View in EDS

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.

Saved in:
Bibliographic Details
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.
Authors: Marson, Anthony (AUTHOR), Burnside, Girvan (AUTHOR), Appleton, Richard (AUTHOR), Smith, Dave (AUTHOR), Leach, John Paul (AUTHOR), Sills, Graeme (AUTHOR), Tudur-Smith, Catrin (AUTHOR), Plumpton, Catrin (AUTHOR), Hughes, Dyfrig A (AUTHOR), Williamson, Paula (AUTHOR), Baker, Gus A (AUTHOR), Balabanova, Silviya (AUTHOR), Taylor, Claire (AUTHOR), Brown, Richard (AUTHOR), Hindley, Dan (AUTHOR), Howell, Stephen (AUTHOR), Maguire, Melissa (AUTHOR), Mohanraj, Rajiv (AUTHOR), Smith, Philip E (AUTHOR), SANAD II collaborators (CORPORATE AUTHOR)
Source: Lancet. 4/10/2021, Vol. 397 Issue 10282, p1375-1386. 12p.
Subjects: Valproic acid, Anticonvulsants, National Institute for Health Research (Great Britain), Cost effectiveness, Technology assessment, Epilepsy, Medical technology, Levetiracetam, Research, Research methodology, Medical cooperation, Evaluation research, Comparative studies, Randomized controlled trials
Abstract: Background: Valproate 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.Methods: We 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).Findings: 520 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.Interpretation: Compared 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.Funding: National Institute for Health Research Health Technology Assessment Programme. [ABSTRACT FROM AUTHOR]
Copyright of Lancet is the property of Lancet and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
FullText Text:
  Availability: 0
Header DbId: pbh
DbLabel: Psychology and Behavioral Sciences Collection
An: 149762980
AccessLevel: 6
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 0
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: 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.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Marson%2C+Anthony%22">Marson, Anthony</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Burnside%2C+Girvan%22">Burnside, Girvan</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Appleton%2C+Richard%22">Appleton, Richard</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Smith%2C+Dave%22">Smith, Dave</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Leach%2C+John+Paul%22">Leach, John Paul</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Sills%2C+Graeme%22">Sills, Graeme</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Tudur-Smith%2C+Catrin%22">Tudur-Smith, Catrin</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Plumpton%2C+Catrin%22">Plumpton, Catrin</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Hughes%2C+Dyfrig+A%22">Hughes, Dyfrig A</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Williamson%2C+Paula%22">Williamson, Paula</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Baker%2C+Gus+A%22">Baker, Gus A</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Balabanova%2C+Silviya%22">Balabanova, Silviya</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Taylor%2C+Claire%22">Taylor, Claire</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Brown%2C+Richard%22">Brown, Richard</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Hindley%2C+Dan%22">Hindley, Dan</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Howell%2C+Stephen%22">Howell, Stephen</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Maguire%2C+Melissa%22">Maguire, Melissa</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Mohanraj%2C+Rajiv%22">Mohanraj, Rajiv</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Smith%2C+Philip+E%22">Smith, Philip E</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22SANAD+II+collaborators%22">SANAD II collaborators</searchLink> (CORPORATE AUTHOR)
– Name: TitleSource
  Label: Source
  Group: Src
  Data: <searchLink fieldCode="JN" term="%22Lancet%22">Lancet</searchLink>. 4/10/2021, Vol. 397 Issue 10282, p1375-1386. 12p.
