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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.

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SUBMITTER: Marson A

PROVIDER: S-EPMC8047799 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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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.

Marson Anthony A Burnside Girvan G Appleton Richard R Smith Dave D Leach John Paul JP Sills Graeme G Tudur-Smith Catrin C Plumpton Catrin C Hughes Dyfrig A DA Williamson Paula P Baker Gus A GA Balabanova Silviya S Taylor Claire C Brown Richard R Hindley Dan D Howell Stephen S Maguire Melissa M Mohanraj Rajiv R Smith Philip E PE

Lancet (London, England) 20210401 10282

<h4>Background</h4>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.<h4>Methods</h4>This randomised, ...[more]

PMID: 33838757

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Project description:IntroductionAntiepileptic drugs (AEDs) are the mainstay of epilepsy treatment. Over the past 20 years, a number of new drugs have been approved for National Health Service (NHS) use on the basis of information from short-term trials that demonstrate efficacy. These trials do not provide information about the longer term outcomes, which inform treatment policy. This trial will assess the long-term clinical and cost-effectiveness of the newer treatment levetiracetam and zonisamide.Methods and analysisThis is a phase IV, multicentre, open-label, randomised, controlled clinical trial comparing new and standard treatments for patients with newly diagnosed epilepsy. Arm A of the trial randomised 990 patients with focal epilepsy to standard AED lamotrigine or new AED levetiracetam or zonisamide. Arm B randomised 520 patients with generalised epilepsy to standard AED sodium valproate or new AED levetiracetam. Patients are recruited from UK NHS outpatient epilepsy, general neurology and paediatric clinics. Included patients are aged 5 years or older with two or more spontaneous seizures requiring AED monotherapy, who are not previously treated with AEDs. Patients are followed up for a minimum of 2 years. The primary outcome is time to 12-month remission from seizures. Secondary outcomes include time to treatment failure (including due to inadequate seizure control or unacceptable adverse reactions); time to first seizure; time to 24-month remission; adverse reactions and quality of life. All primary analyses will be on an intention to treat basis. Separate analyses will be undertaken for each arm. Health economic analysis will be conducted from the perspective of the NHS to assess the cost-effectiveness of each AED.Ethics and disseminationThis trial has been approved by the North West-Liverpool East REC (Ref. 12/NW/0361). The trial team will disseminate the results through scientific meetings, peer-reviewed publications and patient and public involvement.Trial registration numbersEudraCT 2012-001884-64; ISRCTN30294119.

Project description:ImportanceAfter the recent limitations to prescribing valproate, many studies have highlighted the challenging management of female patients of reproductive age with idiopathic generalized epilepsy (IGE). However, no study, to the authors' knowledge, has addressed the comparative effectiveness of alternative antiseizure medications (ASMs) in these patients.ObjectiveTo compare the effectiveness and safety of levetiracetam and lamotrigine as initial monotherapy in female patients of childbearing age with IGE.Design, setting, and participantsThis was a multicenter, retrospective, comparative effectiveness cohort study analyzing data from patients followed up from 1994 to 2022. Patients were recruited from 22 primary, secondary, and tertiary adult and child epilepsy centers from 4 countries. Eligible patients were female individuals of childbearing age, diagnosed with IGE according to International League Against Epilepsy (2022) criteria and who initiated levetiracetam or lamotrigine as initial monotherapy. Patients were excluded due to insufficient follow-up after ASM prescription.ExposuresLevetiracetam or lamotrigine as initial monotherapy.Main outcomes and measuresInverse probability of treatment weighting (IPTW)-adjusted Cox proportional hazards regression was performed to compare treatment failure (TF) among patients who received levetiracetam or lamotrigine as initial monotherapy.ResultsA total of 543 patients were included in the study, with a median (IQR) age at ASM prescription of 17 (15-21) years and a median (IQR) follow-up of 60 (24-108) months. Of the study population, 312 patients (57.5%) were prescribed levetiracetam, and 231 (42.5%) were prescribed lamotrigine. An IPTW-adjusted Cox model showed that levetiracetam was associated with a reduced risk of treatment failure after adjustment for all baseline variables (IPTW-adjusted hazard ratio [HR], 0.77; 95% CI, 0.59-0.99; P = .04). However, after stratification according to different IGE syndromes, the higher effectiveness of levetiracetam was confirmed only in patients with juvenile myoclonic epilepsy (JME; IPTW-adjusted HR, 0.47; 95% CI, 0.32-0.68; P < .001), whereas no significant differences were found in other syndromes. Patients treated with levetiracetam experienced adverse effects more frequently compared with those treated with lamotrigine (88 of 312 [28.2%] vs 42 of 231 [18.1%]), whereas the 2 ASMs had similar retention rates during follow-up (IPTW-adjusted HR, 0.91; 95% CI, 0.65-1.23; P = .60).Conclusions and relevanceResults of this comparative effectiveness research study suggest the use of levetiracetam as initial alternative monotherapy in female patients with JME. Further studies are needed to identify the most effective ASM alternative in other IGE syndromes.

