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

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

doi:10.1016/s0140-6736(21)00247-6

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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

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, 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, Hemalata Bentur, Tom Heafield, Anna Mathew, David Smith, Praveen Jauhari, Robert Powell

The Lancet, Volume: 397, Issue: 10282, Pages: 1363 - 1374

Swansea University Author: Robert Powell

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DOI (Published version): 10.1016/s0140-6736(21)00247-6

Abstract

BackgroundLevetiracetam 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 lo...

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ISSN:	0140-6736
Published:	Elsevier BV 2021
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fullrecord	<?xml version="1.0"?><rfc1807><datestamp>2022-08-15T12:37:27.1870662</datestamp><bib-version>v2</bib-version><id>60621</id><entry>2022-07-25</entry><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</title><swanseaauthors><author><sid>7c8ac48bb6ae4281930e4138f94a51b6</sid><firstname>Robert</firstname><surname>Powell</surname><name>Robert Powell</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2022-07-25</date><deptcode>FGMHL</deptcode><abstract>BackgroundLevetiracetam 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.MethodsThis 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).Findings990 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 £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs.InterpretationThese 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.</abstract><type>Journal Article</type><journal>The Lancet</journal><volume>397</volume><journalNumber>10282</journalNumber><paginationStart>1363</paginationStart><paginationEnd>1374</paginationEnd><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0140-6736</issnPrint><issnElectronic/><keywords/><publishedDay>10</publishedDay><publishedMonth>4</publishedMonth><publishedYear>2021</publishedYear><publishedDate>2021-04-10</publishedDate><doi>10.1016/s0140-6736(21)00247-6</doi><url/><notes/><college>COLLEGE NANME</college><department>Medicine, Health and Life Science - Faculty</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>FGMHL</DepartmentCode><institution>Swansea University</institution><apcterm/><funders>National Institute for Health Research Health Technology Assessment programme.</funders><projectreference/><lastEdited>2022-08-15T12:37:27.1870662</lastEdited><Created>2022-07-25T11:10:49.9569842</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Anthony</firstname><surname>Marson</surname><order>1</order></author><author><firstname>Girvan</firstname><surname>Burnside</surname><order>2</order></author><author><firstname>Richard</firstname><surname>Appleton</surname><order>3</order></author><author><firstname>Dave</firstname><surname>Smith</surname><order>4</order></author><author><firstname>John Paul</firstname><surname>Leach</surname><order>5</order></author><author><firstname>Graeme</firstname><surname>Sills</surname><order>6</order></author><author><firstname>Catrin</firstname><surname>Tudur-Smith</surname><order>7</order></author><author><firstname>Catrin</firstname><surname>Plumpton</surname><order>8</order></author><author><firstname>Dyfrig A</firstname><surname>Hughes</surname><order>9</order></author><author><firstname>Paula</firstname><surname>Williamson</surname><order>10</order></author><author><firstname>Gus A</firstname><surname>Baker</surname><order>11</order></author><author><firstname>Silviya</firstname><surname>Balabanova</surname><order>12</order></author><author><firstname>Claire</firstname><surname>Taylor</surname><order>13</order></author><author><firstname>Richard</firstname><surname>Brown</surname><order>14</order></author><author><firstname>Dan</firstname><surname>Hindley</surname><order>15</order></author><author><firstname>Stephen</firstname><surname>Howell</surname><order>16</order></author><author><firstname>Melissa</firstname><surname>Maguire</surname><order>17</order></author><author><firstname>Rajiv</firstname><surname>Mohanraj</surname><order>18</order></author><author><firstname>Philip