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Official websites use. Share sensitive information only on official, secure websites. 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. 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 to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. 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 month remission. 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. The ITT analysis included all participants and the PP analysis included participants randomly allocated to valproate and randomly allocated to levetiracetam. The PP analysis showed that the month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years. 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. At the time of the design of this trial SANAD II , valproate was recommended as a first-line treatment for patients with newly diagnosed generalised epilepsy, which includes syndromes such as absence epilepsies, juvenile myoclonic epilepsy, and generalised epilepsy with tonic-clonic seizures on waking, and for unclassified epilepsy. The evidence base from randomised controlled trials to support this recommendation was scarce, partly because valproate became accepted as a first-line treatment in an era before rigorous trials were undertaken. The first SANAD trial published in identified valproate as a clinically effective and cost-effective first-line treatment compared with lamotrigine and topiramate. Prognostic modelling of data from SANAD also found similar treatment responses in the differing epilepsy types. A week double-blind randomised trial in patients with absence epilepsies found valproate and ethosuximide superior to lamotrigine for treatment failure. A Cochrane review identified possible confounding in previous studies due to misclassification of focal epilepsy as generalised epilepsy. That review included an individual participant network meta-analysis, which found no evidence of superiority of valproate over other treatments for seizure control, but valproate was superior to carbamazepine, topiramate, and phenobarbital for treatment failure. Treatment decisions are now particularly difficult for women and girls with generalised epilepsy, which typically starts during childhood and adolescence. The main alternatives to valproate are lamotrigine, which is less effective than valproate, and levetiracetam, which previously had unknown effectiveness compared with valproate as no head-to-head randomised trials had been undertaken. To the best of our knowledge, this study is the first randomised controlled trial to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam versus valproate for patients with newly diagnosed generalised or unclassified epilepsy. The study is pragmatic in design and recruited a cohort of participants aged over 5 years from routine UK National Health Service clinics, and the results are relevant to every day clinical practice. Levetiracetam did not meet our definition of non-inferiority for time to month remission compared with valproate and it was inferior for times to treatment failure, 2-year remission from seizures, and first subsequent seizure. In addition, levetiracetam was not found to be a cost-effective alternative. For people with generalised epilepsies, the available evidence identifies valproate as more clinically effective and cost-effective than lamotrigine and levetiracetam. Ethosuximide and valproate have similar efficacy for absence epilepsies but ethosuximide is inefficacious for other seizure types ie, generalised tonic-clonic seizures and myoclonic seizures. For men, valproate should remain a first-line treatment for generalised epilepsies. For women, there should now be further debate to inform practice and policy about avoiding the most effective treatment to minimise the potential risk of harm in future pregnancies. Around a third of people with epilepsy have idiopathic generalised epilepsy, also referred to as genetic generalised epilepsy, which includes several syndromes classified according to seizure types and age of onset, such as childhood absence epilepsy and juvenile myoclonic epilepsy. Also, at the time of diagnosis, some people cannot be classified as having either a focal or generalised epilepsy, although for many a syndromic diagnosis can be made, usually following further investigation or as more seizures are witnessed. Valproate is currently recommended as a first-line treatment for generalised and for unclassifiable epilepsy as it has a broad spectrum of action, 10 although there is little evidence from randomised controlled trials RCTs to support this recommendation. Cochrane reviews have not found superiority of valproate over other anti-seizure mediations 11 , 12 , 13 and highlight problems with epilepsy classification and sample size of studies analysed. SANAD I identified valproate as a clinically and cost-effective alternative to either lamotrigine or topiramate, 14 and a double-blind trial 15 of 16 week therapy in childhood and juvenile absence epilepsy found valproate and ethosuximide superior to lamotrigine for time to treatment failure. Levetiracetam has been increasingly used as first-line treatment in both focal and generalised epilepsy, particularly for women of childbearing age with a generalised epilepsy. Although there is evidence from RCTs of efficacy as an add-on treatment for some generalised seizure types, 16 , 17 and evidence of tolerability as monotherapy compared with valproate, 18 there is no evidence from RCTs of the clinical efficacy or cost-effectiveness of levetiracetam when used as monotherapy or as first-line treatment in patients with generalised or unclassifiable epilepsy. For women with an idiopathic generalised epilepsy, the two main alternatives are lamotrigine, which is less effective but safer in pregnancy, and levetiracetam, which has increasing evidence to support its safety in pregnancy, 21 , 22 but its effectiveness compared with valproate is unknown. The aim of SANAD II was to compare the long term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy. Participants were eligible for recruitment if they were aged 5 years or older, had a history of at least two unprovoked epileptic seizures requiring treatment, their clinical epilepsy diagnosis was a generalised epilepsy syndrome or was unclassifiable, and had never been treated with an anti-seizure medicine except for emergency treatment in the 2 week period before enrolment. Exclusion criteria included having provoked or acute symptomatic seizures only, currently taking