Project description:ObjectiveWe evaluated adherence to and 1-year persistence of two third-generation anti-seizure medications (ASMs), lacosamide and perampanel, in adult patients with focal epilepsy, compared with lamotrigine and levetiracetam.MethodsA cohort study was conducted using a Japanese health insurance claims database (JMDC Inc.). We identified patients with adult-onset focal epilepsy who initiated any of the four ASMs between August 31, 2016, and October 31, 2019. Patients were further classified into ASM-naïve patients initiating any of the four ASMs as first-line treatment, and ASM-experienced patients initiating any of the four ASMs as second- or later-line treatment. Outcomes included adherence (proportion of days covered [PDC], defined as the total number of days covered by ASMs divided by the total number of days in the follow-up period) and 1-year persistence for the four ASMs.ResultsWe identified 141 lacosamide, 75 perampanel, 80 lamotrigine, and 530 levetiracetam initiators. Among these, the proportion of ASM-naïve patients was highest in the levetiracetam group (60.8%), followed by the lamotrigine (25.0%), lacosamide (20.6%), and perampanel groups (1.3%). Mean PDC (standard deviation) was similar across the four groups, at 0.95 (0.08) for lacosamide, 0.93 (0.12) for perampanel, 0.92 (0.10) for lamotrigine and 0.94 (0.11) for levetiracetam. The proportion of patients persisting with treatment for 1 year was highest in the lacosamide group (73.0%), followed by the levetiracetam (58.3%), lamotrigine (57.5%), and perampanel groups (54.7%). In ASM-naïve patients, adherence and 1-year persistence were almost identical in the lacosamide, lamotrigine, and levetiracetam groups. Results for ASM-experienced patients did not significantly differ from those of all patients.SignificanceWith regard to adherence and 1-year persistence, lacosamide may be equal to or better than lamotrigine and levetiracetam, especially in patients with experienced ASM, while perampanel may be comparable to lamotrigine and levetiracetam in patients with experienced ASM.

Project description:Importance:More than half of infants with new-onset epilepsy have electroencephalographic and clinical features that do not conform to known electroclinical syndromes (ie, nonsyndromic epilepsy). Levetiracetam and phenobarbital are the most commonly prescribed medications for epilepsy in infants, but their comparative effectiveness is unknown. Objective:To compare the effectiveness of levetiracetam vs phenobarbital for nonsyndromic infantile epilepsy. Design, Setting, and Participants:The Early Life Epilepsy Study-a prospective, multicenter, observational cohort study conducted from March 1, 2012, to April 30, 2015, in 17 US medical centers-enrolled infants with nonsyndromic epilepsy and a first afebrile seizure between 1 month and 1 year of age. Exposures:Use of levetiracetam or phenobarbital as initial monotherapy within 1 year of the first seizure. Main Outcomes and Measures:The binary outcome was freedom from monotherapy failure at 6 months, defined as no second prescribed antiepileptic medication and freedom from seizures beginning within 3 months of initiation of treatment. Outcomes were adjusted for demographics, epilepsy characteristics, and neurologic history, as well as for observable selection bias using propensity score weighting and for within-center correlation using generalized estimating equations. Results:Of the 155 infants in the study (81 girls and 74 boys; median age, 4.7 months [interquartile range, 3.0-7.1 months]), those treated with levetiracetam (n = 117) were older at the time of the first seizure than those treated with phenobarbital (n = 38) (median age, 5.2 months [interquartile range, 3.5-8.2 months] vs 3.0 months [interquartile range, 2.0-4.4 months]; P < .001). There were no other significant bivariate differences. Infants treated with levetiracetam were free from monotherapy failure more often than those treated with phenobarbital (47 [40.2%] vs 6 [15.8%]; P = .01). The superiority of levetiracetam over phenobarbital persisted after adjusting for covariates, observable selection bias, and within-center correlation (odds ratio, 4.2; 95% CI, 1.1-16; number needed to treat, 3.5 [95% CI, 1.7-60]). Conclusions and Relevance:Levetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.

Dataset Information

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.

Publications

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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