– Name: Subject
  Label: Subjects
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Valproic+acid%22">Valproic acid</searchLink><br /><searchLink fieldCode="DE" term="%22Anticonvulsants%22">Anticonvulsants</searchLink><br /><searchLink fieldCode="DE" term="%22National+Institute+for+Health+Research+%28Great+Britain%29%22">National Institute for Health Research (Great Britain)</searchLink><br /><searchLink fieldCode="DE" term="%22Cost+effectiveness%22">Cost effectiveness</searchLink><br /><searchLink fieldCode="DE" term="%22Technology+assessment%22">Technology assessment</searchLink><br /><searchLink fieldCode="DE" term="%22Epilepsy%22">Epilepsy</searchLink><br /><searchLink fieldCode="DE" term="%22Medical+technology%22">Medical technology</searchLink><br /><searchLink fieldCode="DE" term="%22Levetiracetam%22">Levetiracetam</searchLink><br /><searchLink fieldCode="DE" term="%22Research%22">Research</searchLink><br /><searchLink fieldCode="DE" term="%22Research+methodology%22">Research methodology</searchLink><br /><searchLink fieldCode="DE" term="%22Medical+cooperation%22">Medical cooperation</searchLink><br /><searchLink fieldCode="DE" term="%22Evaluation+research%22">Evaluation research</searchLink><br /><searchLink fieldCode="DE" term="%22Comparative+studies%22">Comparative studies</searchLink><br /><searchLink fieldCode="DE" term="%22Randomized+controlled+trials%22">Randomized controlled trials</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: <bold>Background: </bold>Valproate 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.<bold>Methods: </bold>We 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).<bold>Findings: </bold>520 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.<bold>Interpretation: </bold>Compared 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.<bold>Funding: </bold>National Institute for Health Research Health Technology Assessment Programme. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Lancet is the property of Lancet and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=149762980
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1016/S0140-6736(21)00246-4
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 12
        StartPage: 1375
    Subjects:
      – SubjectFull: Valproic acid
        Type: general
      – SubjectFull: Anticonvulsants
        Type: general
      – SubjectFull: National Institute for Health Research (Great Britain)
        Type: general
      – SubjectFull: Cost effectiveness
        Type: general
      – SubjectFull: Technology assessment
        Type: general
      – SubjectFull: Epilepsy
        Type: general
      – SubjectFull: Medical technology
        Type: general
      – SubjectFull: Levetiracetam
        Type: general
      – SubjectFull: Research
        Type: general
      – SubjectFull: Research methodology
        Type: general
      – SubjectFull: Medical cooperation
        Type: general
      – SubjectFull: Evaluation research
        Type: general
      – SubjectFull: Comparative studies
        Type: general
      – SubjectFull: Randomized controlled trials
        Type: general
    Titles:
      – TitleFull: 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.
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Marson, Anthony
      – PersonEntity:
          Name:
            NameFull: Burnside, Girvan
      – PersonEntity:
          Name:
            NameFull: Appleton, Richard
      – PersonEntity:
          Name:
            NameFull: Smith, Dave
      – PersonEntity:
          Name:
            NameFull: Leach, John Paul
      – PersonEntity:
          Name:
            NameFull: Sills, Graeme
      – PersonEntity:
          Name:
            NameFull: Tudur-Smith, Catrin
      – PersonEntity:
          Name:
            NameFull: Plumpton, Catrin
      – PersonEntity:
          Name:
            NameFull: Hughes, Dyfrig A
      – PersonEntity:
          Name:
            NameFull: Williamson, Paula
      – PersonEntity:
          Name:
            NameFull: Baker, Gus A
      – PersonEntity:
          Name:
            NameFull: Balabanova, Silviya
      – PersonEntity:
          Name:
            NameFull: Taylor, Claire
      – PersonEntity:
          Name:
            NameFull: Brown, Richard
      – PersonEntity:
          Name:
            NameFull: Hindley, Dan
      – PersonEntity:
          Name:
            NameFull: Howell, Stephen
      – PersonEntity:
          Name:
            NameFull: Maguire, Melissa
      – PersonEntity:
          Name:
            NameFull: Mohanraj, Rajiv
      – PersonEntity:
          Name:
            NameFull: Smith, Philip E
      – PersonEntity:
          Name:
            NameFull: SANAD II collaborators
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 10
              M: 04
              Text: 4/10/2021
              Type: published
              Y: 2021
          Identifiers:
            – Type: issn-print
              Value: 01406736
          Numbering:
            – Type: volume
              Value: 397
            – Type: issue
              Value: 10282
          Titles:
            – TitleFull: Lancet
              Type: main
ResultId 1