared with the new treatment. For the focal epilepsy trial, the non-inferiority limit (lamotrigine vs. new treatments) was 1.329. For the generalised and unclassified epilepsy trial, the non-inferiority limit (valproate vs. new treatments) was 1.314. Secondary outcomes included time to treatment failure, time to first seizure, time to 24-month remission, adverse reactions, quality of life and cost-effectiveness.
. A total of 990 participants were recruited, of whom 330 were randomised to receive lamotrigine, 332 were randomised to receive levetiracetam and 328 were randomised to receive zonisamide. Levetiracetam did not meet the criteria for non-inferiority (hazard ratio 1.329) in the primary intention-to-treat analysis of time to 12-month remission (hazard ratio vs. lamotrigine 1.18, 97.5% confidence interval 0.95 to 1.47), but zonisamide did meet the criteria (hazard ratio vs. lamotrigine 1.03, 97.5% confidence interval 0.83 to 1.28). In the per-protocol analysis, lamotrigine was superior to both levetiracetam (hazard ratio 1.32, 95% confidence interval 1.05 to 1.66) and zonisamide (hazard ratio 1.37, 95% confidence interval 1.08 to 1.73). For time to treatment failure, lamotrigine was superior to levetiracetam (hazard ratio 0.60, 95% confidence interval 0.46 to 0.77) and zonisamide (hazard ratio 0.46, 95% confidence interval 0.36 to 0.60). Adverse reactions were reported by 33% of participants starting lamotrigine, 44% starting levetiracetam and 45% starting zonisamide. In the economic analysis, both levetiracetam and zonisamide were more costly and less effective than lamotrigine and were therefore dominated. . Of 520 patients recruited, 260 were randomised to receive valproate and 260 were randomised to receive to levetiracetam. A total of 397 patients had generalised epilepsy and 123 had unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the primary intention-to-treat analysis of time to 12-month remission (hazard ratio 1.19, 95% confidence interval 0.96 to 1.47; non-inferiority margin 1.314). In the per-protocol analysis of time to 12-month remission, valproate was superior to levetiracetam (hazard ratio 1.68, 95% confidence interval 1.30 to 2.15). Valproate was superior to levetiracetam for time to treatment failure (hazard ratio 0.65, 95% confidence interval 0.50 to 0.83). Adverse reactions were reported by 37.4% of participants receiving valproate and 41.5% of those receiving levetiracetam. Levetiracetam was both more costly (incremental cost of £104, 95% central range -£587 to £1234) and less effective (incremental quality-adjusted life-year of -0.035, 95% central range -0.137 to 0.032) than valproate, and was therefore dominated. At a cost-effectiveness threshold of £20,000 per quality-adjusted life-year, levetiracetam was associated with a probability of 0.17 of being cost-effective.
The SANAD II trial was unblinded, which could have biased results by influencing decisions about dosing, treatment failure and the attribution of adverse reactions.
SANAD II data could now be included in an individual participant meta-analysis of similar trials, and future similar trials are required to assess the clinical effectiveness and cost-effectiveness of other new treatments, including lacosamide and perampanel.
Current Controlled Trials ISRCTN30294119 and EudraCT 2012-001884-64.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 75. See the NIHR Journals Library website for further project information.
