Trials Of Antiepileptic Drugs Research Articles

An economic appraisal of carbamazepine, lamotrigine, phenytoin and valproate as initial treatment in adults with newly diagnosed epilepsy.

We undertook an economic appraisal of four drugs used in monotherapy during the first 2 years of treatment for newly diagnosed patients with epilepsy: carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), and valproate (VPA). We adopted the cost-minimization model because, although no single trial compares all four drugs directly, the clinical trials comparing two or more of these drugs in newly diagnosed cases show no significant difference in efficacy between the drugs in terms of seizure frequency. Considered in the cost analyses were frequency of side effects, retention rates, medical consultations, inpatient and accident and emergency costs, laboratory investigations, and drug changes. A Delphi panel provided the treatment pathways, including frequency of clinical consultations, second-line monotherapy, and side-effects management. A sensitivity analysis was performed, varying the assumptions on which the calculations were based. Analysis was completed for a prospective, intention-to-treat perspective and also for those patients continuing the initial drug. The direct medical costs of 2-years therapy (intention-to-treat analysis) calculated for each trial were pound sterling 795-829 for CBZ, pound sterling 1,525-2,076 for LTG, pound sterling 736-768 for PHT, and pound sterling 868-884 for VPA. A sensitivity analysis provided similar relative estimates. We found that LTG for newly diagnosed patients is significantly more expensive in direct health service costs incurred. This analysis incorporated seizure control, side effects, and tolerability. We recommend that a similar type of analysis be considered as part of all clinical trials of antiepileptic drugs in which efficacy of outcome is similar as a guide to assess optimal cost effectiveness.

Alternatives to lithium therapy in the treatment of acute mania.

Manic depressive illness is a poorly understood condition whose causes are primary (possibly hereditary) as well as secondary. It is difficult to diagnose and treat and at the present time, lithium and anticonvulsants remain the preferred medications for the acute phase of mania. However, concomitant use of benzodiazepines or neuroleptics may be helpful to facilitate early response to treatment. Management of lithium refractory patients unresponsive to reasonable trials of anticonvulsants may make it necessary for the psychiatrist to use electroconvulsive therapy, generally considered a safe and effective alternative. Evaluation of concurrent illnesses and recognition of side effects in these treatments are also important to optimize results.

United States Perspective on Definitions and Classifications

Interest in sudden unexpected and unexplained death in individuals with epilepsy (SUDEP) was rekindled in the United States by Jay and Leestma during the early 1980s and more recently by antiepileptic drug (AED) trials and medicolegal issues. The incidence of SUDEP has been and is being evaluated in North America and the United Kingdom. Specific criteria for the classification of definite, probable, possible, and unlikely SUDEP implemented in United States epidemiologic studies are presented. Evidence for the increased relative risk for sudden death in epilepsy compared with the general population is also discussed.

Anticonvulsant trials not applicable to clinical practice

Anticonvulsant trials not applicable to clinical practice

Difficulties in extrapolating from clinical trial data to clinical practice: the case of antiepileptic drugs.

Effective new antiepileptic drugs (AEDs) are needed for the treatment of those with refractory epilepsy. However, with the growing number of these drugs being licensed and marketed, a rational approach to the treatment of epilepsy is becoming essential. New AED trials can determine appropriate use of AEDs but ultimately fail to determine the best use of AEDs and their exact role in treating patients. New AED trials rarely use clinically applicable measures of efficacy, and it is difficult to extrapolate the data from populations used in AED trials to the wider population of patients with epilepsy. Furthermore, AED trials ignore the factors that are most likely to determine prognosis: the etiology, seizure types, and epilepsy syndrome. To resolve these issues, we need large multicenter studies in well-defined populations with well-characterized seizures, epilepsy syndromes, and etiologies. Being seizure free should be the primary measure of efficacy rather than meta-analyses and guidelines based upon incomplete data.

Reappraisal of polytherapy in epilepsy: a critical review of drug load and adverse effects.

