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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.

A study of Standard and New Antiepileptic Drugs – SANAD-II

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Introduction Antiepileptic 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 analysis This is a phase IV, multicentre, open-label, randomised, controlled clinical trial comparing new and standard treatments for patients with newly diagnosed epilepsy. 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 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 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. The trial team will disseminate the results through scientific meetings, peer-reviewed publications and patient and public involvement. This is an open access article distributed in accordance with the Creative Commons Attribution 4. You will be able to get a quick price and instant permission to reuse the content in many different ways. The study is adequately powered to examine the clinical effectiveness of standard and new antiepileptic drugs AEDs. This is a long-term trial that will provide evidence of the long-term effects of some AEDs. A further limitation is the reliance on patient completed questionnaires, which should be offset by access to hospital episode statistic data. It is uniquely stigmatising and has a negative impact on quality of life QoL and employment prospects. The ultimate goal of treatment is to maximise QoL by eliminating seizures at drug doses that do not cause side effects. However, for many patients, there is a necessary trade-off between effective seizure control and side effects, which can diminish QoL. Over the past 20 years, a number of new drugs have become available for the treatment of epilepsy. These new drugs have been approved for National Health Service NHS use on the basis of information from short-term trials. These trials do not provide information about the longer term outcomes, which inform decisions made by doctors and patients, nor do they provide any useful health economic data to inform policy. The standard and new antiepileptic drugs SANAD-I trial began in and compared the effectiveness and cost-effectiveness of standard and new treatments that were available at that time. Since SANAD-I, a number of newer treatments have become available, the most promising of that are levetiracetam and zonisamide. While the focal epilepsies are further classified into a number of syndromes 6 largely according to aetiology and site of onset, it has been common practice to recruit a heterogeneous population with focal onset seizures into epilepsy trials. There are currently no reliable data that indicate whether relative treatment responses differ among the focal epilepsies, indeed prognostic modelling of data from SANAD-I suggests that treatment effects are consistent across focal epilepsy syndromes as currently classified. Levetiracetam is a commonly used AED with evidence for efficacy non-inferiority NI to carbamazepine for 6-month seizure remission as monotherapy in focal epilepsy from regulatory studies with too short a duration of follow-up to inform policy. Zonisamide is a drug that has been available for many years in Japan and other countries in South East Asia where it is commonly used both as initial monotherapy and as an add-on treatment and is licensed for use in the European Union and USA. Evidence for efficacy is from industry-sponsored regulatory studies demonstrating NI when compared with carbamazepine for 6-month seizure remission rates. Arm B generalised or unclassified epilepsy of SANAD-II will compare levetiracetam and valproate in patients with generalised onset seizures or seizures that are difficult to classify. Generalised onset seizures represent a group of syndromes, most of which are currently classified as one of the idiopathic generalised epilepsies, 6 which are largely classified according to seizure type and age of onset. While differing syndromes are recognised, there is currently no reliable evidence that relative treatment responses differ among syndromes, indeed prognostic modelling of data from SANAD-I indicates that relative treatment responses are consistent across syndromes. As in SANAD-I, patients enter Arm B of the trial based on a classification of seizures generalised onset or difficult to classify , with patients further classified by syndrome where and when such a syndromic diagnosis can be made. Few RCTs have been undertaken to assess the comparative effects of AEDs in patients with generalised onset seizures or in those with seizures who are difficult to classify, even though these individuals represent over one-third of people with epilepsy. Valproate has for some time been recommended as a first-line treatment for such patients 11 but without evidence from RCTs to support this recommendation. Cochrane reviews have compared valproate with other AEDs, 12 13 but due to problems with power and epilepsy classification, none has shown an advantage for valproate. Also, a double-blind trial of 16 weeks therapy in childhood and juvenile absence epilepsy, 14 valproate and ethosuximide were significantly superior to lamotrigine for the outcome treatment failure. Time to treatment failure due to inadequate seizure control. Time to treatment failure due to unacceptable adverse events. This event will have occurred when the patient experiences adverse events attributed to the drug necessitating its withdrawal. Health economic outcomes expressed as the incremental cost per quality-adjusted life-year QALY gained. Arm A of the trial recruits participants diagnosed with focal epilepsy and arm B—with generalised or unclassified epilepsy. Trial participants are randomised to an AED within each arm. In arm A, the control treatment is lamotrigine and the new treatments are levetiracetam and zonisamide, in treatment group ratio of In arm B, the new treatment levetiracetam is compared with the control treatment