左乙拉西坦（开浦兰，UCB 制药公司，英国斯劳）和唑尼沙胺（Zonegran，卫材公司，日本东京）被批准为局灶性癫痫的单药治疗药物，左乙拉西坦越来越多地被用作全面性癫痫的一线治疗药物，特别是对于育龄期妇女。然而，由于缺乏临床有效性和成本效益的证据，尚不确定是否应推荐它们作为一线治疗药物。
比较拉莫三嗪（Lamictal，葛兰素史克公司，英国布伦特福德）（标准治疗）与左乙拉西坦和唑尼沙胺（新治疗）治疗局灶性癫痫的临床疗效和成本效益，以及比较丙戊酸钠（Epilim，赛诺菲公司，法国巴黎）（标准治疗）与左乙拉西坦（新治疗）治疗全面性和未分类性癫痫的临床疗效和成本效益。
两项实用随机非盲非劣效性平行试验。
英国国民保健署医院的门诊服务。
年龄≥5 岁、需要抗癫痫药物治疗的有两次或两次以上自发性发作的患者。
局灶性癫痫患者随机接受拉莫三嗪、左乙拉西坦或唑尼沙胺治疗。全面性或未分类性癫痫患者随机接受丙戊酸钠或左乙拉西坦治疗。随机化方法是使用基于网络的程序进行最小化。
主要结局是 12 个月抗癫痫治疗的缓解时间。对于该结局和所有其他时间到事件结局，我们报告了标准治疗与新治疗相比的危险比。对于局灶性癫痫试验，非劣效性限（拉莫三嗪与新治疗）为 1.329。对于全面性和未分类性癫痫试验，非劣效性限（丙戊酸钠与新治疗）为 1.314。次要结局包括治疗失败时间、首次发作时间、24 个月缓解时间、不良反应、生活质量和成本效益。
共招募了 990 名参与者，其中 330 名随机接受拉莫三嗪治疗，332 名随机接受左乙拉西坦治疗，328 名随机接受唑尼沙胺治疗。左乙拉西坦在主要意向治疗分析的 12 个月缓解时间中未达到非劣效性标准（与拉莫三嗪相比的危险比 1.329，97.5%置信区间 0.95 至 1.47），但唑尼沙胺达到了标准（与拉莫三嗪相比的危险比 1.03，97.5%置信区间 0.83 至 1.28）。在符合方案分析中，拉莫三嗪优于左乙拉西坦（危险比 1.32，95%置信区间 1.05 至 1.66）和唑尼沙胺（危险比 1.37，95%置信区间 1.08 至 1.73）。在治疗失败时间方面，拉莫三嗪优于左乙拉西坦（危险比 0.60，95%置信区间 0.46 至 0.77）和唑尼沙胺（危险比 0.46，95%置信区间 0.36 至 0.60）。33%开始拉莫三嗪治疗的患者、44%开始左乙拉西坦治疗的患者和 45%开始唑尼沙胺治疗的患者报告了不良反应。在经济性分析中，左乙拉西坦和唑尼沙胺均比拉莫三嗪成本更高，效果更差，因此被排除。在 520 名招募的患者中，260 名随机接受丙戊酸钠治疗，260 名随机接受左乙拉西坦治疗。397 名患者患有全面性癫痫，123 名患者患有未分类性癫痫。左乙拉西坦在主要意向治疗分析的 12 个月缓解时间中未达到非劣效性标准（危险比 1.19，95%置信区间 0.96 至 1.47；非劣效性边界 1.314）。在 12 个月缓解时间的符合方案分析中，丙戊酸钠优于左乙拉西坦（危险比 1.68，95%置信区间 1.30 至 2.15）。丙戊酸钠在治疗失败时间方面优于左乙拉西坦（危险比 0.65，95%置信区间 0.50 至 0.83）。37.4%接受丙戊酸钠治疗的患者和 41.5%接受左乙拉西坦治疗的患者报告了不良反应。左乙拉西坦的成本更高（增量成本为 104 英镑，95%置信区间下限为-587 英镑至 1234 英镑），效果更差（增量质量调整生命年为-0.035，95%置信区间下限为-0.137 至 0.032），因此被排除。在成本效益阈值为每质量调整生命年 20000 英镑时，左乙拉西坦的成本效益概率为 0.17。
SANAD II 试验未设盲，这可能通过影响剂量、治疗失败和不良反应归因的决策而影响结果。
现在可以将 SANAD II 数据纳入类似试验的个体参与者荟萃分析中，未来还需要开展类似的试验，以评估其他新治疗药物（如拉科酰胺和吡仑帕奈）的临床疗效和成本效益。
-SANAD II 研究结果不支持左乙拉西坦或唑尼沙胺作为局灶性癫痫的一线治疗药物。-SANAD II 研究结果不支持将左乙拉西坦作为新诊断的全面性癫痫的一线治疗药物。对于有生育能力的女性，这些结果告知了关于左乙拉西坦（与丙戊酸钠相比，较低的致畸性）与丙戊酸钠（较差的癫痫发作结局和更高的治疗失败率）的益处和危害的讨论。
当前对照试验 ISRCTN30294119 和 EudraCT 2012-001884-64。
本项目由英国国家卫生研究院（NIHR）卫生技术评估计划资助，将在 ; 第 25 卷，第 75 期。有关该项目的进一步信息，请参见 NIHR 期刊库网站。