anti-seizure medicine treatment, and having known progressive neurological disease. Epileptic seizures and syndromes were classified according to International League Against Epilepsy classifications 3 , 4 on the basis of seizure semiology and electroencephalogram EEG results. Instances in which the precise idiopathic generalised epilepsy syndrome was uncertain eg, for patients with generalised tonic-clonic seizures and generalised spike and wave changes on their EEG , recruiting clinicians were able to classify such patients as having idiopathic generalised epilepsy not specified. The trial protocol has been previously published. After providing consent, participants were randomly allocated to receive either levetiracetam or valproate. We used a secure, centrally controlled, 24h web-based facility to implement a minimisation program with a random element utilising factors, which were not made known to reduce the risk of predicting allocation. Recruiting clinicians were required to initiate trial treatment within 7 days of randomisation. Participants and investigators were not masked were aware of treatment allocation. Trial treatments were prescribed as per routine NHS practice and dispensed by hospital and community pharmacies, and clinicians prescribed the formulation they considered most appropriate. The trial protocol provided guidance on initial drug titration and maintenance doses based on routine practice, although clinicians were able to tailor these as appropriate. All medications were taken orally. For participants aged 12 years or older, the initial advised maintenance doses were mg twice per day for both levetiracetam and valproate. Subsequent dose and treatment changes at follow-up visits were made on the basis of treatment response and in accordance with routine clinical practice. Patients were followed up according to clinical need, and minimum trial visits were expected at 3, 6, and 12 months, and annually thereafter. At visits, data were collected for seizures, anti-seizure medication, and adverse reactions. Participants continued in follow-up whether they were still taking their allocated treatment or not. When participants fell out of hospital follow-up, outcome data were sought from their general practitioner. QOL questionnaires were completed at baseline and annually thereafter. Adults and parents also completed a subset of QOL measures at 3 months and 6 months. For participants aged 5—7 years, only proxy questionnaires were administered. Participants' resource-use associated with secondary care ie, inpatient, outpatient, and accident and emergency care , other health-care and social services ie, primary care and community services , and medicines were measured using routine hospital episode statistics, resource-use questionnaires, 27 and case report form records. Resource-use was valued in monetary terms measured in pounds sterling using national unit costs for —20 using national unit costs. The primary outcome was time to month remission from seizures, calculated as days from randomisation to the first date at which a period of 12 months had elapsed without any seizures. The secondary seizure outcomes were time to month remission and time to first subsequent seizure. There were three secondary outcomes for treatment failure: 1 time to treatment failure overall, defined as days from randomisation to a decision to withdraw the randomised drug or to add a new anti-seizure medication because of either inadequate seizure control or unacceptable adverse reactions; 2 time to treatment failure due to inadequate seizure control alone; and 3 time to treatment failure due to unacceptable adverse reactions alone. The other secondary outcomes were adverse reactions, QOL, and health economic outcomes based on incremental costs and quality-adjusted life-years QALYs gained. At clinic visits, data were collected on adverse reactions reported by the patient and the investigators assessment stated whether the event was possibly, probably, or almost certainly related the anti-seizure medication. These adverse reactions were coded using the MedDRA dictionary. SANAD-II was designed to detect non-inferiority of levetiracetam compared with valproate for the primary outcome of time to month remission. Primary analyses were undertaken on an intention-to-treat ITT basis. The statistical and health economic analysis plans were developed before doing final analyses and are available in appendix 1 and appendix 2. Analyses were done using SAS software version 9. Completeness of follow-up statistics were calculated as the total number of days follow-up for all participants as a percentage of the total potential number of days follow-up. Models were also fitted to include a stratification variable for epilepsy type ie, generalised or unclassified epilepsy. The assumption of proportional hazards was investigated by examining Schoenfeld residual plots and incorporating time-dependent covariates in all models. If the assumption of proportional hazards was not valid, an additional extended Cox model with time-dependent covariates was used. Subgroup effects for patients with absence epilepsies, other generalised epilepsies, or unclassified epilepsy were explored in a post-hoc analysis by adding treatment-covariate interaction terms to the primary Cox model. A per-protocol PP analysis of the primary outcome was also done using a Fine and Gray model, 30 with treatment failure included as a competing risk, and censoring participants with drug failure before achieving remission. This analysis excluded participants with major protocol deviations, participants given an alternative diagnosis to epilepsy after random assignment, and participants who did not receive the drug at all. For time to treatment failure, a competing risks analysis, using the Fine and Gray model, 30 was done to assess the two main reasons for treatment failure ie, inadequate seizure control and unacceptable adverse reactions. The difference in QOL measures between treatment groups was estimated for each population ie, children, adults, and parent-carers and for each outcome applicable within that population by fitting a repeated measures random effects model with a baseline QOL variable, treatment group, and time in days using spatial-power covariance structure for repeated measures and unstructured covariance for the random effect. Analysis sets for the summary of adverse reactions included all patients who received any dose of a study drug. All adverse reactions and serious adverse reactions were coded using the MedDRA dictionary. The number and percentage of patients experiencing each reaction, and the number and percentage of occurrences of each reaction are presented with no formal statistical testing undertaken. Interim monitoring was done by an independent data safety monitoring committee, meeting approximately annually. This process included analyses of the primary outcome and five of the secondary outcomes all using the Haybittle-Peto approach. The economic analysis shown in appendix 2 adopted the costing perspective of the NHS and personal social services and was done using data up to 24 months of follow-up. Missing cost and QALY data were imputed using multiple imputation with chained equations. A subgroup analysis considered cost-effectiveness in children, adults, and adolescents aged 16 years or older at the point of randomisation. