英国利物浦大学Anthony Marson团队比较了左乙拉西坦、唑尼沙胺或拉莫三嗪治疗新诊断局灶性癫痫的有效性和成本-效益。2021年4月10日，《柳叶刀》杂志发表了该研究。

左乙拉西坦和唑尼沙胺可作为局灶性癫痫患者的单一疗法，但由于没有足够的临床疗效和成本效益证据，是否应推荐作为一线治疗尚不确定。为了评估左乙拉西坦和唑尼沙胺与拉莫三嗪对新诊断的局灶性癫痫患者的长期临床疗效和成本-效益，研究组进行了一项随机开放对照试验。

研究组在英国成人和儿科神经内科招募年龄在5岁及以上（没有年龄上限）、有两次及以上无故局灶性癫痫发作的参与者，将其按1：1：1随机分组，分别接受拉莫三嗪、左乙拉西坦或唑尼沙胺治疗。评估左乙拉西坦和唑尼沙胺对拉莫三嗪在12个月缓解疗效的非劣效性。非劣效性限值为1.329，相当于10%的绝对差异。

2013年5月2日至2017年6月20日，研究组共招募了990名参与者，并进行了2年的随访。随机分组后，拉莫三嗪组330例，左乙拉西坦组332例，唑尼沙胺组328例。意向治疗（ITT）分析包括所有参与者，按方案（PP）分析包括拉莫三嗪组的324名参与者、左乙拉西坦组的320名参与者和唑尼沙胺组的315名参与者。

左乙拉西坦与拉莫三嗪在12个月缓解时间的ITT分析中不符合非劣效性标准，但唑尼沙胺与拉莫三嗪在ITT分析中符合非劣效性标准。PP分析显示，拉莫三嗪治疗12个月的缓解率优于左乙拉西坦和唑尼沙胺。试验中共有37人死亡。拉莫三嗪组中有108名（33%）受试者报告了不良反应，左乙拉西坦组中有144名（44%），唑尼沙胺组有146名（45%）。拉莫三嗪在成本效用分析中更优，其净健康效益为1.403 QALY，高于左乙拉西坦的1.222和唑尼沙胺的1.232，每个QALY的成本效益阈值为2万英镑。成本效益基于治疗组在成本和QALY方面的差异。

该研究结果不支持左乙拉西坦或唑尼沙胺作为局灶性癫痫患者的一线治疗。拉莫三嗪仍应是局灶性癫痫患者的一线治疗药物，并应成为未来试验的标准治疗药物。

附：英文原文

Title: The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Author: Anthony Marson, Girvan Burnside, Richard Appleton, Dave Smith, John Paul Leach, Graeme Sills, Catrin Tudur-Smith, Catrin Plumpton, Dyfrig A Hughes, Paula Williamson, Gus A Baker, Silviya Balabanova, Claire Taylor, Richard Brown, Dan Hindley, Stephen Howell, Melissa Maguire, Rajiv Mohanraj, Philip E Smith, Karen Lanyon, Mark Manford, Manali Chitre, Alasdair Parker, Nina Swiderska, Richard Appleton, James Pauling, Adrian Hughes, Rajat Gupta, Sadia Hanif, Mostafa Awadh, Sharmini Ragunathan, Nicola Cable, Paul Cooper, Daniel Hindley, Karl Rakshi, Sophie Molloy, Markus Reuber, Kunle Ayonrinde, Martin Wilson, Satyanarayana Saladi, John Gibb, Lesley-Ann Funston, Damhait Cassidy, Jonathan Boyd, Mal Ratnayaka, Hani Faza, Martin Sadler, Hassan Al-Moasseb, Clare Galtrey, Damien Wren, Anas Olabi, Geraint Fuller, Muhammed Khan, Chetana Kallappa, Ravi Chinthapalli, Baba Aji, Rhys Davies, Kathryn Foster, Nikolas Hitiris, Melissa Maguire, Nahin Hussain, Simon Dowson, Julie Ellison, Basil Sharrack, Vandna Gandhi, Rob Powell, Phil Tittensor, Beatrice Summers, Sastry Shashikiran, Penelope J Dison, Shanika Samarasekera, Doug McCorry, Kathleen White, Kannan Nithi, Martin Richardson, Richard Brown, Rupert Page, David Deekollu, Sean Slaght, Stephen Warriner, Mansoor Ahmed, Abhijit Chaudhuri, Gabriel Chow, Javier Artal, Danute Kucinskiene, Harish Sreenivasa, Singara Velmurugan,, Christos S Zipitis, Brendan McLean, Vaithianathar Lal, Angelous Gregoriou, Paul Maddison, Trevor Pickersgill, Joseph Anderson, Charlotte Lawthom, Stephen Howell, Gabriel Whitlingum, Wojtek Rakowicz, Lucy Kinton, Alisa McLellan, Nitish Vora, Sameer Zuberi, Andrew Kelso, Imelda Hughes, John Martland, Hedley Emsley, Christian de Goede, RP Singh, Carl-Christian Moor, Julia Aram, Rajiv Mohanraj, Kumar Sakthivel, Suresh Nelapatla, Chris Rittey, Ashwin Pinto, John Paul Leach, Hannah Cock, Anna Richardson, Erika Houston, Christopher Cooper, Geoff Lawson, Albert Massarano, Christine Burness, Anthony Marson, Dave Smith, Udo Wieshmann, Indranil Dey, Puthuval Sivakumar, Lap-Kong Yeung, Philip Smith