valproate in treatment group ratio of The sample size for the trial is participants with focal epilepsy and with generalised or unclassified epilepsy. All patients meeting the eligibility criteria table 1 will be invited to participate in the study and provided with an age and development-appropriate patient information sheet and consent form. Patients will be allowed sufficient time to discuss trial and to decide on their participation. Once consent has been obtained, the baseline data will be collected and patient will be progressed to randomisation. The arm A or B to which the patient is assigned will be decided by the recruiting physician based on their epilepsy classification. Patients will then be randomised to one of the following treatments: to lamotrigine, levetiracetam or zonisamide in arm A or to levetiracetam or valproate in arm B. Randomisation will use a minimisation programme with a built-in random element using factors that will not be made known to individuals in charge of recruitment to minimise any potential for predicting allocation. Randomised treatment should begin within 7 days of randomisation. The research team should ensure that the duration between obtaining consent, performing baseline assessments, randomisation and the start of trial treatment does not impact on the well-being of the participant. All treatments will be taken as formulations already licensed to be used in UK and there will be no modifications made to the products or their outer packaging. All treatments will be prescribed as per routine NHS practice and dispensed by hospital and community pharmacies as they would normally be. It is accepted that, for a variety of reasons including perceived or actual efficacy and tolerability, not all patients will take their medicines as prescribed. Patients will be asked about adherence in the QoL questionnaires, but no objective measurements of adherence are planned nor will the primary analyses be adjusted for actual or estimated adherence. All patients will be titrated to an initial maintenance dose, with dose adjustments made at subsequent appointments according to the clinical response and adverse effects. Guidelines for titration and initial maintenance dose are provided within the protocol table 2 , however, clinicians will be able to alter this to choose the titration rate and initial maintenance they think most appropriate for individual patients. The aim of treatment will be to control seizures with a minimum effective dose of drug. This will necessitate dosage modification dose increased or reduced if further seizures or adverse events occur as is usual clinical practice. Any changes in medication must be documented along with the justification for those changes. At the end of trial participation, the participants may continue their treatment as per local policy. To avoid potentially confounding issues, ideally patients should not be recruited into other epilepsy trials. Patients were recruited over a 4. The maximum time that a patient will receive their randomised treatment is 6. Table 3 shows the schedule of follow-up. All participants will be followed up whether they are still taking their allocated treatment or not. Where patients default from clinic follow-up, additional information will be sought from general practitioners who will be the main prescribers of AEDs in this trial. Patients will be followed up as per routine clinical practice and typically at 3, 6 and 12 months and annually thereafter. Patients may be seen at other times as clinically indicated. Where treatment is stopped, the participant will be asked to continue with the trial follow-up and to attend the follow-up visits. Efficacy of the trial treatments will be measured throughout the trial using a number of measures. Data on seizures will provide a subjective measure of efficacy. QoL data obtained throughout the trial using age-appropriate questionnaire booklets table 4 can be used as a subjective measure of efficacy. The currently recommended approach of using parental proxy reports of QoL for this age group will be used. Direct costs of healthcare resources used by patients in the trial will be collected in three ways:. Downloaded Healthcare Resource Group data will include information on outpatient epilepsy, general neurology and paediatric clinics visits; accident and emergency attendance and length and nature of hospitalisations. Resources triggered by ARs will be captured in the follow-up case report form CRF for each patient experiencing a serious AR requiring hospitalisation. Because of potential issues related to completeness of routine data, these will be used to compliment HES data. Unit costs will be taken from the NHS reference costs database 25 and other appropriate sources. Whole blood or saliva samples will be shipped to a central laboratory at The University of Liverpool for extraction and storage. Samples will instead be genotyped in future projects and data arising from that analysis included in international epilepsy genomics initiatives. Identification of genetic factors associated with response to treatment in epilepsy is important and may ultimately help to optimise efficacy, tolerability and safety of AEDs. A new drug might become a standard first-line treatment if it is proven to be non-inferior for efficacy but superior for tolerability when compared with a standard treatment—tolerability is examined in secondary outcomes including time to treatment failure for adverse effects. Powering the study for NI will also provide sufficient power to detect important differences between treatment policies. No empirical work has yet been undertaken to underpin the choice of equivalence or NI margins in epilepsy trials. Calculations have been informed by the SANAD-I study, which estimated the month remission-free probability at 24 months as 0. The calculations assume a HR of 1. For patients with focal-onset seizures arm A , two primary comparisons are of interest levetiracetam