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The first participant was randomly assigned on April 30, , and the last participant was randomly assigned on Aug 2, , after which every effort was made to follow up the trial cohort for a further 2 years. The last participant visit was on Jan 13, Baseline characteristics were well balanced across treatment groups table 1. Approximately three-quarters of the participants participants had generalised epilepsy and the remainder of the participants participants had unclassifiable epilepsies. Participants were randomly assigned a median of 4 days 0—26 after their most recent seizure. Post-traumatic amnesia lasting over 24 h or compound depressed fracture. In this analysis, the median days of follow-up was IQR — for valproate and — for levetiracetam; follow-up was shorter for valproate as participants allocated valproate achieved the primary outcome sooner. Estimates for the primary and secondary analyses are provided in appendix 3 p 1. Consequently, the possibility of a clinically important difference could not be excluded. Interval specific HR estimates appendix 3 p 1 indicate significant benefit of valproate within the first year, but not in subsequent years. Kaplan Meier plot of time to month remission: levetiracetam versus valproate, intention to treat analysis. The per-protocol analysis showed that month remission was superior with valproate than with levetiracetam; although this trial was powered for non-inferiority, it was also designed to show superiority. Furthermore, the assumption of a constant HR across time appeared reasonable in the PP analysis, suggesting that treatment failures before remission largely explain the non-constant effect seen in the ITT analysis. Annual treatment failure rates and differences in failure rates between valproate and levetiracetam are shown in appendix 3 p 7. The doses taken at treatment failure or at the point of last follow-up are summarised in appendix 3 p 8 , and the findings indicate that reasonable dose ranges were tried before deciding failure had occurred. SANAD II recorded data for adverse reactions that were judged by the treating clinicians to be possibly, probably, or definitely caused by anti-seizure medicines. The safety analysis included the participants who were randomly assigned to levetiracetam and the participants who were randomly assigned to valproate and who received at least one dose of their allocated treatment. Adverse reactions according to the MedRA system organ classification are shown in table 2 , and adverse reactions by MedRA preferred term are given in appendix 3 p None were classified as suspected unexpected serious adverse reactions. One participant randomly assigned to initiate valproate became pregnant. The pregnancy was conceived while taking levetiracetam monotherapy and resulted in a healthy baby without any malformations at postnatal examination. Nine participants randomly assigned to levetiracetam reported a pregnancy with four healthy babies at postnatal examination, three miscarriages all of whom were taking levetiracetam at the time of reporting pregnancy , one baby with low birthweight levetiracetam taken at the time of reporting pregnancy and one baby with major malformations carbamazepine taken at the time of reporting pregnancy. For participants who provided QOL data, the mean follow-up time was days SD and the maximum was days. Results from the repeated measures random effects models appendix 3 p 14 suggested there might be small differences in favour of levetiracetam for QOL emotional child , family child and parent , and school child domains. However, because of the high level of missing data, these results cannot be considered reliable. We did not consider imputation reasonable because of the high level of missing data. Health economic analysis data were available for participants, and self-reported resource-use data were available for participants at 3 months, participants at 6 months, participants at 12 months, and participants at 24 months. Most of the costs were related to hospital outpatient clinic attendance, admitted care, and anti-seizure medications appendix 3 p EQ-5D utilities were available for participants at baseline, and they could be calculated for participants at 12 months and for participants at 24 months. Incremental net health benefits were similarly negative for both subgroups table 3. Sensitivity analyses are provided in appendix 4 pp 26— SANAD II found that levetiracetam is neither clinically effective nor cost-effective compared with valproate in patients with newly diagnosed generalised or unclassified epilepsy. This pragmatic, multicentre, open-label, randomised trial was powered to assess non-inferiority of levetiracetam compared with standard treatment, valproate, in patients with newly diagnosed generalised and unclassified epilepsy. Levetiracetam did not meet our non-inferiority definition for time to month remission from seizures. Levetiracetam was inferior to valproate for time to treatment failure, time to 2 year remission, and time to first subsequent seizure. Inadequate seizure control leading to treatment change was the likely explanation for finding non-proportional hazards in the primary ITT month remission analysis. These results are particularly important when considering treatment choices for women of childbearing potential. To explore the treatment effects further, the cohort was split into three groups: participants with absence epilepsies, participants with other generalised epilepsies, and participants with unclassified epilepsy. Participants with other generalised epilepsies were mainly those with generalised tonic-clonic