Issue&Volume: 2021/04/10

Abstract:

Background

Levetiracetam and zonisamide are licensed as monotherapy for patients with focal epilepsy, but there is uncertainty as to whether they should be recommended as first-line treatments because of insufficient evidence of clinical effectiveness and cost-effectiveness. We aimed to assess the long-term clinical effectiveness and cost-effectiveness of levetiracetam and zonisamide compared with lamotrigine in people with newly diagnosed focal epilepsy.

Methods

This randomised, open-label, controlled trial compared levetiracetam and zonisamide with lamotrigine as first-line treatment for patients with newly diagnosed focal epilepsy. Adult and paediatric neurology services across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked focal seizures. Participants were randomly allocated (1:1:1) using a minimisation programme with a random element utilising factor to receive lamotrigine, levetiracetam, or zonisamide. Participants and investigators were not masked and were aware of treatment allocation. SANAD II was designed to assess non-inferiority of both levetiracetam and zonisamide to lamotrigine for the primary outcome of time to 12-month remission. Anti-seizure medications were taken orally and for participants aged 12 years or older the initial advised maintenance doses were lamotrigine 50 mg (morning) and 100 mg (evening), levetiracetam 500 mg twice per day, and zonisamide 100 mg twice per day. For children aged between 5 and 12 years the initial daily maintenance doses advised were lamotrigine 1·5 mg/kg twice per day, levetiracetam 20 mg/kg twice per day, and zonisamide 2·5 mg/kg twice per day. All participants were included in the intention-to-treat (ITT) analysis. The per-protocol (PP) analysis excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analysis included all participants who received one dose of any study drug. The non-inferiority limit was a hazard ratio (HR) of 1·329, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on lamotrigine. The trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64).

Findings

990 participants were recruited between May 2, 2013, and June 20, 2017, and followed up for a further 2 years. Patients were randomly assigned to receive lamotrigine (n=330), levetiracetam (n=332), or zonisamide (n=328). The ITT analysis included all participants and the PP analysis included 324 participants randomly assigned to lamotrigine, 320 participants randomly assigned to levetiracetam, and 315 participants randomly assigned to zonisamide. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission versus lamotrigine (HR 1·18; 97·5% CI 0·95–1·47) but zonisamide did meet the criteria for non-inferiority in the ITT analysis versus lamotrigine (1·03; 0·83–1·28). The PP analysis showed that 12-month remission was superior with lamotrigine than both levetiracetam (HR 1·32 [97·5% CI 1·05 to 1·66]) and zonisamide (HR 1·37 [1·08–1·73]). There were 37 deaths during the trial. Adverse reactions were reported by 108 (33%) participants who started lamotrigine, 144 (44%) participants who started levetiracetam, and 146 (45%) participants who started zonisamide. Lamotrigine was superior in the cost-utility analysis, with a higher net health benefit of 1·403 QALYs (97·5% central range 1·319–1·458) compared with 1·222 (1·110–1·283) for levetiracetam and 1·232 (1·112, 1·307) for zonisamide at a cost-effectiveness threshold of ￡20000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs.

Interpretation

These findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy. Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials.

DOI: 10.1016/S0140-6736(21)00247-6

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00247-6/fulltext