We reviewed the literature to determine whether an analysis of published data could clarify the relationship between antiepileptic drug (AED) polytherapy and adverse affects (AE). We highlight the problems encountered. We made a Medline-search for articles published between 1974 and 1994 reporting the number of AE and doses or serum levels of every AED, per patient or treatment group, and used the PDD/DDD ratio to calculate AED load per patient from doses or the OSL/AToxL ratio to do so from serum levels of individual drugs. The PDD/DDD is the sum of ratios of the actual prescribed daily doses divided by the published average therapeutic dose of each drug. The OSL/AToxL is the sum of each observed serum level divided by its average toxic level. We retrieved 118 trial reports. Most had to be excluded because of incomplete reporting of concomitant medication or AE. The data of the 15 articles selected for further analysis indicate a relationship between drug load and number of AE. We noted no relationship between the number of AEDs administered and AE. In add-on studies, the difference in neurotoxicity between the active and placebo arm may be obscured if the relative increase in drug load is small, as exemplified by the study of McGuire et al.. Articles reporting add-on trials of new AEDs generally do not provide detailed information about the basic medication to which the new AED is added, which makes calculation of total drug load impossible. Furthermore, often only frequency of AE is reported, not severity or development of tolerance, making it difficult to judge the impact of AE. However, despite the paucity of available information, we present some evidence that toxicity in AED polytherapy may be related to total drug load, rather than to the number of drugs administered. Therefore, the present trend to reject polytherapy for fear of increased toxicity is not warranted, which removes one of the objections to initiating specific research to prove or disprove the value of AED combinations as long as the drug load is appropriate.

New antiepileptic drug trials in developing countries: are they necessary?

In recent times, antiepileptic drug (AED) development has expanded with at least seven new AEDs being marketed in a variety of countries. However, in this same period there have been very few trials of new AEDs in the developing world where the majority of people with epilepsy reside. There are many problems with the extrapolation of results from AED trials in developed countries, thus underlining the need for new AED trials in developing countries. This, however, presents a number of ethical and logistical problems, as the majority of people with epilepsy in developing countries are inadequately treated with established drugs. Additionally, there are further problems involving the cost of treatment and the allocation of sparse resources. If trials of new AEDs are to take place in developing countries, strict ethical guidelines must be adhered to, the trials must not be purely marketing exercises, and there must be the continued availability of the new AED to those in the trials who have benefited.

Update on Epilepsy in Pediatric Patients

Epilepsy is a common condition that affects 0.5 to 1% of all children. Although most children with epilepsy have well-controlled seizures with use of one antiepileptic drug (AED), some children have medically refractory seizures. This situation can be the result of inaccurate classification of the paroxysmal event, use of an inappropriate AED, of a truly medically refractory seizure disorder. Paramount to the initial assessment of a child with presumed epilepsy is the appropriate classification of the paroxysmal event. Several nonepileptic conditions, such as motor tics or breath-holding spells, can cause paroxysmal abnormalities in children, which can be confused with epilepsy. The common pediatric epileptic and nonepileptic conditions are reviewed, and the standard and new AEDs and their side effects are discussed. When a child's seizure disorder is intractable despite adequate trials of AEDs, surgical treatment is increasingly becoming an effective option. Such procedures should ideally be performed at centers with extensive experience in this area and with a multidisciplinary team approach. With improved magnetic resonance imaging technology, increasing numbers of children with medically intractable localization-related epilepsy are being found to have underlying focal cortical dysplasia, tumors, or hippocampal atrophy. These abnormalities can often be surgically resected with excellent results. A generalized epilepsy may also be remediable with surgical treatment. Specifically, preliminary data suggest that infantile spasms, when triggered by an underlying focal cortical dysplasia, may be effectively treated by surgical resection. Patients with certain catastrophic seizure disorders, such as Sturge-Weber syndrome or hemimegalencephaly, require prompt intervention with hemispherectomy. The presurgical evaluation relies heavily on the magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography scan data as well as the electroencephalogram in identifying the area of epileptogenic abnormality.

Altered Cognitive Functioning in Children With Idiopathic Epilepsy Receiving Valproate Monotherapy

Once a child is diagnosed with epilepsy, a primary concern is whether or not the child's behavior and cognitive abilities will be affected by the disease, by the drug prescribed for seizure control, or both. Direct cognitive effects by the epileptic condition have been described. On the other hand, cognitive effects in epilepsy have been attributed to antiepileptic drug therapy. Valproate is an antiepileptic drug of choice in managing the commonest childhood epilepsy syndromes. Although frequently prescribed in pediatric neurology practice, there have been relatively few studies investigating the cognitive effects of valproate therapy in children. Cognitive effects of valproate reported in normal adult volunteers and in adults with epilepsy cannot be generalized to the pediatric population. The results of investigations on children are less conclusive. Guidelines for antiepileptic drug trials in children have recently been formulated. Carefully designed studies are required in determining the cognitive effects of valproate in the pediatric population. Neuropsychological measures that are likely to assess subtle changes in higher brain functions crucial to learning in children should be employed. We propose a test battery to assess for cognitive changes associated with anticonvulsant therapy in children.