seizures, for whom seizure rates are low and many months of observation are typically required to record seizures and make incremental changes to dose and drug. Conversely, participants with absence seizures typically have a high seizure rate, enabling more rapid decisions about dose and drug changes to gain early seizure control. There were ten pregnancies during the study, none of which were exposed to valproate, and only one of these women was randomly assigned to initiate valproate. Analysis of QOL outcomes did not indicate benefit for either drug, but the return rate of questionnaires was disappointingly low. The cost utility analysis found that levetiracetam was not cost-effective compared with valproate at thresholds of cost-effectiveness operating in the UK NHS. Levetiracetam was associated with fewer QALYs and higher costs than valproate. The finding of a negative incremental net health benefit for levetiracetam compared with valproate was consistent for both adult and children subgroups and was stable in most sensitivity analyses, apart from two that were limited by the missing data in NEWQOL-6D utilities and costs. This study has several important limitations. Data for the occurrence of seizures were collected using seizure diaries and reports at clinic visits and it is possible that seizures were missed or not reported. SANAD II was open-label, which might have influenced decisions about dose and treatment changes, thereby biasing results for time to treatment failure, seizure outcomes, and the reporting of adverse reactions. It is not possible to state whether this factor might have increased or diminished the treatment effects observed, but it is interesting to note that in the subgroup analysis for month remission the estimate in participants who were unclassified favoured levetiracetam. In addition, other than for participants with absence epilepsies, the number of participants classified with a specific generalised epilepsy syndrome at the time of random assignment was small, precluding subgroup analyses for syndromes, such as juvenile myoclonic epilepsy. Although there is no reason to expect important differences in clinical effectiveness by gender, 7 differing approaches to dosing and treatment choices for men and some women could influence seizure remission rates, adverse events, and decisions about treatment failure. There was also a low return rate for questionnaires, which diminished our ability to identify QOL consequences and also affected the economic analysis. For costs, the use of free text questions might have introduced bias, as also the assumption that unanswered questions implied no use of resources. However, these issues were largely mitigated by more complete data for the costs of hospital care and anti-seizure medicines, which were more difficult to recall while also being the main cost drivers. This requirement represents a weakness in many economic evaluations of interventions in paediatric populations, 36 although a valuation of children's EQ-5D-3L-Y health states should soon be available. These results should be put into context with previous studies, although few studies have assessed the long term effectiveness of treatments for patients with generalised epilepsies. SANAD I 14 identified valproate as a first-line treatment as it was superior to lamotrigine for seizure control and superior to topiramate for treatment failure. Valproate was superior to carbamazepine, topiramate, and phenobarbital for treatment failure. A clinical trial 14 in participants with absence epilepsies found valproate and ethosuximide superior to lamotrigine for treatment failure. To the best of our knowledge, SANAD II is the only trial that provides much needed head-to-head data for the long term effectiveness of valproate versus levetiracetam. These results have important implications for clinical practice and research. For men with generalised onset seizures, valproate should continue as a first-line treatment. For women of childbearing potential, levetiracetam was inferior to valproate, as is lamotrigine, 14 the other commonly prescribed alternative. Regulators, guideline developers, clinicians, and patient groups should now consider the benefit-to-risk ratio of each treatment. For people with unclassified epilepsy, the subgroup analysis found no significant difference between treatments, but estimates favour levetiracetam. Future studies should not group generalised and unclassified epilepsy together and the international epilepsy community should identify a better strategy for assessing treatment policies in this common scenario. All requests for data sharing should be addressed to the trial co-sponsors. Co-sponsors will process the requests by involving all applicable parties in their decision making outcome eg, joint data controllers and pharmaceutical companies. Data sharing packs are prepared at the end of trial and involve as a minimum all versions of the trial protocol, all versions of the annotated trial case report forms, and dataset. All other authors declare no competing interests. We would like to thank the independent members of the trial oversight committees; the past and present staff members at the Liverpool Clinical Trials Centre, and in particular Andrew McKay for the quality control analysis and Barbara Arch for writing the statistical analysis plan and carrying out the blind review. We wish to acknowledge Colin Ridyard and Yankier Pijeira Perez for their assistance with the analysis of the cost data. Lastly, we are grateful to all the participants for their commitment to the trial. We would like to thank all the principal investigators, research nurses, and other members of the team who recruited patients and supported them during the trial. AM conceived the research question, was the grant holder, and the chief investigator. CT-S was the statistical lead. GB prepared data for reports throughout the trial and did the final statistical analysis. GS coordinated the collection and archiving of DNA samples. CP did the economic analysis under the supervision of DAH, who was the lead on the health economic evaluation. GAB led on quality of life assessments. SB and CT provided trial management. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. GB and CT-S have accessed and verified the data. The principle investigator names within one hospital site are listed in reverse chronological order. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Find articles by Anthony Marson. Find articles by Girvan Burnside. Find articles by Richard Appleton. Find articles by Dave Smith. Find articles by John Paul Leach. Find articles by Graeme Sills. Find articles by Catrin Tudur-Smith. Find articles by Catrin Plumpton. Find articles by Dyfrig A Hughes. Find articles by Paula Williamson. Find articles by Gus A Baker. Find articles by Silviya Balabanova. Find articles by Claire Taylor. Find articles by Richard Brown. Find articles by Dan Hindley. Find articles by Stephen Howell. Find articles by Melissa Maguire. Find articles by Rajiv Mohanraj. Find articles by Philip E Smith. Published by Elsevier Ltd. This article has been corrected. See Lancet. See ' Newer versus older antiseizure medications: further forward? Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Interval between first and most recent seizure, days. Generalised abnormality slow wave activity without spiking. Focal abnormality paroxysmal slow activity without spiking.