vs lamotrigine and zonisamide vs lamotrigine , therefore, the one-sided significance level has been divided by two one-side alpha 0. For patients with generalised-onset seizures or seizures that are difficult to classify arm B , there is only one comparison of interest levetiracetam vs valproate. Therefore, with a one-sided alpha of 0. The total number of patients required is All primary analyses will be on an intention to treat ITT basis including all randomised patients retained in their randomised treatment groups. Separate analyses will be undertaken for each randomisation arm. The interval in days from randomisation to occurrence of a month remission will be summarised by Kaplan-Meier curves for each treatment group. Survival regression models will be explored; two different models will be used: 1 including the treatment effect only using treatment indicator variables and 2 including the treatment effect together with covariates. The impact of centre effect on the treatment comparison will be investigated using both fixed and random effect models. A per protocol analysis will be undertaken to assess the robustness of ITT analyses. A similar analysis strategy will be employed for the other secondary time to event outcomes. For time to treatment failure, further analysis will be undertaken to assess the two main reasons for treatment failure—inadequate seizure control and unacceptable adverse effects. To allow for possible dependence between the different withdrawal risks, cumulative incidence analyses will be presented. The Haybittle-Peto approach will be employed for each interim analysis, with The final analysis will be undertaken at the end of the trial when all patients have a minimum 2-year follow-up data 6. QoL data will be analysed longitudinally to explore between treatment changes in scale scores over time, taking account of baseline QoL. For the analysis of ARs, all patients who received any amount of each study drug will be included in the safety analysis dataset in the treatment group they actually received. All ARs and serious ARs reported by the clinical investigators will be presented, identified by treatment group. ARs will be grouped according to a prespecified coding system and tabulated. The number and percentage of patients experiencing each AR, and the number and percentage of occurrences of each AR will be presented. No formal statistical testing will be undertaken. For the health economic analyses, the perspective of the NHS and Personal Social Services will be adopted for costing purposes. It will be assessed whether levetiracetam or zonisamide as monotherapy in newly treated focal epilepsy is cost-effective by estimating the incremental cost-utility and cost-effectiveness ratios relative to lamotrigine and to each other. The same approach will be used to compare levetiracetam and valproate for generalised-onset seizures. A cost consequence analysis 30 will be conducted to consider non-health benefits that are neither captured within the QALY calculation, nor in the cost-effectiveness analyses. Sensitivity analyses will be conducted to test the robustness of our findings. These analyses will be based on the observed distributions of outcome and costs to test whether, and to what extent, the incremental cost-utility and cost-effectiveness ratios are sensitive to key assumptions in the analysis. Uncertainty in parameter estimates will be addressed through the application of bootstrapping and the estimation of cost-effectiveness acceptability curves. The estimated incremental cost per QALY will be compared with the threshold for cost-effectiveness operating in the UK, and the incremental cost per seizure will be avoided and per month remission will be compared with the results of other economic assessments of AEDs. The trial protocol complies with the Standard Protocol Items: Recommendations for Interventional Trials reporting guidelines. Participating centres will be expected to each maintain a file of essential trial documentation Site File , which will be provided by the coordinating centre and keep copies of all completed CRFs. Data collection will use paper CRFs and participant completed questionnaires. Trial Oversight Committees have been formed in relation to the monitoring. This includes an Independent Data and Safety Monitoring Committee IDSMC , consisting of independent epilepsy experts and statisticians; A Trial Management Group TMG consisting of the chief investigator, trial manager, trial statisticians, sponsor representatives, several principal investigators and a Trial Steering Committee TSC consisting of two independent epilepsy clinicians, an independent statistician and a lay representative, in addition to select members of the TMG. Trial monitoring is informed by a risk assessment to determine the level and type of monitoring required for specific hazards. The study opened to recruitment in and completed recruitment in June Participants are followed up for a minimum of 2 years and a maximum of 6. Follow-up visits and data collection will continue until June We would like to acknowledge the input of the wider SANAD-II team and to thank the research sites and participants for being involved in this study. We would like to specifically thank Epilepsy Action for their invaluable contribution throughout the trial. All authors were able to contribute to the draft and approved the final text. Refer to the Methods section for further details. Provenance and peer review Not commissioned; externally peer reviewed. Skip to main content. Log In More Log in via Institution. Log in via OpenAthens. Log in using your username and password For personal accounts OR managers of institutional accounts. Forgot your log in details? Register a new account? Forgot your user name or password? Search for this keyword. Advanced search. Latest content Archive For authors About Browse by collection. Log in via Institution. You are here Home Archive Volume 10, Issue 8 Study