E</firstname><surname>Smith</surname><order>19</order></author><author><firstname>Karen</firstname><surname>Lanyon</surname><order>20</order></author><author><firstname>Mark</firstname><surname>Manford</surname><order>21</order></author><author><firstname>Manali</firstname><surname>Chitre</surname><order>22</order></author><author><firstname>Alasdair</firstname><surname>Parker</surname><order>23</order></author><author><firstname>Nina</firstname><surname>Swiderska</surname><order>24</order></author><author><firstname>Richard</firstname><surname>Appleton</surname><order>25</order></author><author><firstname>James</firstname><surname>Pauling</surname><order>26</order></author><author><firstname>Adrian</firstname><surname>Hughes</surname><order>27</order></author><author><firstname>Rajat</firstname><surname>Gupta</surname><order>28</order></author><author><firstname>Sadia</firstname><surname>Hanif</surname><order>29</order></author><author><firstname>Mostafa</firstname><surname>Awadh</surname><order>30</order></author><author><firstname>Sharmini</firstname><surname>Ragunathan</surname><order>31</order></author><author><firstname>Nicola</firstname><surname>Cable</surname><order>32</order></author><author><firstname>Paul</firstname><surname>Cooper</surname><order>33</order></author><author><firstname>Daniel</firstname><surname>Hindley</surname><order>34</order></author><author><firstname>Karl</firstname><surname>Rakshi</surname><order>35</order></author><author><firstname>Sophie</firstname><surname>Molloy</surname><order>36</order></author><author><firstname>Markus</firstname><surname>Reuber</surname><order>37</order></author><author><firstname>Kunle</firstname><surname>Ayonrinde</surname><order>38</order></author><author><firstname>Martin</firstname><surname>Wilson</surname><order>39</order></author><author><firstname>Satyanarayana</firstname><surname>Saladi</surname><order>40</order></author><author><firstname>John</firstname><surname>Gibb</surname><order>41</order></author><author><firstname>Lesley-Ann</firstname><surname>Funston</surname><order>42</order></author><author><firstname>Damhait</firstname><surname>Cassidy</surname><order>43</order></author><author><firstname>Jonathan</firstname><surname>Boyd</surname><order>44</order></author><author><firstname>Mal</firstname><surname>Ratnayaka</surname><order>45</order></author><author><firstname>Hani</firstname><surname>Faza</surname><order>46</order></author><author><firstname>Martin</firstname><surname>Sadler</surname><order>47</order></author><author><firstname>Hassan</firstname><surname>Al-Moasseb</surname><order>48</order></author><author><firstname>Clare</firstname><surname>Galtrey</surname><order>49</order></author><author><firstname>Damien</firstname><surname>Wren</surname><order>50</order></author><author><firstname>Anas</firstname><surname>Olabi</surname><order>51</order></author><author><firstname>Geraint</firstname><surname>Fuller</surname><order>52</order></author><author><firstname>Muhammed</firstname><surname>Khan</surname><order>53</order></author><author><firstname>Chetana</firstname><surname>Kallappa</surname><order>54</order></author><author><firstname>Ravi</firstname><surname>Chinthapalli</surname><order>55</order></author><author><firstname>Baba</firstname><surname>Aji</surname><order>56</order></author><author><firstname>Rhys</firstname><surname>Davies</surname><order>57</order></author><author><firstname>Kathryn</firstname><surname>Foster</surname><order>58</order></author><author><firstname>Nikolas</firstname><surname>Hitiris</surname><order>59</order></author><author><firstname>Melissa</firstname><surname>Maguire</surname><order>60</order></author><author><firstname>Nahin</firstname><surname>Hussain</surname><order>61</order></author><author><firstname>Simon</firstname><surname>Dowson</surname><order>62</order></author><author><firstname>Julie</firstname><surname>Ellison</surname><order>63</order></author><author><firstname>Basil</firstname><surname>Sharrack</surname><order>64</order></author><author><firstname>Vandna</firstname><surname>Gandhi</surname><order>65</order></author><author><firstname>Rob</firstname><surname>Powell</surname><order>66</order></author><author><firstname>Phil</firstname><surname>Tittensor</surname><order>67</order></author><author><firstname>Beatrice</firstname><surname>Summers</surname><order>68</order></author><author><firstname>Sastry</firstname><surname>Shashikiran</surname><order>69</order></author><author><firstname>Penelope 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spelling	2022-08-15T12:37:27.1870662 v2 60621 2022-07-25 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 7c8ac48bb6ae4281930e4138f94a51b6 Robert Powell Robert Powell true false 2022-07-25 FGMHL BackgroundLevetiracetam 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.MethodsThis 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).Findings990 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 £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs.InterpretationThese 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. Journal Article The Lancet 397 10282 1363 1374 Elsevier BV 0140-6736 10 4 2021 2021-04-10 10.1016/s0140-6736(21)00247-6 COLLEGE NANME Medicine, Health and Life Science - Faculty COLLEGE CODE FGMHL Swansea University National Institute for Health Research Health Technology Assessment programme. 