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

Abstract

Summary 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 lamot...

Efficacy and tolerability of antiseizure drugs

“… 41 The SANAD II (2021) has shown that lamotrigine was superior to levetiracetam and zonisamide for time to 12-month remission and should remain the first-line treatment in patients with new-onset focal epilepsy and should be the standard treatment in future trials as an alternative to carbamazepine. 74 Kwan and Brodie also found that pregabalin has similar tolerability but seems to have inferior efficacy to lamotrigine for the treatment of new-onset focal epilepsy. 75 In patients with new-onset generalized and unclassified epilepsy, the SANAD (2007) has shown that valproate is better tolerated than topiramate and more effective than lamotrigine, 42 whereas the SANAD II (2021) has suggested that levetiracetam is inferior to valproate for time to 12-month remission.…”

“…Table 2 in this article presents the efficacy of ASDs against common seizure types and epilepsy syndrome. Data in Table 2 are based largely on the results of RCTs comparing the newer versus older drugs including the SANAD studies, 41 , 42 , 43 , 74 and others. 57 , 59 – 62 , 64 , 67 , 69 , 71 , 73 , 75 – 88 Table 3 and the remainder sections of this articles present guidance for ASD selection for different seizure types and epilepsy syndromes according to the 2017 ILAE classification.…”

Neuropharmacology of Antiseizure Drugs

“…Table 3 presents the efficacy of ASDs against common seizure types and epilepsy syndrome. The data supplemented in the table are based primarily on the results of RCTs comparing the newer versus older drugs, including the SANAD studies 34‐37 and others, 38‐62 and recently published meta‐analyses 63‐69 . Table 4 and the remainder sections of this article present guidance for ASD selection for the specific seizure type according to the 2017 ILAE classification of seizure types and epilepsy syndromes 14‐17 .…”

“…Focal‐onset seizures account for 60% of all epilepsies. The RCTs and meta‐analyses have demonstrated comparable efficacy of several ASDs in controlling new‐onset focal seizures 22,34,37‐44,46,58,62‐64,72,77‐83 . The drug of the first choice for “focal” and “focal to bilateral” (secondarily generalized) tonic‐clonic seizures is lamotrigine 22,34,37 .…”

“…The RCTs and meta‐analyses have demonstrated comparable efficacy of several ASDs in controlling new‐onset focal seizures 22,34,37‐44,46,58,62‐64,72,77‐83 . The drug of the first choice for “focal” and “focal to bilateral” (secondarily generalized) tonic‐clonic seizures is lamotrigine 22,34,37 . Phenytoin is the drug of choice for the urgent treatment of new‐onset or recurrent focal epilepsy.…”