protocol for a pragmatic randomised controlled trial comparing the effectiveness and cost-effectiveness of levetiracetam and zonisamide versus standard treatments for epilepsy: a comparison of standard and new antiepileptic drugs SANAD-II. Email alerts. Article Text. Article menu. Study protocol for a pragmatic randomised controlled trial comparing the effectiveness and cost-effectiveness of levetiracetam and zonisamide versus standard treatments for epilepsy: a comparison of standard and new antiepileptic drugs SANAD-II. Statistics from Altmetric. The study is adequately powered to examine the cost-effectiveness of standard and AEDs. A limitation is that the study is not blinded. Arm B Arm B generalised or unclassified epilepsy of SANAD-II will compare levetiracetam and valproate in patients with generalised onset seizures or seizures that are difficult to classify. Trial outcomes Primary outcome The primary outcome of the trial is time to month remission from seizures. Secondary outcomes The secondary outcomes are Time to treatment failure. Time to first seizure. Time to month remission. Adverse reactions ARs. Enrolment and randomisation Screening and baseline The SANAD-II trial will take place in NHS outpatient epilepsy, general neurology and paediatric epilepsy and general clinics in the UK a full list of participating sites is available from the trial website. View this table: View inline View popup. Table 1 Eligibility criteria. Randomisation The arm A or B to which the patient is assigned will be decided by the recruiting physician based on their epilepsy classification. Table 2 Titration and initial maintenance dose. Assessments and procedures Schedule for follow-up Patients were recruited over a 4. Table 3 Schedule of follow-up. Table 4 Age-appropriate questionnaire booklets. Statistical analysis All primary analyses will be on an intention to treat ITT basis including all randomised patients retained in their randomised treatment groups. Health economic evaluation For the health economic analyses, the perspective of the NHS and Personal Social Services will be adopted for costing purposes. Ethics and dissemination Ethics The trial protocol complies with the Standard Protocol Items: Recommendations for Interventional Trials reporting guidelines. Trial monitoring Trial Oversight Committees have been formed in relation to the monitoring. Time frame and trial status The study opened to recruitment in and completed recruitment in June Acknowledgments We would like to acknowledge the input of the wider SANAD-II team and to thank the research sites and participants for being involved in this study. Epilepsy: frequency, causes and consequences. New York : Demos Publications , Labor market participation following onset of seizures and early epilepsy: findings from a UK cohort. Epilepsia ; 50 : — 9. Schachter SC. Quality of life for patients with epilepsy is determined by more than seizure control: the role of psychosocial factors. Expert Rev Neurother ; 6 : — 8. OpenUrl PubMed. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet ; : — The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia ; 30 : — Developing a prognostic model for epilepsy data. Montpellier : ISCB , Levetiracetam monotherapy study G comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology ; 68 : — 8. KOMET: an unblinded, randomised, two parallel-group, stratified trial comparing the effectiveness of levetiracetam with controlled-release carbamazepine and extended-release sodium valproate as monotherapy in patients with newly diagnosed epilepsy. J Neurol Neurosurg Psychiatry ; 84 : — Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. Lancet Neurol ; 11 : — National Institute for Health and Clinical Excellence. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care , Carbamazepine versus valproate monotherapy for epilepsy. Phenytoin versus valproate monotherapy for partial onset seizures and generalized onset tonic-clonic seizures. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK epilepsy and pregnancy register. J Neurol Neurosurg Psychiatry ; 77 : — 8. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med ; : — New measures to avoid valproate exposure in pregnancy endorsed: member state representatives agree new restrictions and pregnancy prevention programme , Measuring the impact of epilepsy: the development of a novel scale. Epilepsy Res ; 16 : 83 — 8. Ravens-Sieberer U , Bullinger M. Assessing health-related quality of life in chronically ill children with the German KINDL: first psychometric and content analytical results. Qual Life Res ; 7 : — Epilepsia ; 40 : — Quality-adjusted life-years lack quality in pediatric care: a critical review of published cost-utility studies in child health. Pediatrics ; : e — Measuring health preferences for use in cost-utility and cost-benefit analyses of interventions in children: theoretical and methodological considerations. Pharmacoeconomics ; 25 : — Epilepsia ; 41 : — Beecham JKM. Costing psychiatric interventions. In : Measuring mental health needs. London : Gaskell , : — BMJ group and pharmaceutical press , Curtis LA. Unit costs of health and social care Canterbury : University of Kent , Chadwick D. Considerations on designing clinical trials to evaluate the place of new antiepileptic drugs in the treatment of newly diagnosed and chronic patients with epilepsy. Epilepsia ; 39 : — Importance of competing risks in the analysis of anti-epileptic drug failure. Trials ; 8 : The role of cost-consequence analysis in healthcare decision-making. Pharmacoeconomics ; 13 : — The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. A systematic review. Health Technol Assess ; 10 doi Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation. Health Technol Assess ; 9 : 1 — Ann Intern Med ; : — 7. Competing interests None declared. Patient consent for publication Not required. Read the full text or download the PDF:. Log in.

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