2022-08-15T12:37:27.1870662 2022-07-25T11:10:49.9569842 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Anthony Marson 1 Girvan Burnside 2 Richard Appleton 3 Dave Smith 4 John Paul Leach 5 Graeme Sills 6 Catrin Tudur-Smith 7 Catrin Plumpton 8 Dyfrig A Hughes 9 Paula Williamson 10 Gus A Baker 11 Silviya Balabanova 12 Claire Taylor 13 Richard Brown 14 Dan Hindley 15 Stephen Howell 16 Melissa Maguire 17 Rajiv Mohanraj 18 Philip E Smith 19 Karen Lanyon 20 Mark Manford 21 Manali Chitre 22 Alasdair Parker 23 Nina Swiderska 24 Richard Appleton 25 James Pauling 26 Adrian Hughes 27 Rajat Gupta 28 Sadia Hanif 29 Mostafa Awadh 30 Sharmini Ragunathan 31 Nicola Cable 32 Paul Cooper 33 Daniel Hindley 34 Karl Rakshi 35 Sophie Molloy 36 Markus Reuber 37 Kunle Ayonrinde 38 Martin Wilson 39 Satyanarayana Saladi 40 John Gibb 41 Lesley-Ann Funston 42 Damhait Cassidy 43 Jonathan Boyd 44 Mal Ratnayaka 45 Hani Faza 46 Martin Sadler 47 Hassan Al-Moasseb 48 Clare Galtrey 49 Damien Wren 50 Anas Olabi 51 Geraint Fuller 52 Muhammed Khan 53 Chetana Kallappa 54 Ravi Chinthapalli 55 Baba Aji 56 Rhys Davies 57 Kathryn Foster 58 Nikolas Hitiris 59 Melissa Maguire 60 Nahin Hussain 61 Simon Dowson 62 Julie Ellison 63 Basil Sharrack 64 Vandna Gandhi 65 Rob Powell 66 Phil Tittensor 67 Beatrice Summers 68 Sastry Shashikiran 69 Penelope J Dison 70 Shanika Samarasekera 71 Doug McCorry 72 Kathleen White 73 Kannan Nithi 74 Martin Richardson 75 Richard Brown 76 Rupert Page 77 David Deekollu 78 Sean Slaght 79 Stephen Warriner 80 Mansoor Ahmed 81 Abhijit Chaudhuri 82 Gabriel Chow 83 Javier Artal 84 Danute Kucinskiene 85 Harish Sreenivasa 86 Singara Velmurugan, 87 Christos S Zipitis 88 Brendan McLean 89 Vaithianathar Lal 90 Angelous Gregoriou 91 Paul Maddison 92 Trevor Pickersgill 93 Joseph Anderson 94 Charlotte Lawthom 95 Stephen Howell 96 Gabriel Whitlingum 97 Wojtek Rakowicz 98 Lucy Kinton 99 Alisa McLellan 100 Sameer Zuberi 101 Andrew Kelso 102 Imelda Hughes 103 John Martland 104 Hedley Emsley 105 Christian de Goede 106 RP Singh 107 Carl-Christian Moor 108 Julia Aram 109 Rajiv Mohanraj 110 Kumar Sakthivel 111 Suresh Nelapatla 112 Chris Rittey 113 Ashwin Pinto 114 John Paul Leach 115 Hannah Cock 116 Anna Richardson 117 Erika Houston 118 Christopher Cooper 119 Geoff Lawson 120 Albert Massarano 121 Christine Burness 122 Anthony Marson 123 Dave Smith 124 Udo Wieshmann 125 Indranil Dey 126 Puthuval Sivakumar 127 Lap-Kong Yeung 128 Philip Smith 129 Hemalata Bentur 130 Tom Heafield 131 Anna Mathew 132 David Smith 133 Praveen Jauhari 134 Robert Powell 135 60621__24916__394ca9f48899404a88c2bbd23a8d23d0.pdf 60621.pdf 2022-08-15T12:34:48.0536033 Output 1262727 application/pdf Version of Record true © 2021 The Author(s). This is an Open Access article under the CC BY 4.0 license. true eng https://creativecommons.org/licenses/by/4.0/
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
spellingShingle	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 Robert Powell
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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_id_str_mv	7c8ac48bb6ae4281930e4138f94a51b6
author_id_fullname_str_mv	7c8ac48bb6ae4281930e4138f94a51b6_***_Robert Powell
author	Robert Powell
author2	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 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 Hemalata Bentur Tom Heafield Anna Mathew David Smith Praveen Jauhari Robert Powell
format	Journal article
container_title	The Lancet
container_volume	397
container_issue	10282
container_start_page	1363
publishDate	2021
institution	Swansea University
issn	0140-6736
doi_str_mv	10.1016/s0140-6736(21)00247-6
publisher	Elsevier BV
college_str	Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id	facultyofmedicinehealthandlifesciences
hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id	facultyofmedicinehealthandlifesciences
hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str	1
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description	BackgroundLevetiracetam 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.MethodsThis 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).Findings990 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 £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs.InterpretationThese 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.
published_date	2021-04-10T04:18:53Z
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score	11.016614

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

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