The National Hospital Seizure Severity Scale: a further development of the Chalfont Seizure Severity Scale.

Seizure severity scales have recently been identified as an important additional outcome measure in trials of new antiepileptic drugs (AEDs). The National Hospital Seizure Severity Scale (NHS3) is presented as a refined version of the Chalfont Seizure Severity Scale. The principal advantages of the new version are that it is quicker and simpler to apply, the limits of reliability are now clearly defined, and construct validity for the scale is available. The scale is administered by a health professional during an interview with a patient and a witness to the seizures. It contains seven seizure-related factors and generates a score from 1 to 27. An intraclass correlation coefficient of 0.90 was obtained during interobserver and test-retest reliability assessment, suggesting that the scale is sufficiently reliable for group studies. Scores for an individual patient should be interpreted with caution in light of the limits of agreement obtained. Validation experiments indicate that NHS3 measures seizure severity in a manner compatible with the subjective impression of people with epilepsy. We suggest that the NHS3 is a valid, easily applicable measure of seizure severity that is acceptably reliable for use in trials of novel AEDs.

Monotherapy antiepileptic drug trials in patients undergoing presurgical assessment: methodological problems and possibilities

It may fairly be claimed that up to the last decade no antiepileptic drug (AED) had undergone rigorous testing. Coatsworth I in a comprehensive review of AED assessment reported three controlled trials up to 1971, and Richens (1976) was able to identify some 17. Gram and coworkers found 51 by 1982, but the majority suffered gross methodological deficiencies. In the past decade the situation has changed dramatically, the number of controlled AED trials currently in progress must exceed the total of those completed before 1983. The development programmes of the new AEDs registered in recent years have necessarily been innovative, and methods of AED testing are still undergoing rapid evolutionary change. Conventional phase II AED trials are usually placebo controlled studies employing designs of either single period parallel groups or multiple periods within patients. Since it is, in general, unacceptable to withhold effective treatment from a patient with epilepsy, during conventional AED trials the experimental drug is added to the presumably partially effective medication already being taken (add-on trials). Although widely regarded as an ethical necessity, this approach poses a number of problems which often makes this design difficult to interpret: (1) Drug interactions may confound both therapeutic and adverse effects. Elevation of blood levels of comedication may cause intoxication, which may be wrongly attributed to the experimental agent 45 and efficacy can be wrongly ascribed to a new product because it causes an increase in concentrations of comedication 6. Conversely increased clearance of the comedication may reduce apparent efficacy. (2) Induction of metabolism by the comedication may produce lower than expected blood levels and result in a failure to demonstrate any effect of the experimental drug. (3) Efficacy and adverse events may depend on a pharmacodynamic synergy with the comedication. A number of alternative trial designs are now available and increasing attention has recently been directed to ethically acceptable monotherapy designs 7. One approach, first adopted by Bourgois et al 8, in the development of Felbamate, is the performance of monotherapy trials in patients whose AEDs had been withdrawn to facilitate capture of seizures by telemetry, as part of a preoperative assessment protocol. The conduct of such trials is difficult and complex. The patients are in an unstable state and there may be only a brief interval between capturing sufficient seizures to meet the needs of preoperative assessment and the onset of serial seizures demanding immediate control. To be of demonstrable efficacy under these circumstances, the test drug must act swiftly. If the onset of drug action is delayed by one or two days, the opportunity to prove an effect may be missed. This may happen if the half life is long or efficacy depends on an active metabolite or if there are constraints on the rate of dose escalation. In many patients, it is impossible to achieve monotherapy if seizure frequency increases rapidly before existing medication is fully withdrawn 8. We report two variants of this design: an open trial of remacemide hydrochloride (Fisons CR 2083), and a controlled trial of tiagabine (Abbott M90-511 TIA-102) in which the test treatment was introduced prior to withdrawal of other

