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

Abstract

Summary 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 t...

Efficacy and tolerability of antiseizure drugs

“…For many years, carbamazepine was considered the first-line treatment for focal-onset seizures, and the standard treatment for focal epilepsy in clinical trials, whereas valproate, with its broad-spectrum efficacy, was, and still, recommended first-line treatment for generalized-onset and unclassified seizures. 8 , 9 , 41 – 43 These recommendations were based largely on the results of RCTs comparing carbamazepine and/or valproate with other older drugs. 44 – 51 A large meta-analysis by Marson and colleagues 52 emphasizes that carbamazepine and valproate are broadly similar in terms of clinical outcomes of efficacy, tolerability, and drug retention after randomization.…”

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 .…”

“…There has been a limited number of ASDs that can be used as first‐line agents for GTCS. Valproate remains the first‐line drug for many patients with generalized and unclassified epilepsies, 22,35,36,72 while phenobarbital (or primidone) is a primary drug in infants (for neonatal seizures) and an alternative in adults. However, valproate should not be prescribed for women of childbearing potential because of its dose‐dependent teratogenic profile; unless other ASDs cannot control the seizures, in which case the dose should be kept as low as possible 84 .…”

“…The other most widely used monotherapies for GTCS include lamotrigine, levetiracetam, brivaracetam, topiramate, clobazam, and zonisamide 22 . However, there appears to be no evidence to support any second‐generation or third‐generation ASDs to be as efficacious as valproate monotherapy for generalized and unclassified epilepsies 35,36 . The combination of lamotrigine and valproate is believed to be particularly efficacious 85 .…”

A Comparative Study of the Effects of Valproate and Oxcarbazepine on Sexual Function, Sperm Quality, and Sex Hormones in Males with Epilepsy

“…Approximately 60% of people with epilepsy can achieve seizure control with antiseizure medication (ASM) monotherapy [ 2 ]. An increasing number of studies have demonstrated that valproate (VPA) and oxcarbazepine (OXC) continue to be commonly used ASMs for patients with epilepsy [ 3 , 4 ]. Meanwhile, concerns have been raised by patients and clinicians regarding the risk of sexual dysfunction, reduction of sperm quality, and sex hormone disorders in males with epilepsy [ 5 , 6 ].…”