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Official websites use. Share sensitive information only on official, secure websites. Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. Arm B of the study recruited patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, , and Aug 31, , and follow-up data were obtained up to Jan 13, Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered. Such epilepsies tend to present in childhood and adolescence and have generalised spike-wave abnormalities in an electroencephalogram. Common syndromes include childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and generalised epilepsy with tonic clonic seizures on waking. Compared with the partial epilepsies, the comparative effects of antiepileptic drugs for patients with generalised onset seizures are poorly studied. Guidelines recommend valproate as a treatment of first choice for patients with generalised onset seizures, 4 , 5 although evidence to support this from randomised controlled trials is scarce. Meta-analyses of randomised controlled trials that recruited patients with generalised onset tonic clonic seizures reported no difference between valproate and either carbamazepine or phenytoin 6 , 7 for time to treatment failure, month remission, or first seizure. However, results were potentially confounded by errors in seizure classification and failure to measure seizures other than tonic clonic during follow-up. A systematic review of small randomised trials that assessed treatments for absence seizures showed no evidence of a difference between valproate and either ethosuximide or lamotrigine. To our knowledge, no randomised controlled trials have specifically examined treatment effects in this subgroup of patients. The past decade and a half has seen the licensing and introduction of several new antiepileptic drugs. These have all been licensed initially on the basis of placebo-controlled add-on randomised trials in patients with refractory partial epilepsy, with few studies examining these drugs in patients with refractory generalised onset seizures. Similarly, few randomised controlled trials have assessed the effects of these new drugs as monotherapy for patients with generalised onset seizures. However, lamotrigine and topiramate have been licensed in the UK as treatments for patients with generalised onset tonic clonic seizures. Lamotrigine has been suggested as an alternative to valproate, particularly for women of childbearing age, because of concerns about higher rates of teratogenicity and delayed cognitive development in children exposed to valproate in utero. We therefore have no reliable evidence about the relative effectiveness of valproate and lamotrigine to inform clinical decisions. There is also little evidence about topiramate, which has been compared with valproate in a randomised trial that reported no difference between the two drugs for short-term outcomes of efficacy, although CIs were wide, and longer-term outcomes were not examined. Since most patients who develop epilepsy are treated with one drug and might be on medication for many years, standard and new drugs need to be compared so as to establish which should, in the future, be first choice for appropriate groups of patients. We have therefore undertaken two concurrent pragmatic parallel-group unblinded randomised trials comparing Standard and New Antiepileptic Drugs SANAD , which examined seizure control, tolerability, quality of life, and health economic outcomes. Arm B of SANAD is reported here and compares valproate, lamotrigine, and topiramate in patients for whom valproate was viewed as the optimum first-line treatment when compared with carbamazepine. Patients were included in arm B of SANAD if they had a history of two or more clinically definite unprovoked epileptic seizures in the previous year and if the recruiting clinician regarded valproate the better standard treatment option than carbamazepine. This criteria allowed inclusion of patients with newly diagnosed epilepsy, patients who had failed treatment with previous monotherapy as long as the drug failure did not include one of the drugs present in the randomisation , and patients in remission of epilepsy who had relapsed after withdrawal of treatment. Patients were excluded if the clinician or patient felt that treatment was contraindicated, if all their seizures had been acute symptomatic seizures including febrile seizures , they were aged 4 years or younger, or if there was a history of progressive neurological disease. Information recorded at study entry included patient demographics, a history of learning disability or developmental delay, neurological history including head injury, stroke, intracerebral infection, or acute symptomatic seizures, and a history of epilepsy in a first-degree family member. Clinicians were asked to identify seizures and epilepsy syndromes by International League Against Epilepsy classifications 20 , 21 as far as was possible, at least to differentiate between partial onset focal or generalised onset seizures. However, where there was uncertainty, patients were recorded as having unclassified convulsive or other unclassified seizures. Results of any electroencephalogram or brain imaging around the time of randomisation were recorded. Participating patients in arm B were randomly allocated in a ratio to valproate, lamotrigine, or topiramate. To randomise a patient, the clinician telephoned a central randomisation service, and provided patient identifying information and the clinical factors used for stratification of randomisation, which were centre, sex, and treatment