Design of clinical antiepileptic drug trials

It may fairly be claimed that up to the last decade no antiepileptic drug (AED) had undergone rigorous testing. The development programmes of the new AEDs registered in recent years have necessarily been innovative, and methods of AED testing are still undergoing rapid evolutionary change. Clinical evaluation of AEDs is both difficult and complex, due mainly to two factors: (1) intermittence of clinical events, which means that dosing for periods of several weeks is generally necessary, leading to problems of poor compliance and inaccurate reporting of events by carers and patients; and (2) therapeutic necessity, which means that it is, in general, unacceptable to withhold effective treatment from a person with epilepsy. Consequently monotherapy, either with a trial drug or with placebo, can rarely be justified. In consequence most phase II trials use add-on therapy which in turn causes various problems. Conventional phase II AED trials are usually placebo-controlled add-on studies employing either a parallel or crossover design. The latter is subject to a number of practical and theoretical objections, notably on grounds of carry-over and order effects. Increasing attention has recently been directed to ethically acceptable monotherapy designs. One approach first exploited in the development of felbamate is the performance of monotherapy trials in patients whose AEDs have been withdrawn as part of a preoperative assessment protocol. Other possibilities for achieving monotherapy are also discussed.

Trials of anticonvulsants in elderly needed

Trials of anticonvulsants in elderly needed

Gabapentin: discussion.

Gabapentin (GBP, Neurontin) is a novel antiepileptic drug (AED) that was shown to be effective against refractory partial seizures in five placebo-controlled trials. However, a number of patients with complex partial seizures experienced an increase in seizure frequency, suggesting that patients suffering from complex partial seizures are not a homogeneous group. In fact, we found that currently available AEDs are likely to be ineffective when staring is a prominent component of complex partial seizures. The poor response of this group of patients may reflect the fact that staring spells are inhibitory seizures and that the AEDs prescribed for partial seizures appear to facilitate inhibitory mechanisms. GBP resembles phenytoin (PHT) and carbamazepine (CBZ) in depressing segmental and reticular excitatory mechanisms and facilitating segmental inhibitory mechanisms, just as it resembles PHT and CBZ in efficacy against some partial seizures and against secondarily generalized seizures. Perhaps the patients in whom GBP increased seizure frequency had complex partial seizures with staring and were therefore unlikely to benefit from drugs such as GBP, CBZ, and PHT, which enhance inhibitory mechanisms in the brain. These findings suggest that future AED trials would greatly benefit from a categorization of complex partial seizures into nosologically distinct groups.

Clinical trials of antiepileptic drugs performed in the private practice setting.

Clinical trials of antiepileptic drugs (AEDs) are usually performed only in major teaching centers, thus ignoring the very real contribution available from private practice. The relation between the consultant and the referring family physician is often much closer in private practice, allowing much earlier recruitment of de novo patients into clinical trials. Between October 1988 and February 1992, 50 subjects were entered into various clinical trials including gabapentin (both an open add-on trial and parallel-arm add-on study in generalized epilepsies), vigabatrin (placebo-controlled cross-over study in focal epilepsies), and lamotrigine (both placebo-controlled cross-over add-on studies and parallel-arm comparative monotherapy study in newly diagnosed patients with epilepsy). All these trials were coordinated in private neurologic practice in Sydney, Australia, as part of either national or international multicenter AED studies. The experience demonstrated the improved ease of recruitment and patient liaison available in the private sector. It also highlighted the very real logistic problems, such as the need for a noninstitutional-based ethics committee, the training of support staff and a modified primary information resource system. Inclusion of private practice centers in clinical trials demonstrates the potential for improved patient recruitment and administrative management, especially in studies requiring newly diagnosed patients.

Guidelines for Antiepileptic Drug Trials in Children

EpilepsiaVolume 35, Issue 1 p. 94-100 Guidelines for Antiepileptic Drug Trials in Children Commission on Antiepileptic Drugs of the International League Against Epilepsy First published: January 1994 https://doi.org/10.1111/j.1528-1157.1994.tb02917.xCitations: 28 Members of the commission on antiepileptic drugs L. Gram, O. Dulac, H. H. Frey, A. Gonzales-Astiazaran, I. Leppik, P. Loiseau, and A. Perret sought advice from several consultants (C. Dravet, K. Farrell, J. Mumford, W. O. Renier, and J. Roger). AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume35, Issue1January 1994Pages 94-100 RelatedInformation

Posthypoxic treatment with felbamate is neuroprotective in a rat model of hypoxia‐ischemia

