The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable 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)00246-4

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The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised control...

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: 1375 - 1386

Swansea University Author: Robert Powell

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DOI (Published version): 10.1016/s0140-6736(21)00246-4

Abstract

BackgroundValproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of...

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Published in:	The Lancet
ISSN:	0140-6736
Published:	Elsevier BV 2021
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URI:	https://cronfa.swan.ac.uk/Record/cronfa60619
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fullrecord	<?xml version="1.0"?><rfc1807><datestamp>2022-08-15T13:01:56.8667057</datestamp><bib-version>v2</bib-version><id>60619</id><entry>2022-07-25</entry><title>The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable 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>BackgroundValproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy.MethodsWe did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5–12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64).Findings520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0–94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 [95% CI 0·96–1·47]); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of −0·040 (95% central range −0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of £20 000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years.InterpretationCompared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate.</abstract><type>Journal Article</type><journal>The Lancet</journal><volume>397</volume><journalNumber>10282</journalNumber><paginationStart>1375</paginationStart><paginationEnd>1386</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)00246-4</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>2022-08-15T13:01:56.8667057</lastEdited><Created>2022-07-25T11:06:06.8142959</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	2022-08-15T13:01:56.8667057 v2 60619 2022-07-25 The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial 7c8ac48bb6ae4281930e4138f94a51b6 Robert Powell Robert Powell true false 2022-07-25 FGMHL BackgroundValproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy.MethodsWe did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5–12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64).Findings520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0–94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 [95% CI 0·96–1·47]); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of −0·040 (95% central range −0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of £20 000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years.InterpretationCompared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate. Journal Article The Lancet 397 10282 1375 1386 Elsevier BV 0140-6736 10 4 2021 2021-04-10 10.1016/s0140-6736(21)00246-4 COLLEGE NANME Medicine, Health and Life Science - Faculty COLLEGE CODE FGMHL Swansea University National Institute for Health Research Health Technology Assessment Programme. 2022-08-15T13:01:56.8667057 2022-07-25T11:06:06.8142959 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 60619__24920__3f4b43b010954ec49071a5d6106a49a5.pdf 60619.pdf 2022-08-15T13:00:48.3297818 Output 1260036 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 valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial
spellingShingle	The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable 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 valproate versus levetiracetam for newly diagnosed generalised and unclassifiable 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 valproate versus levetiracetam for newly diagnosed generalised and unclassifiable 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 valproate versus levetiracetam for newly diagnosed generalised and unclassifiable 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 valproate versus levetiracetam for newly diagnosed generalised and unclassifiable 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 valproate versus levetiracetam for newly diagnosed generalised and unclassifiable 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	1375
publishDate	2021
institution	Swansea University
issn	0140-6736
doi_str_mv	10.1016/s0140-6736(21)00246-4
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
active_str	0
description	BackgroundValproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy.MethodsWe did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5–12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64).Findings520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0–94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 [95% CI 0·96–1·47]); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of −0·040 (95% central range −0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of £20 000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years.InterpretationCompared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate.
published_date	2021-04-10T04:18:52Z
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score	11.016614

The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised control...

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