history newly diagnosed and untreated, treated with ineffective monotherapy, relapse after remission of epilepsy. The central randomisation service then allocated patients with a computer programme using a minimisation procedure. Although choice of drug was randomised, drug dose and preparation was that used by the clinician in their everyday practice. The rate of titration, initial maintenance dose, and any subsequent increments or decrements were decided by the clinician, who was aided by guidelines webtable 1. The aim of treatment was to control seizures with a minimum effective dose of drug, which necessitated dose increments if further seizures took place as is usual clinical practice. There were two primary outcome measures: 1 the time from randomisation to treatment failure stopping the randomised drug because of inadequate seizure control, intolerable side-effects, or both; or the addition of other antiepileptic drugs, whichever was the earliest ; and 2 the time from randomisation to a 1-year period of remission of seizures. Secondary clinical outcomes were: the time from randomisation to a first seizure; time to achieve a 2-year remission; and the frequency of clinically important adverse events and side-effects emerging after randomisation. Quality of life outcomes and cost-effectiveness were also assessed. For the health economic assessment, patients' use of resources were classified under three general headings: consumption of antiepileptic drugs; resource use associated with the management of adverse events needing hospitalisation; and use of other health care and social services resources. The calculations of sample size were based on the two primary outcomes and informed by a meta-analysis of individual patient data comparing valproate and carbamazepine. The study received appropriate multicentre and local ethics and research committee approvals, and was managed according to Medical Research Council Good Clinical Practice Guidelines. The funding sources had no role in study design, data collection, analysis, and interpretation of data or in writing this report. All authors had full access to the data. The corresponding author had full access to the data and had final responsibility for the decision to submit for publication. The first patient was randomised into the study on Jan 12, , and randomisation continued up to Aug 31, Attempts were made to follow-up all patients to, at the latest, a point in time between May 1, , and Aug 31, , although some follow-up data were obtained up to Jan 13, The treatment groups were well balanced for demographic and clinical factors table 1. The ratio of men to women indicates that there might have been some reluctance on the part of clinicians to randomise younger women to arm B, where they could have been randomised to valproate. A further 16 declined further follow-up during the study and another two were lost to follow-up for other reasons, and data for these 18 patients were included in the analyses up to the date of their last follow-up. Missing data for epilepsy syndrome for one individual on topiramate. Because of the pragmatic nature of the trial design and the absence of blinding, the doses of drugs used needed to be assessed and the degree to which the full dose ranges were explored before treatment failure events took place needed to be considered table 2. There is satisfactory evidence that clinicians did explore a full dose range before accepting treatment failure due to inadequate seizure control. As would be expected, doses associated with treatment failure due to unacceptable adverse events were consistently lower than doses associated with treatment failure due to inadequate seizure control. The treatment failure events are summarised in webtable 3. Treatment failure for unacceptable adverse events is mostly limited to the early post randomisation period, whereas the timing of treatment failure for inadequate seizure control, with or without unacceptable adverse events takes place later. The median number of days to failure 25th—75th centile for unacceptable adverse effects was 90 28— and inadequate seizure control was — Results are presented in figure 2 , table 3 , and webfigures 1 and 2. For time to treatment failure for any reason, there were significant differences between drugs, and valproate was the best option. Results for time to month remission are shown in table 4 , and figure 3 , and webfigure 3. However, the survival curves for topiramate and valproate overlap notably from a point about days after randomisation. Because intention-to-treat analysis includes seizure data after treatment failure events, a per protocol analysis has been undertaken table 4. The comparisons between the intention-to-treat and per-protocol analyses indicate that the similarity for the outcome between valproate and topiramate for the intention-to-treat analysis is probably because patients who had treatment failure on topiramate were switched to valproate webtable 4. Data for the clinically important month outcome are consistent with those for the month remission outcome table 4. For time to first seizure, valproate was the most effective, lamotrigine the least effective, and topiramate intermediate between the two but nevertheless significantly better than lamotrigine. As noted for all analyses, valproate was more effective than lamotrigine and topiramate, an effect that seemed greater when analysis was restricted to patients classified as having idiopathic generalised epilepsy compared with the overall analysis. This finding was further explored by testing for an interaction between treatment and epilepsy syndrome in a Cox regression model. Comparisons of outcomes were made between the patients with idiopathic generalised epilepsy, unclassified patients, and 52 classified as partial or other syndromes numbers included in analyses might deviate from these if outcome data are not available. Tests for an interaction were done to assess any differences in treatment effects in the subgroup with an idiopathic generalised epilepsy compared with the subgroup with difficult to classify seizures. For these seizure outcomes, the overall analysis suggested that valproate was the better treatment, but the advantage of valproate was more extreme in the subgroup with an idiopathic generalised epilepsy than in the subgroup with difficult to classify seizure. Table 5 summarises adverse events deemed clinically important by the reporting clinician. An intention-to-treat approach summarises adverse events associated