Felbamate, a novel dicarbamate anticonvulsant that blocks the glycine site of the N-methyl-D-aspartate receptor and protects the hippocampal slice from hypoxic damage, shows remarkably low toxicity in animals and in humans. Since most treatment of human cerebral ischemia will have to be delivered after the insult, we investigated the neuroprotective potency of post hoc felbamate in rat pups with bilateral carotid ligations exposed to an atmosphere of 6.5% O2 for 1 hour. Brain temperature was unaffected by surgery, hypoxia, or felbamate. Neuroprotection was greatest at 300 mg/kg, less effective at 200 and 400 mg/kg, and ineffective at 100 mg/kg. Post hoc felbamate (300 mg/kg) reduced the volume of infarction from 67% +/- 7% of neocortex in unmedicated rats to 32% +/- 8%, 51% +/- 12%, 38% +/- 19%, and 53% +/- 10% when given 0, 1, 2, and 4 hours after hypoxic exposure, respectively. By 6 hours, post hoc protection was no longer significant. Delayed neuronal necrosis in hippocampal granule cells was reduced from 156 +/- 33 neurons to 12 +/- 7 (0 hours, p < 0.01) and 37 +/- 17 (1 hour, p < 0.05). These effects were obtained at plasma concentrations (60 to 120 mg/ml) that have occasionally been reached without serious toxicity in human anticonvulsant trials. These data suggest that, in this animal model, felbamate given after a hypoxic-ischemic insult is effective in reducing cerebral infarction and extremely effective in preventing delayed neuronal necrosis, but that the window of opportunity for post hoc treatment is only 1 to 4 hours.

Parietal and occipital lobe epilepsy: a review.

There has been considerable recent interest in frontal lobe epileptic syndromes, and less attention paid to occipital and parietal epilepsies. The occipital and parietal lobes have arbitrary anatomical borders. The prinicpal seizure symptomatology includes somatosensory (paresthetic, painful, thermal, sexual, apraxia, disturbances of body image); visual (amaurotic, elementary and complex hallucinations, illusions) and other phenomena (anosognosia, apraxia, acalculia, alexia, aphemia, confusional states, gustatory, vertiginous, adversive, oculoclonic and eyelid flutter). The seizure symptoms are of varying localizing and lateralizing value and seizure discharges may spread rapidly and perceived symptoms may reflect secondary spread rather than the primary site of seizure onset. Recognized parietal and occipital epilepsy syndromes include benign epilepsy of childhood with centrotemporal spikes, benign epilepsy of childhood with parietal evoked spikes, benign occipital epilepsy of childhood, migraine/epilepsy syndromes, and epilepsy with bilateral occipital calcification. In addition, occipital and parietal epilepsy may be on the basis of any underlying structural lesion. There is frequently a poor correlation between clinical and EEG features. MRI and functional imaging often reveals underlying pathology. There have been no specific trials of different antiepileptic drugs for occipital and parietal seizures. Surgical treatment has its place, with attention to the risk of causing a fixed neurological deficit.

Clinical Trials of Investigational Antiepileptic Drugs: Monotherapy Designs

The standard designs for safety and efficacy trials of investigational antiepileptic drugs are placebo-controlled, add-on trials and active control equivalence studies. These designs, motivated by medical ethics, have serious evidential limitations. Add-on trials are frequently criticized as insensitive and difficult to interpret in the presence of drug interactions; active control equivalence studies are not probative of test drug activity. As an alternative, we describe two trial designs: a placebo-control design with inpatients who in undergoing a presurgery seizure evaluation have had all antiepileptic drugs discontinued; and an active-control design aimed at showing the test drug superior to the control treatment, thus avoiding the interpretational difficulties of no-difference outcomes. A critical feature of these new designs is the limitation of subject exposure to unacceptable treatments. This is accomplished through protocol criteria--corresponding to therapeutic failure--which both terminate a subject's trial participation and form the basis of efficacy comparisons.

Clinical trials of investigational antiepileptic drugs: Monotherapy designs

Summary: The standard designs for safety and efficacy trials of investigational antiepileptic drugs are placebo-controlled, add-on trials and active control equivalence studies. These designs, motivated by medical ethics, have serious evidential limitations. Add-on trials are frequently criticized as insensitive and difficult to interpret in the presence of drug interactions; active control equivalence studies are not probative of test drug activity. As an alternative, we describe two trial designs: a placebo-control design with inpatients who in undergoing a presurgery seizure evaluation have had all antiepileptic drugs discontinued; and an active-control design aimed at showing the test drug superior to the control treatment, thus avoiding the interpretational difficulties of no-difference outcomes. A critical feature of these new designs is the limitation of subject exposure to unacceptable treatments. This is accomplished through protocol criteria–corresponding to therapeutic failure–which both terminate a subject's trial participation and form the basis of efficacy comparisons.