with the randomised policy, but as patients could have had their treatment changed during follow up, this approach does not clearly present adverse events attributable to specific drugs. In table 5 therefore we present adverse event rates for both intention to treat and per protocol. For adverse effects, intention-to-treat analysis outside brackets, per-protocol analysis inside brackets. Sorted by descending total frequency: abdominal pain, dyspepsia; alopecia; other general; other visual disturbance; word finding difficulty; vomiting; aches and pains; other gastrointestinal; other musculoskeletal; other respiratory or pulmonary; diarrhoea; psychosis; anorexia; bruising; constipation; diplopia; renal or bladder stones; influenza-like symptoms; hallucinations; infection; vaginal bleeding; arthritis; asthma; chest infection; child birth; faints; hypertension; ischaemic heart disease or myocardial infarct; other cardiac or vascular; other haematological; psoriasis; short of breath; status epilepticus; urinary tract infection; urinary retention. For the individual symptoms reported, tiredness and fatigue, psychiatric symptoms most frequently for topiramate , and weight gain most frequently associated with valproate were the most common. Rash was a prominent non-CNS symptom, especially with lamotrigine. These adverse event profiles were consistent across intention-to-treat and per-protocol summaries. The adverse events associated with treatment failure were most commonly psychiatric and cognitive symptoms and tiredness and fatigue, all of which were more common with topiramate. We should note that in the study neither patients nor clinicians were masked to drug treatment, which might have affected the symptoms reported to the clinicians and their assessment of the clinical importance. There were no significant differences in response rates between treatment groups webtable 5 , although, like in arm A, 22 there was evidence of response bias, with patients with a poorer quality of life at baseline less likely to return quality of life questionnaires at 2 years. There were no significant differences for the outcomes assessed webtable 6. However, data from questionnaires completed by patients do not indicate an increase in anxiety or depression associated with topiramate, compared with adverse event data recorded by clinicians. There were differences for quality of life between patients who had a positive ie, remission of seizures clinical outcome and those who did not; and between patients who had a negative ie, treatment failure clinical outcome and those who did not webtable 7 ; though for some comparisons, the differences did not reach significance and the CIs were fairly wide. Nonetheless, the direction of effects indicates better quality of life for those who achieved remission or had not been withdrawn from the randomised drug. Since the estimate of quality adjusted life years QALYs and resource use were dependent on patients returning completed quality of life questionnaires, results might have a response bias as outlined above. Tables 6 and 7 show the point estimates of the incremental cost effectiveness ratios for lamotrigine and topiramate, which were estimated using the lowest costs for valproate and lamotrigine. Disaggregated costs are presented in webtable 8. Lamotrigine has a positive incremental cost and a negative incremental QALY gain and is therefore dominated by topiramate—ie, it is more expensive and less effective than topiramate. The same pattern of results is seen when using different combinations of high and low costs for valproate and lamotrigine. The cost per seizure avoided analysis is based on adults and children for whom we have data on seizures and resource use. Tables 6 and 7 show the point estimates of the incremental cost effectiveness ratios for lamotrigine and topiramate, which have been estimated using low costs for valproate and lamotrigine. Topiramate and lamotrigine have positive incremental costs and negative incremental seizures avoided and are therefore both dominated by valproate. The same pattern of results is noted when using different combinations of high and low costs for valproate and lamotrigine. For patients with generalised onset seizures or seizures that are difficult to classify, valproate is significantly more effective than topiramate for treatment failure and significantly more effective than lamotrigine for month remission. Thus valproate should remain a first line treatment for such patients. SANAD was designed as a pragmatic trial to assess whether any of the newly licensed antiepileptic drugs should become first-line treatment and thereby replace the existing first-line agents, carbamazepine and valproate. Here we have reported results for arm B, which compared valproate, lamotrigine, and topiramate. Although arm B failed to achieve the desired recruitment, we were fortunate in that differences between drugs were larger than expected and there were sufficient events during protracted follow-up to allow robust conclusions. One factor that could have reduced recruitment was a reluctance by clinicians to randomise women of child-bearing age into a study in which they could be allocated to treatment with valproate, a drug that is associated with a relative high fetal malformation rate 13 and a risk of neurodevelopmental delay. However, in the intention-to-treat analyses of clinical, quality of life, and health economic outcomes, patients were analysed in the treatment groups to which they had been allocated, and were followed up, even if the allocated treatment had been withdrawn and switched to another. Thus, our analyses take into account the clinical and cost-effectiveness of the differing policies and associated treatment switches. The clinical results identify valproate as first choice treatment. For time to treatment failure, valproate was the most effective drug and topiramate was least effective. The factors affecting this outcome were the better tolerability of lamotrigine compared with valproate intermediate for failure for unacceptable adverse events and topiramate worst. By contrast, valproate was least likely to be associated with treatment failure for inadequate seizure control, followed by topiramate, with lamotrigine being most likely. There was a similar ordering of drugs when analysis was restricted to patients with idiopathic generalised epilepsy syndromes, but valproate was significantly better than both comparator drugs. Valproate was therefore the preferred drug for time to month and month remission, being significantly better than lamotrigine for this outcome, with topiramate intermediate. Although the differences were small in the intention-to-treat analysis, the efficacy of valproate was enhanced in the per-protocol analysis, indicating that the switching from lamotrigine for inadequate seizure control, and from topiramate for unacceptable adverse events, to valproate was largely responsible for obscuring the superiority of valproate for this outcome in intention-to-treat analyses. A similar ordering of drugs for time to first seizure was evident, with both valproate and topiramate significantly better than lamotrigine. Although lamotrigine was the poorest option for seizure control in arm B, it was the overall preferred option in arm A. The claims for lamotrigine to be regarded as a broad-spectrum antiepileptic drug are based on limited randomised study data in patients with generalised seizures. Results from SANAD could be interpreted as indicating that lamotrigine should not be regarded as a broad spectrum antiepileptic drug, but as a first line treatment that should be reserved for treatment of partial onset seizures and localisation-related epilepsy syndromes. The differences between drugs were greater in the subgroup of patients with idiopathic generalised epilepsy than in the entire group of patients randomised to this arm, and interaction testing indicates that valproate might be the least effective drug for patients with partial and other epilepsy syndromes. This interpretation has implications for industry-sponsored comparative monotherapy studies of new antiepileptic drugs, which have been used to show non-inferiority of a new drug compared to a standard drug to support a licensing application for monotherapy indications in Europe. Such studies have tended to compare a new antiepileptic drug with carbamazepine, and have recruited a heterogeneous population typically both patients with partial onset seizures and patients with generalised onset tonic-clonic seizures. SANAD shows that valproate has the greatest efficacy for patients with idiopathic generalised epilepsy. Thus, a study comparing a new antiepileptic drug with a standard such as carbamazepine or perhaps lamotrigine in the future that recruits both patients with partial onset seizure and generalised onset seizures will not be exposing those with generalised onset seizures to the optimum treatment. An overall analysis, ignoring epilepsy type, might lead to an erroneous conclusion that a new drug is not inferior to a standard. Therefore, in future monotherapy studies patients should be classified by epilepsy syndrome and where this is impossible, as unclassified , testing for interactions between epilepsy classification and treatment are undertaken, and that studies are adequately powered to do so. There were no differences between treatment groups in quality of life outcomes that would detract from the conclusions drawn from clinical outcomes. Possible reasons for this have been discussed elsewhere. This apparently conflicting result might be due to the QALY picking up effects on health-related quality of life besides those attributable to seizures alone, or could be due to some other event such as the unrepresentative patient sample on which the cost per QALY analysis is based. In conclusion, results of SANAD show that valproate should remain the first line treatment for most patients with an idiopathic generalised epilepsy or seizures that are difficult to classify, whereas lamotrigine should be generally avoided because of its inferior efficacy, and topiramate because of inferior tolerability. However, there will always be some individual circumstances that would favour the choice of an alternative drug drug interactions, family planning. There is insufficient power for us to make definite statements about the relative efficacy and effectiveness of the drugs for individual seizure types and sub-syndromes within the idiopathic generalised epilepsies. For women of child-bearing age SANAD does provide estimates of the relative efficacy and tolerability of valproate, lamotrigine and topiramate that can be used whilst counselling women. The study was not designed or powered to examine pregnancy outcomes, something of concern, when valproate is used in women of child-bearing potential. Improvements here will await further obser vational data on pregnancy outcomes from registries. Two further antiepileptic drugs have been licensed in the UK since this study was designed levetiracetam and zonisamide , both of which are said to be effective in generalised epilepsies. The same questions that applied to lamotrigine and topiramate now apply to these drugs, for which we need similarly robust comparative trials against valproate in similar populations of patients. The study was supported by a grant from the Health Technology Assessment Programme. As a library, NLM provides access to scientific literature. Published in final edited form as: Lancet. Find articles by Anthony G Marson. Find articles by Asya M Al-Kharusi. Find articles by Muna Alwaidh. Find articles by Richard Appleton. Find articles by Gus A Baker. Find articles by David W Chadwick. Find articles by Celia Cramp. Find articles by Oliver C Cockerell. Find articles by Paul N Cooper. Find articles by Julie Doughty. Find articles by Barbara Eaton. Find articles by Carrol Gamble. Find articles by Peter J Goulding. Find articles by Stephen J L Howell. Find articles by Adrian Hughes. Find articles by Margaret Jackson. Find articles by Ann Jacoby. Find articles by Mark Kellett. Find articles by Geoffrey R Lawson. Find articles by John Paul Leach. Find articles by Paola Nicolaides. Find articles by Richard Roberts. Find articles by Phil Shackley. Find articles by Jing Shen. Find articles by David F Smith. Find articles by Philip E M Smith. Find articles by Catrin Tudur Smith. Find articles by Alessandr a Vanoli. PMC Copyright notice. The publisher's version of this article is available at Lancet. Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Median interval between first and most recent seizure 25th—75th centile , days. Median interval between most recent seizure and randomisation 25th—75th centile , days. Inadequate seizure control and unacceptable adverse events. For inadequate seizure control. Time to month remission—intention to treat. Time to month remission—per protocol. Time to 24 month-remission—intention to treat. Time to first seizure—intention to treat.

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